naloxone and Body-Weight

Topics: Analysis of Variance; Animals; Body Weight; Female; Fetal Diseases; Growth; Humans; Methadone; Naloxone; Narcotics; Placental Insufficiency; Pregnancy; Prenatal Exposure Delayed Effects; Research Design; Substance Withdrawal Syndrome

The endogenous opiate system is involved in the regulation of numerous bodily functions, but the literature suggests that the effects of endogenous opioids differ among species and between animals and man. Naltrexone, a relatively pure opiate antagonist, appears to have significant effects on the secretion of the gonadotropins (luteinizing hormone and follicle-stimulating hormone), adrenocorticotropin (ACTH), cortisol, and probably catecholamines. Naltrexone appears to have minor or no effects on prolactin, the pituitary-thyroid axis, growth hormone, insulin, glucagon, vasopressin, and the gut hormones. Naltrexone also seems to reduce food intake and cause weight loss in humans. The dosages of opiate antagonist and the presence of other variables play a major role in the responses seen in various studies.

Topics: Adrenocorticotropic Hormone; Animals; Body Weight; Eating; Endocrine Glands; Female; Follicle Stimulating Hormone; Hormones; Humans; Hydrocortisone; Luteinizing Hormone; Male; Mice; Naloxone; Naltrexone; Rats; Vasopressins

Topics: Adrenal Glands; Animals; Body Weight; Central Nervous System; Diet; Digestive System Physiological Phenomena; Eating; Energy Intake; Energy Metabolism; Feeding Behavior; Humans; Hyperphagia; Hypothalamus; Models, Biological; Morphine; Naloxone; Obesity; Satiety Response

Topics: Administration, Oral; Animals; Body Weight; Colitis; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Fertility; Haplorhini; Injections, Subcutaneous; Lethal Dose 50; Male; Mice; Naloxone; Naltrexone; Rats; Reproduction; Rhinitis; Teratogens

To evaluate the influence of the opioid system on the hypothalamic-pituitary-adrenal axis in women with polycystic ovary syndrome (PCOS).. Controlled clinical study.. Academic research environment.. Eight lean and 12 obese women with PCOS, and seven lean and 5 obese control subjects.. Each patient received an i.v. bolus of naloxone at a dose of 125 microgram per kilogram of body weight; 48 hours later, each patient received 16 mg of loperamide p.o.. Samples were collected for 2 hours for the naloxone test and for 3 hours for the loperamide test. Levels of adrenocorticotropic hormone (ACTH) and cortisol were measured in all plasma samples.. The obese women with PCOS had a greater ACTH and cortisol response to opiate blockade than either the lean women with PCOS or the control subjects, but there was no difference between the lean or obese control subjects and the lean women with PCOS. There was no difference in the responsiveness of the hypothalamic-pituitary-adrenal axis to loperamide between the PCOS and control groups.. The data indicate that the sensitivity of the hypothalamic-pituitary-adrenal axis to opioids cannot be altered in women with PCOS. However, abnormalities of the hypothalamic-pituitary-adrenal axis in women with PCOS could be central in origin, as suggested by the effects of naloxone administration, and probably are related to the anthropometric characteristics of these hyperandrogenic patients.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Adult; Body Weight; Female; Humans; Hydrocortisone; Hypothalamus; Loperamide; Naloxone; Narcotic Antagonists; Narcotics; Obesity; Pituitary Gland; Polycystic Ovary Syndrome

Preferences and cravings for sweet high-fat foods observed among obese and bulimic patients may involve the endogenous opioid peptide system. The opioid antagonist naloxone, opioid agonist butorphanol, and saline placebo were administered by intravenous infusion to 14 female binge eaters and 12 normal-weight controls. Eight of the binge eaters were obese. During infusion, the subjects tasted 20 sugar/fat mixtures and were allowed to select and consume snack foods of varying sugar and fat content. Naloxone reduced taste preferences relative to baseline in both binge eaters and controls. Total caloric intake from snacks was significantly reduced by naloxone in binge eaters but not in controls. This reduction was most pronounced for sweet high-fat foods such as cookies or chocolate. No consistent effects on taste preferences or food intakes were observed with butorphanol. Endogenous opioid peptides may be involved in mediating taste responses and preferences for palatable foods, notably those rich in sugar and fat.

Topics: Adolescent; Adult; Body Weight; Bulimia; Butorphanol; Dietary Carbohydrates; Dietary Fats; Endorphins; Energy Intake; Female; Food Preferences; Humans; Naloxone; Receptors, Opioid; Satiety Response; Taste

In anorexia nervosa alterations in the hypothalamic-pituitary-gonadal unit were previously thought to have been connected to an increase of endogenous opiate tone. The authors tried to prove that the replacement of normal endogenous steroid levels could restore the functional coupling between opiatergic and luteinizing hormone-releasing hormone (LH-RH) neurons in patients with anorexia nervosa. Pulsatile LH-RH therapy has been used to achieve normal ovarian activity. The authors studied gonadotropin levels before and during intravenously (IV) pulsatile LH-RH therapy (50 to 100 ng/kg body weight/90 to 120 minutes) in three anorexia nervosa and two weight loss amenorrhea patients, during both placebo and naloxone administration (2 mg IV bolus plus 4 mg infusion lasting 120 minutes). Before therapy, naloxone administration did not significantly change gonadotropin levels in three out of five patients, while a decrease in gonadotropin levels was observed in the other two subjects. During LH-RH therapy, normal pituitary-gonadal activity was demonstrated and ovulatory cycles were found in all patients. Naloxone administration did not change gonadotropin release during LH-RH therapy. Data could support the hypothesis of either a primitive impairment of LH-RH neurons, or an alteration in central regulation of LH-RH pulsar in anorexia nervosa.

Topics: Adolescent; Adult; Amenorrhea; Anorexia Nervosa; Body Weight; Estrogens; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Naloxone; Progesterone

To investigate the effects of the long-acting opiate antagonist naltrexone on spontaneous human eating behavior, eight moderately obese male paid volunteers were housed in a hospital metabolic unit for 28 days and offered palatable foods ad lib by a platter service method. Under double-blind conditions, equally divided doses of 100, 200 and 300 mg naltrexone, or an acetaminophen placebo, were administered twice daily in tablet form for 3-day periods each, according to a Latin Square design. The doses of naltrexone resulted in decreases of daily caloric intake from placebo level, but these reductions were neither statistically significant nor dose-related. When the averaged effects of the doses were compared to placebo, five subjects showed intake reductions but the overall intake reduction of 301.5 +/- 198.1 kcal/day (mean +/- SEM) was not statistically significant. Naltrexone administration failed to selectively alter intakes of individual meals and snacks or macronutrient consumption patterns. During active drug periods, subjects lost 0.62 +/- 0.22 lb over 3 days, while during the placebo period, subjects gained 0.46 +/- 0.68 lb. However, there was no reliable change of basal metabolic rate as a function of naltrexone administration. The present results, which indicate that naltrexone administration is relatively ineffective in reducing food intake and inducing body weight loss in obese humans, are thus in contrast with reports that administration of opiate antagonist agents promote significant reductions of food intake and attenuations of body weight gain in experimental animals.

Topics: Adult; Basal Metabolism; Body Weight; Clinical Trials as Topic; Drug Administration Schedule; Energy Intake; Feeding Behavior; Humans; Male; Naloxone; Naltrexone; Obesity

Topics: Acetylcholine; Analgesia; Animals; Body Weight; Brain; Brain Chemistry; Choline; Drug Tolerance; Hemicholinium 3; Humans; Male; Mice; Morphine; Morphine Dependence; Naloxone; Placebos; Reaction Time; Substance Withdrawal Syndrome; Time Factors

Topics: Adolescent; Adult; Aged; Analgesia; Blood Pressure; Body Weight; Clinical Trials as Topic; Doxapram; Drug Interactions; Heart Rate; Humans; Middle Aged; Morphine; Naloxone; Pain; Postoperative Care; Respiration; Time Factors

Opiate withdrawal/negative reinforcement has been implicated as one of the mechanisms for the progression from impulsive to compulsive drug use. Increase in the intracellular cAMP level and protein kinase A (PKA) activities within the neurocircuitry of addiction has been a leading hypothesis for opiate addiction. This increase requires the phosphorylation of μ-opioid receptor (MOR) at Tyr

Topics: Animals; Behavior, Animal; Benzodioxoles; Body Weight; HEK293 Cells; Humans; Locomotion; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Naloxone; Narcotic Antagonists; Phosphorylation; Proto-Oncogene Proteins c-fyn; Quinazolines; Receptors, Opioid, mu; RNA Interference; RNA, Small Interfering; src-Family Kinases; Tyrosine

Toll-like receptor 4 (TLR4) is a critical component of innate immune signaling and has been implicated in alcohol responses in preclinical and clinical models. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium tested the hypothesis that TLR4 mediates excessive ethanol drinking using the following models: (1) Tlr4 knock-out (KO) rats, (2) selective knockdown of Tlr4 mRNA in mouse nucleus accumbens (NAc), and (3) injection of the TLR4 antagonist (+)-naloxone in mice. Lipopolysaccharide (LPS) decreased food/water intake and body weight in ethanol-naive and ethanol-trained wild-type (WT), but not Tlr4 KO rats. There were no consistent genotypic differences in two-bottle choice chronic ethanol intake or operant self-administration in rats before or after dependence. In mice, (+)-naloxone did not decrease drinking-in-the-dark and only modestly inhibited dependence-driven consumption at the highest dose. Tlr4 knockdown in mouse NAc did not decrease drinking in the two-bottle choice continuous or intermittent access tests. However, the latency to ethanol-induced loss of righting reflex increased and the duration decreased in KO versus WT rats. In rat central amygdala neurons, deletion of Tlr4 altered GABA. Toll-like receptor 4 (TLR4) is a key mediator of innate immune signaling and has been implicated in alcohol responses in animal models and human alcoholics. Members of the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune) consortium participated in the first comprehensive study across multiple laboratories to test the hypothesis that TLR4 regulates excessive alcohol consumption in different species and different models of chronic, dependence-driven, and binge-like drinking. Although TLR4 was not a critical determinant of excessive drinking, it was important in the acute sedative effects of alcohol. Current research efforts are directed at determining which neuroimmune pathways mediate excessive alcohol drinking and these findings will help to prioritize relevant pathways and potential therapeutic targets.

Topics: Alcohol Drinking; Alcoholism; Animals; Body Weight; Conditioning, Operant; Female; Gene Knockout Techniques; Lipopolysaccharides; Male; Mice; Mice, Knockout; Naloxone; Narcotic Antagonists; Nucleus Accumbens; Rats; Receptors, GABA-A; Toll-Like Receptor 4

Rats suppress intake of a palatable taste cue when paired with a rewarding or an aversive stimulus in appetitive or aversive conditioning, respectively. A similar phenomenon occurs with drugs of abuse, but the nature of this conditioning has been subject for debate. While relatively little is known about the underlying neural circuitry, we recently reported bilateral lesions of the thalamic trigeminal orosensory area isolate drug-induced suppression of intake of a taste cue. The lesion blocks avoidance of the taste cue when paired with experimenter delivered drugs of abuse, yet has no effect on avoidance of the same cue when paired with an aversive agent or when it predicts access to a highly palatable sucrose solution. We hypothesize the lesion may blunt the rewarding properties of the drug. To test this, we used a runway apparatus, as running speed has been shown to increase with increasing reward value. Our hypothesis was supported by failure of the lesioned rats to increase running speed for morphine. Interestingly, lesioned rats did avoid intake of the drug-paired cue when presented in the runway apparatus and displayed naloxone-precipitated withdrawal. Using a partial crossover design, the lesion prevented avoidance of a cocaine-paired cue when presented in the home cage. We conclude that the lesion disrupts avoidance of a taste cue in anticipation of the rewarding properties of a drug but, at least in the presence of contextual cues, allows for avoidance of a taste cue as it elicits the onset of an aversive conditioned state of withdrawal.

Topics: Analysis of Variance; Anesthetics, Local; Animals; Body Weight; Cocaine; Conditioning, Psychological; Drug-Seeking Behavior; Male; Motivation; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Reward; Saccharin; Statistics as Topic; Sweetening Agents; Taste; Taste Perception; Thalamus

Insulin resistance is a metabolic disorder which affects the diabetes mellitus pathophysiology and alters the cell excitability. This study has been designed to evaluate the anti-nociceptive and anti-inflammatory effects of chronic administration of Withania somnifera root (WSR) in fructose drinking water rats.. An experiment was carried out on 48 Wistar-Albino male rats, weighting 200±30 g, which were divided into six groups (n=8): control group (C), control morphine (CM), W. somnifera group (WS) which received WSR (62.5 mg/g diet), W. somnifera naloxone group (WSN) which received WSR and naloxone, fructose (F) group which received fructose drinking water and FWS group which received fructose-enriched drinking water and WSR during the trial period. A biphasic pain response was induced after intraplantar injection of formalin (50 μL, 1%). Pain behavior was measured using Dubuisson methods. The obtained data were analyzed by SPSS software V. 18, using ANOVA and Tukey test. Results were expressed as mean±SD. Statistical differences were considered significant at p<0.05.. The results showed that the insulin resistance index, blood sugar, insulin, IL-6, TNF-α, and acute and chronic pain score in the F group were significantly increased in comparison with the control group, but these parameters in the FWS group were significantly decreased compared with the F group (p<0.001).. Our findings indicated that chronic oral administration of WSR has analgesic and anti-inflammatory effects in fructose drinking water rats and causes improved insulin resistance index.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Blood Glucose; Body Weight; Diet; Fructose; Glucose Tolerance Test; Insulin; Insulin Resistance; Interleukin-6; Male; Naloxone; Pain; Plant Extracts; Plant Roots; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Withania

There is large body evidence indicating that stress can lead to cardiovascular disease. However, the exact brain areas and the mechanisms involved remain to be revealed. Here, we performed a series of experiments to characterize the role of CRF1 receptor (CRF1R) in the stress response induced by naloxone-precipitated morphine withdrawal. The experiments were performed in the hypothalamic paraventricular nucleus (PVN) ventrolateral medulla (VLM), brain regions involved in the regulation of cardiovascular activity, and in the right ventricle by using genetically engineered mice lacking functional CRF1R levels (KO). Mice were treated with increasing doses of morphine and withdrawal was precipitated by naloxone administration. Noradrenaline (NA) turnover, c-Fos, expression, PKA and TH phosphorylated at serine 40, was evaluated by high-performance liquid chromatography (HPLC), immunohistochemistry and immunoblotting. Morphine withdrawal induced an enhancement of NA turnover in PVN in parallel with an increase in TH neurons expressing c-Fos in VLM in wild-type mice. In addition we have demonstrated an increase in NA turnover, TH phosphorylated at serine 40 and PKA levels in heart. The main finding of the present study was that NA turnover, TH positive neurons that express c-Fos, TH phosphorylated at serine 40 and PKA expression observed during morphine withdrawal were significantly inhibited in CRF1R KO mice. Our results demonstrate that CRF/CRF1R activation may contribute to the adaptive changes induced by naloxone-precipitated withdrawal in the heart and in the brain areas which modulate the cardiac sympathetic function and suggest that CRF/CRF1R pathways could be contributing to cardiovascular disease associated to opioid addiction.

Topics: Animals; Body Weight; Cyclic AMP-Dependent Protein Kinases; Heart; Hypothalamus; Male; Mice, Knockout; Morphine Dependence; Myocardium; Naloxone; Narcotic Antagonists; Neurons; Norepinephrine; Proto-Oncogene Proteins c-fos; Receptors, Corticotropin-Releasing Hormone; Substance Withdrawal Syndrome; Tyrosine 3-Monooxygenase

Recent research suggests an involvement of pro-opiomelanocortin (POMC) gene products (e.g., beta-endorphin) in modulating cocaine-induced reward and addiction-like behaviors in rodents. In this study, we investigated whether chronic "binge" cocaine and its withdrawal altered POMC gene expression in the brain of rats. Male Fischer rats were treated with two different chronic (14-day) "binge" pattern cocaine administration regimens (three injections at 1-h intervals, i.p.): steady-dose (45mg/kg/day) and escalating-dose (90mg/kg on the last day). Although there was no POMC mRNA alteration after chronic steady-dose cocaine, a significant decrease in POMC mRNA levels in the hypothalamus was found after chronic escalating-dose cocaine. In contrast, after acute (1-day) withdrawal from chronic "binge" escalating-dose regimen, but not steady-dose regimen, there were increased hypothalamic POMC mRNA levels that persisted into 14days of protracted withdrawal. To study the role of the endogenous opioid systems in the cocaine withdrawal effects, we administered a single naloxone injection (1mg/kg) that caused elevated POMC mRNA levels observed 24h later in cocaine naïve rats, but it did not lead to further increases in cocaine-withdrawn rats. Our results suggest that during withdrawal from chronic "binge" escalating-dose cocaine: (1) there was a persistent increase in hypothalamic POMC gene expression; and (2) hyposensitivity of the POMC gene expression to naloxone indicates altered opioidergic tone at or above the hypothalamic level.

Topics: Amygdala; Animals; Body Weight; Cocaine; Cocaine-Related Disorders; Corticosterone; Dopamine Uptake Inhibitors; Hypothalamus; Male; Naloxone; Narcotic Antagonists; Pro-Opiomelanocortin; Rats, Inbred F344; Reinforcement Schedule; RNA, Messenger; Substance Withdrawal Syndrome

Extinction period of positive affective memory of drug taking and negative affective memory of drug withdrawal, as well as the different response of men and women might be important for the clinical treatment of drug addiction. We investigate the role of corticotropin releasing factor receptor type one (CRF1R) and the different response of male and female mice in the expression and extinction of the aversive memory.. We used genetically engineered male and female mice lacking functional CRF1R. The animals were rendered dependent on morphine by intraperitoneally injection of increasing doses of morphine (10-60 mg/kg). Negative state associated with naloxone (1 mg/kg s.c.)-precipitated morphine withdrawal was examined by using conditioned place aversion (CPA) paradigm. No sex differences for CPA expression were found in wild-type (n = 29) or CRF1R knockout (KO) mice (n = 29). However, CRF1R KO mice presented less aversion score than wild-type mice, suggesting that CRF1R KO mice were less responsive than wild-type to continuous associations between drug administration and environmental stimuli. In addition, CPA extinction was delayed in wild-type and CRF1R KO male mice compared with females of both genotypes. The genetic disruption of the CRF1R pathway decreased the period of extinction in males and females suggesting that CRF/CRF1R is implicated in the duration of aversive memory. Our results also showed that the increase in adrenocorticotropic hormone (ACTH) levels observed in wild-type (n = 11) mice after CPA expression, were attenuated in CRF1R KO mice (n = 10). In addition, ACTH returned to the baseline levels in males and females once CPA extinction was finished.. These results suggest that, at least, CPA expression is partially due to an increase in plasma ACTH levels, through activation of CRF1R, which can return when CPA extinction is finished.

Topics: Adrenocorticotropic Hormone; Animals; Body Weight; Corticosterone; Female; Genotype; Hypothalamo-Hypophyseal System; Male; Mice; Mice, Knockout; Morphine; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System; Receptors, Corticotropin-Releasing Hormone; Substance Withdrawal Syndrome

Neuropathic pain is one of the most common complications of diabetes mellitus. As efficacy and tolerability of current therapy for neuropathic pain are not ideal, we need to develop the novel drug for better treatment. Curcumin as a natural flavonoid from Curcuma longa has considerable effects on nervous system such as, antidepressant, antinociceptive and neuroprotective effects. The present study was designed to investigate the effect of curcumin on diabetic peripheral neuropathic pain and possible involvement of opioid system. A single dose of 60mg/kg streptozotocin was injected intraperitoneally to induce diabetes in rats. STZ-induced diabetic rats were treated with curcumin (50mg/kg/day) acute and chronically. Thermal hyperalgesia and mechanical allodynia were measured on the days 0, 7, 14 and 21 after diabetes induction as behavioral scores of neuropathic pain. Chronic, but not acute, treatment with curcumin prevents the weight loss and attenuates mechanical allodynia in STZ-induced diabetic rats. Pretreatment with naloxone (1mg/kg) significantly reduced anti-allodynic effect of chronic curcumin in von Frey filament test. Our results suggest that curcumin can be considered as a new therapeutic potential for the treatment of diabetic neuropathic pain and the activation of opioid system may be involved in the antinociceptive effect of curcumin.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Body Weight; Curcumin; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Hyperalgesia; Male; Naloxone; Narcotic Antagonists; Neuralgia; Phytotherapy; Rats; Rats, Wistar

In the present study, the potential involvement of nitric oxide (NO) system in attenuating effects of low-intensity laser therapy (LILT) on naloxone-induced morphine withdrawal signs was evaluated. A hundred mice were rendered morphine-dependent using three escalating doses of morphine sulfate during three consecutive days. After the last dose on day 4, animals were given naloxone HCl (2 mg/kg s.c) to induce withdrawal signs. The effects of LILT (12.5 J/cm(2)) and L-NG-nitroarginine methyl ester (L-NAME) (10, 20, 50, and 100 mg/kg) and their coadministration on escape jump count and stool weight as typical withdrawal signs were assessed. LILT and L-NAME (20, 50, and 100 mg/kg) per se significantly decreased escape jump count and stool weight in morphine-dependent naloxone-treated mice (p < 0.01). Coadministration of LILT and L-NAME (20, 50, and 100 mg/kg) also reduced escape jump and stool weight (p < 0.05) but with no synergetic or additive response. Here, LILT at this fluence may show its maximal effects on NO and therefore no noticeable effects appeared during coadministration use. Moreover, LILT and L-NAME follow the same track of changes in escape jump and stool weight. Conceivably, it seems that LILT acts partly via NO system, but the exact path is still obscure and rather intricate. The precise mechanisms need to be clarified.

Topics: Animals; Body Weight; Low-Level Light Therapy; Male; Mice; Morphine; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide; Substance Withdrawal Syndrome

Previous research suggests that the acute anorectic effect of cannabinoid CB1 receptor antagonist/inverse agonists may be secondary to response competition from the compulsive scratching and grooming syndrome characteristic of these agents.. As the pruritic effect of rimonabant can be attenuated by the opioid receptor antagonist naloxone, these studies test the prediction that naloxone co-treatment should prevent acute rimonabant anorexia.. Two experiments comprehensively profiled the behavioural effects of an anorectic dose of rimonabant (1.5 mg/kg) in the absence or presence of naloxone (experiment 1: 0.01 or 0.1 mg/kg; experiment 2: 0.05 mg/kg).. In both experiments, rimonabant not only significantly suppressed food intake and time spent eating but also induced compulsive scratching and grooming. In experiment 1, although the lower dose of naloxone seemed to weakly attenuate the effects of rimonabant both on ingestive and compulsive behaviours, the higher dose more strongly suppressed the compulsive elements but did not significantly affect the anorectic response. The results of experiment 2 showed that naloxone at a dose which markedly attenuated rimonabant-induced grooming and scratching did not alter the effects of the compound on food intake or time spent feeding. The apparent independence of the ingestive and compulsive effects of rimonabant was confirmed by the observation that despite a 'normalising' effect of naloxone co-treatment on behavioural structure (BSS), the opioid antagonist did not impact the suppressant effect of rimonabant on peak feeding.. The acute anorectic response to rimonabant would not appear to be secondary to compulsive scratching and grooming.

Topics: Animals; Appetite; Behavior, Animal; Body Weight; Cannabinoid Receptor Antagonists; Compulsive Behavior; Dose-Response Relationship, Drug; Feeding Behavior; Food; Grooming; Locomotion; Male; Naloxone; Narcotic Antagonists; Piperidines; Pruritus; Pyrazoles; Rats; Rimonabant

Alterations in transcription factors that regulate the development and maintenance of dopamine (DA) neurons (such as Nurr1 and Pitx3) play an important role in the pathogenesis of addiction diseases. We have examined the effects of acute and chronic morphine and morphine withdrawal on TH expression and activity as well as expression of Nurr1, Pitx3 and Ago2 in the ventral tegmental area (VTA) and nucleus accumbens (NAc) of the rat.. Rats were injected acutely with morphine and decapitated 1 or 2 h later. Another set of rats were made dependent on morphine by implantation of two morphine pellets. Precipitated withdrawal was induced by injection of naloxone. Ago2, Pitx3, Nurr1, total TH (tTH), TH phosphorylated at Ser31 and at Ser40, and 3,4-Dihydroxyphenylacetic acid, and DA determination in the VTA and/or NAc were measured using immunoblotting, HPLC and immunofluorescence.. Acute morphine produced a marked increase in TH activity and DA turnover in the NAc, concomitantly with increased Nurr1 and Pitx3 expression in the VTA. In contrast, precipitated morphine withdrawal decreased TH activation, TH expression and did not increase DA turnover in the NAc. These effects paralleled decreases in Ago2 expression, which was accompanied by increased Nurr1 and Pitx3, TH activity and normalized TH protein levels in the VTA.. The combined decrease in Ago2 and increases in Nurr1 and Pitx3 might represent some of the mechanisms that served to protect against accumbal TH regulation observed in morphine withdrawn rats, which may be critical for DA bioavailability to influence behaviour.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Argonaute Proteins; Body Weight; Dopamine; Drug Implants; Gene Expression Regulation; Homeodomain Proteins; Injections, Intraperitoneal; Male; Mesencephalon; Morphine; Naloxone; Nuclear Receptor Subfamily 4, Group A, Member 2; Nucleus Accumbens; Phosphorylation; Rats; Rats, Wistar; Substance-Related Disorders; Transcription Factors; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

We hypothesized that protein source in the nutritionally adequate AIN-93G diets fed during gestation, lactation, and weaning influences food intake (FI) regulation in male offspring of Wistar rats. Pregnant rats were fed the recommended casein-based (C) or soy protein-based (S) diet during gestation (experiment 1) or during gestation and lactation (experiment 2). Pups (n = 12 per group) weaned to C or S diets were followed for 9 wk (experiment 1) or 14 wk (experiment 2). At termination, body weight was 5.4% and 9.4% higher, respectively, in offspring of dams fed the S diet. Altered FI regulation was shown by failure of devazepide (a CCK-A receptor blocker) to block FI reduction after protein preloads in offspring of S diet-fed dams, whereas it had a strong effect on offspring of C diet-fed dams (P < 0.005). Similarly, naloxone (an opioid receptor blocker) blocked FI reduction more after casein than after soy protein preloads (P < 0.01). In experiment 2, offspring of dams fed the S diet had higher hypothalamic gene expression of agouti related protein at weaning (P < 0.05), and higher FI was found throughout postweaning (P < 0.0001). FI reduction after protein preloads at week 7 and after glucose preloads at week 13 was greater in offspring of C diet-fed dams (P < 0.05). Plasma insulin at weaning and insulin, ghrelin, and glucagon-like peptide-1 at week 15 were higher in offspring of S diet-fed dams (all P < 0.05). In conclusion, nutritionally complete C and S diets consumed during gestation and lactation differ in their effects on body weight and FI regulation in the offspring. Extending the diet from gestation alone to throughout gestation and lactation exaggerated the adverse effects of the S diet. However, the diet consumed postweaning had little effect on the outcome.

Topics: Agouti-Related Protein; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Appetite Regulation; Behavior, Animal; Body Weight; Caseins; Devazepide; Dietary Proteins; Female; Gestational Age; Ghrelin; Glucagon-Like Peptide 1; Hormone Antagonists; Hypothalamus; Insulin; Lactation; Male; Maternal Nutritional Physiological Phenomena; Naloxone; Narcotic Antagonists; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Receptor, Cholecystokinin A; Soybean Proteins; Time Factors; Weaning

Previous studies suggest that binge eating sugar leads to behavioral and neurochemical changes similar to those seen with drug addiction, including signs of opiate-like withdrawal. Studies are emerging that show multiple neurochemical and behavioral indices of addiction when animals overeat a fat-rich diet. The goal of the present study was to utilize liquid and solid diets high in sugar and fat content to determine whether opiate-like withdrawal is seen after binge consumption of these diets in Sprague-Dawley rats. Control groups were given ad libitum access to the sweet-fat food or standard chow. All rats were then given a battery of tests to measure signs of opiate-like withdrawal, which included somatic signs of distress, elevated plus-maze anxiety, and locomotor hypoactivity. Neither naloxone-precipitated (3 mg/kg) nor deprivation-induced withdrawal was observed in rats that were maintained on a nutritionally complete pelleted sweet-fat diet or a sweet, high-fat diet supplemented with standard rodent chow. Naloxone-precipitated withdrawal was also not seen in rats fed a liquid sweet-fat food. Further, body weight reduction to 85%, which is known to potentiate the reinforcing effects of substances of abuse, did not affect naloxone-precipitated signs of opiate-like withdrawal. Thus, unlike previous findings reported regarding rats with binge access to a sucrose solution, rats that binge eat sweet-fat combinations do not show signs of opiate-like withdrawal under the conditions tested. These data support the idea that excessive consumption of different nutrients can induce behaviors associated with addiction in different ways, and that the behaviors that could characterize "food addiction" may be subtyped based on the nutritional composition of the food consumed.

Topics: Analysis of Variance; Animals; Behavior, Addictive; Body Weight; Bulimia; Diet, High-Fat; Disease Models, Animal; Eating; Exploratory Behavior; Feeding Behavior; Food; Male; Maze Learning; Motor Activity; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Time Factors

Cholestasis is associated with endotoxinemia and elevated serum levels of bile acids, cholesterol, bile salts and opioids. Opioid systems have been reported to modulate anxiety. In the present study, the possible involvement of opioidergic system on anxiolytic-like behaviors induced by cholestasis was investigated. Cholestasis was induced in male Wistar rats by ligation of the main bile duct using two ligatures and transecting the duct at the midpoint between them. A standard elevated plus-maze was used to determine anxiety levels in animals. The data indicated that there is an increase, 13 days (but not 10 days) after bile duct ligation, in the percentage of open arm time (%OAT) and open arm entries (%OAE) but not locomotor activity, grooming, rearing and defecation, showing anxiolytic-like effects of cholestasis. Intraperitoneal (i.p.) injection of a subthreshold dose of morphine (4 mg/kg), 15 min before testing 10 days after bile duct ligation, showed an increase in %OAT and %OAE, suggesting an anxiolytic-like effect for the drug. Furthermore, injection of subthreshold doses of naloxone (0.4 and 0.6 mg/kg, i.p.), 15 min before testing 13 days after bile duct ligation, decreased %OAT and %OAE. This indicates that naloxone blocks anxiolytic-like behaviors induced by cholestasis. Also, injection of a subthreshold dose of naloxone (0.4 mg/kg, i.p.), 15 min before the injection of a subthreshold dose of morphine (4 mg/kg, i.p.), 10 days after bile duct ligation, decreased %OAT and %OAE but not other behaviors. In conclusion, the results show the involvement of opioidergic system in anxiolytic-like behaviors induced by cholestasis.

Topics: Analgesics, Opioid; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Bile Ducts; Body Weight; Cholestasis; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Morphine; Naloxone; Rats; Rats, Wistar; Time Factors

Effect of afobazole upon morphine dependency has been studied in rats upon the administration of incremental doses of morphine (10-20 mg/kg, i.p.) for 5 days. The state of dependency was evaluated by monitoring sixteen specific behavioral indices of "spontaneous" (24 h after the last morphine injection) or naloxone-induced withdrawal syndrome. The effect of afobazole (a single dose of 5 mg/kg injected before the test or subchronically for 5 days) was estimated through its influence upon the total index of withdrawal syndrome, which was calculated using the set of behavioural signs. It is established that afobazole upon either single or subchronic injections significantly decreased the expression of spontaneous morphine withdrawal syndrome. The effect was also statistically significant but less pronounced in the case of naloxone-induced withdrawal syndrome. The obtained data suggest that afobazole can be considered as potential effective drug for the correction of various clinical symptoms of morphine withdrawal syndrome.

Topics: Animals; Animals, Outbred Strains; Anti-Anxiety Agents; Behavior, Animal; Benzimidazoles; Body Weight; Drug Administration Schedule; Drug Dosage Calculations; Male; Maze Learning; Morphine; Morpholines; Motor Activity; Naloxone; Narcotic Antagonists; Narcotics; Rats; Substance Withdrawal Syndrome

Sibutramine is one of a small number of clinically approved anti-obesity agents while naloxone not only has intrinsic anorectic efficacy but, in low doses, also produces additive/synergistic anorectic effects in combination with other compounds. In view of the potential advantages of drug polytherapy over conventional monotherapy, the present study explored the effects of acute low dose combinations of sibutramine (0.125, 0.25 mg/kg) and naloxone (0.1 mg/kg) on food intake, feeding and non-feeding behaviour, and post-treatment weight gain in male rats. Neither drug, alone or in combination, significantly affected weight gain. Naloxone per se modestly though significantly suppressed both food intake and time spent feeding without disrupting the behavioural satiety sequence (BSS). However, neither dose of sibutramine affected these measures nor did they further enhance the anorectic response to the opioid receptor antagonist. Indeed, the combination of naloxone and 0.25 mg/kg sibutramine produced effects on intake and feeding behaviour that were substantially lower than those predicted on the basis of the sum of the individual drug effects (i.e. an infra-additive profile). These data, which contrast directly with reported positive interactions between opioid receptor antagonists and other anorectic agents (e.g. rimonabant, bupropion), would not support naloxone-sibutramine polytherapy in the clinical management of obesity.

Topics: Analysis of Variance; Animals; Appetite; Appetite Depressants; Behavior, Animal; Body Weight; Cyclobutanes; Dose-Response Relationship, Drug; Drug Synergism; Eating; Feeding Behavior; Male; Naloxone; Narcotic Antagonists; Rats; Time Factors

Stimuli that are paired with opioid withdrawal can themselves produce effects similar to withdrawal that might promote relapse.. This study compared precipitated and conditioned withdrawal and tested whether withdrawal is modified by clonidine or morphine.. Morphine-treated rats (10 mg/kg/12 h) received naloxone (3.2 mg/kg) in a novel environment (conditioned stimuli [CS]). Other rats received naloxone in the absence of the CS. Body weight and observable signs were used to measure withdrawal.. Naloxone produced weight loss and withdrawal signs in morphine-treated rats. Following pairings of the CS and naloxone, the CS alone had effects similar to naloxone; conditioned withdrawal was greater after three naloxone/CS pairings, as compared to one, and with longer morphine treatment. Antagonist-precipitated withdrawal was greater in rats that previously were physically dependent on morphine, as compared to withdrawal in rats that were never dependent; however, conditioned withdrawal did not differ between groups. When administered concurrently with naloxone, clonidine (0.1 mg/kg) attenuated some precipitated withdrawal signs, although conditioned withdrawal was largely unchanged. Administration of 10 mg/kg of morphine before the CS alone attenuated all conditioned withdrawal signs, whereas 0.1 mg/kg of clonidine before the CS alone reduced some directly observable signs and not weight loss.. Conditioned withdrawal occurs rapidly and is greater with longer periods of morphine treatment or more pairings of naloxone and the CS; however, a history of physical dependence does not increase conditioned withdrawal. Modification of conditioned withdrawal by drugs might be a useful approach for treating relapse.

Topics: Animals; Body Weight; Clonidine; Conditioning, Classical; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

The Fischer 344 (F344) and Lewis (LEW) rat strains are genetically divergent populations that are used to study the effects of and responses to drugs of abuse. In this context, LEW rats display faster acquisition of drug self-administration than F344 rats. Interestingly, these strains have also been reported to differ in their somatic responses to morphine withdrawal. To address possible strain differences in the affective response to withdrawal, the present study assessed the ability of naloxone-precipitated withdrawal from morphine to induce conditioned taste aversions in male F344 and LEW rats. Specifically, subjects from each of these strains were given chronic morphine to induce dependence and then given access to a novel saccharin solution followed by naloxone. These pairings were given every fourth day for a total of two conditioning trials after which subjects were given access to saccharin but without naloxone administration to assess extinction of the naloxone-induced aversion. Behavioral assays of withdrawal were also performed after each naloxone administration. Both F344 and LEW subjects acquired aversions to the naloxone-associated taste with no significant differences in the rate of acquisition of the aversions. Differences did appear during extinction with LEW animals extinguishing the taste aversion significantly faster than F344 animals. The data were discussed in terms of the relative strength of the affective responses during withdrawal and the role of such responses to drug use and abuse.

Topics: Animals; Avoidance Learning; Behavior, Animal; Body Weight; Conditioning, Operant; Extinction, Psychological; Morphine Dependence; Naloxone; Narcotic Antagonists; Rats; Rats, Inbred F344; Rats, Inbred Lew; Species Specificity; Taste

Exercise improves cardiovascular health, strengthens muscles and bones, stimulates neuroplasticity, and promotes feelings of well-being. However, when taken to extremes, exercise can develop into an addictive-like behavior. To assess the addictive potential of exercise, withdrawal symptoms following injections of 1.0 mg/kg naloxone were compared in active and inactive male and female rats. Active and inactive rats were given food for 1 hr or 24 hr/day. Additionally, a group of inactive rats was pair-fed the amount of food consumed on the previous day by food-restricted active rats. Rats fed for 1 hr/day decreased food intake and lost weight. Additionally, food-restricted active rats increased wheel running. There was a direct relationship between the intensity of running and the severity of withdrawal symptoms. Active food-restricted rats displayed the most withdrawal symptoms, followed by active rats given 24-hr access to food. Only minimal withdrawal symptoms were observed in inactive rats. These findings support the hypothesis that exercise-induced increases in endogenous opioid peptides act in a manner similar to chronic administration of opiate drugs.

Topics: Analysis of Variance; Animals; Anorexia; Body Weight; Disease Models, Animal; Feeding Behavior; Female; Male; Motor Activity; Naloxone; Narcotic Antagonists; Physical Conditioning, Animal; Rats; Rats, Long-Evans; Sex Characteristics; Substance Withdrawal Syndrome

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in opiate dependence and withdrawal. Functional antagonists of glutamatergic system, including compounds acting on both ionotropic and metabotropic glutamate receptors (group I mGlu receptor antagonists and group II mGlu receptor agonists), have been shown to decrease behavioural signs of opiate withdrawal in rodents. In the present study we analyzed an influence of group III mGlu receptor agonist, ACPT-I, on opioid withdrawal syndrome, induced by repeated morphine administration and final naloxone injection. We show, that ACPT-I significantly attenuated typical symptoms of naloxone-induced morphine withdrawal, after peripheral administration in C57BL/6J mice. These data indicate an important role of group III mGlu receptors in morphine withdrawal states and suggest that activation of group III mGlu receptors may reduce opiate withdrawal symptoms.

Topics: Analysis of Variance; Animals; Body Weight; Cyclopentanes; Disease Models, Animal; Dose-Response Relationship, Drug; Head Movements; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Receptors, Metabotropic Glutamate; Substance Withdrawal Syndrome; Time Factors; Tremor; Tricarboxylic Acids

Ghrelin, an endogenous growth hormone secretagogue, is a known accelerator of feeding behavior and suppresses pulsatile secretion of luteinizing hormone (LH) in ovariectomized rats. However, the mechanisms underlying this action remain unclear. We examined the effects of naloxone (NAL), a specific opioid antagonist, on the suppression of pulsatile LH secretion by ghrelin to determine whether beta-endorphin (beta-END) is involved in this suppressive effect.. Ghrelin was administered intracerebroventricularly, and NAL was injected intravenously in ovariectomized rats; then, serum LH concentrations were measured by radioimmunoassay in blood samples drawn every 6 min for 2 h to analyze pulsatile secretion.. Administration of ghrelin significantly reduced mean LH concentration and pulse frequency. Coadministration of NAL with ghrelin significantly restored mean LH concentration and pulse frequency.. Suppressive effect of intracerebroventricular injection of ghrelin on pulsatile LH secretion was mediated by beta-END, suggesting that hypothalamic ghrelin suppressed pulsatile gonadotropin-releasing hormone secretion via beta-END in female rats.

Topics: Animals; beta-Endorphin; Body Weight; Catheterization; Female; Ghrelin; Hypothalamus; Luteinizing Hormone; Naloxone; Narcotic Antagonists; Ovariectomy; Radioimmunoassay; Rats; Rats, Wistar; Time Factors

Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg.d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 alpha-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg.d) dose dependently inhibited this effect. ICI (3.0 mg/kg.d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg.d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg.d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.

Topics: Animals; Blood-Brain Barrier; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Ethinyl Estradiol; Female; Fulvestrant; Hot Flashes; Hypothalamus; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Ovariectomy; Rats; Rats, Sprague-Dawley; Skin Temperature; Uterus

Morphine has been used for pain treatment with a long history. Some data suggest that morphine is toxic to neurons and induces apoptosis, while other evidence shows that morphine could have beneficial effects against cell death. To determine how morphine affects pro-apoptotic protein Bax and molecular chaperone Hsp70, different concentrations of morphine were examined. Our results show that prolonged morphine administration for 5 days at 1microM concentration protects against serum deprivation induced cell death in rat primary neurons. Morphine treatment decreases Bax and Hsp70 levels in cultured rat primary neurons, suggesting morphine may have a protective role in staurosporine and serum deprivation induced cytotoxicity.

Topics: Analgesics, Opioid; Animals; Animals, Newborn; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Body Weight; Brain; Cell Death; Cells, Cultured; Culture Media, Serum-Free; Cytoprotection; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; HSP72 Heat-Shock Proteins; Morphine; Naloxone; Narcotic Antagonists; Neurons, Afferent; Neuroprotective Agents; Rats; Staurosporine

Kratom (Mitragyna speciosa Korth.) is an indigenous plant of Thailand used traditionally in folk medicine although it is claimed to cause addiction. It is used to treat diarrhea, however, there is no scientific evidence to support the use. The aim of this study is to investigate the effect of methanolic extract of kratom leaves on the rat gastrointestinal tract. Kratom extract at 50, 100, 200 and 400 mg/kg (p.o.) caused a dose dependent protection against castor oil-induced diarrhea in rats and also inhibited intestinal transit. The antidiarrheal effect was not antagonized by naloxzone. The inhibition of intestinal transit by kratom extract was significantly different from the control when treated with a single dose for 1 day. For longer-term treatments of 15 and 30 days, kratom extract did not decrease the intestinal transit time indicating that adaptation had occurred. Kratom extract at a dose level of 200 and 400 mg/kg for 30 days and morphine at 3 mg/kg (i.p.) caused a decrease in the increment of body weight that was significantly different from the control and kratom extract at lower doses (50 and 100 mg/kg). However it had no effect on the level of plasma cholecystokinin. The results suggested that methanolic kratom extract exhibited its antidiarrheal effect on rat gastrointestinal tract. The effects may occur via pathways in addition to the action on opioid receptors. High does of kratom extract decreased the increment of body weight similar to the effect of morphine.

Topics: Animals; Antidiarrheals; Body Weight; Cholecystokinin; Gastrointestinal Transit; Medicine, East Asian Traditional; Mitragyna; Naloxone; Plant Extracts; Plant Leaves; Rats; Rats, Wistar

Growing evidence suggests substantial crosstalk between endogenous opioid and cannabinoid systems in the regulation of appetite. Not only is cannabinoid-induced hyperphagia abolished by opioid receptor antagonists (and vice versa), but several laboratories have reported supra-additive anorectic responses following co-administration of opioid and CB1 receptor antagonists. In the present study, videoanalysis has been used to characterise the acute effects of sub-anorectic doses of rimonabant (0.25, 0.75 mg/kg) and naloxone (0.1 mg/kg), alone and in combination, on mash intake, ingestive and non-ingestive behaviour, and post-treatment weight gain in male rats. The results confirmed that, when administered alone, none of these treatments significantly altered mash consumption, various measures of feeding behaviour, or weight gain. Although most non-ingestive behaviours were also unaffected, 0.75 mg/kg rimonabant induced compulsive scratching and grooming. However, when naloxone was given in combination with either dose of rimonabant, both food intake and time spent feeding were significantly decreased while the behavioural satiety sequence (BSS) was accelerated. On further analysis, the co-treatment reductions in food intake and feeding behaviour were found to be of an additive rather than supra-additive nature. Intriguingly, the co-administration of naloxone also virtually abolished the compulsive scratching response to the higher dose of rimonabant. Findings are discussed in relation to current views on the molecular bases of opioid-cannabinoid system interactions and the unexpected 'dual' advantage (reduction in appetite plus attenuation of side-effect) of low-dose combinations of opioid and cannabinoid CB1 receptor antagonists.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Appetite; Behavior, Animal; Body Weight; Cannabinoids; Eating; Grooming; Locomotion; Naloxone; Narcotic Antagonists; Piperidines; Pyrazoles; Rats; Reaction Time; Rimonabant; Time Factors

To investigate the effects of chronic ethanol intake on the locomotor activity and the levels of calcium/calmodulin-dependent protein kinase IV (CaM kinase IV) in the nucleus accumbens (NAc) of rats. Simultaneously, the effects of nonselective opioid antagonist (naloxone) on the CaM kinase IV expression in the NAc and ethanol consumption of rats were also observed.. Ethanol was administered in drinking water at the concentrations of 6% (v/v), for 28 d. The locomotor activity of rats was investigated in the open-field apparatus. CaM kinase IV levels in the NAc were analyzed using Western blotting.. Rats consuming ethanol solution exhibited a significant decrease of ambulation activity, accompanied by a reduced frequency of explorative rearing in an open-field task on d 7 and d 14 of chronic ethanol ingestion, whereas presumed adaptation to the neurological effects of ethanol was observed on d 28. Chronic ethanol intake elicited a significant decrease of the CaM kinase IV expression in the nuclei, but not in the cytoplasm of the NAc on d 28. Naloxone treatment significantly attenuated ethanol intake of rats and antagonized the decrease of CaM kinase IV in the nuclei of NAc neurons. The cytosolic CaM kinase IV protein levels of the NAc also increased in rats exposed to ethanol plus naloxone.. Chronic ethanol intake-induced changes in explorative behavior is mediated at least partly by changes in CaM kinase IV signaling in the nuclei of the NAc, and naloxone attenuates ethanol consumption through antagonizing the downregulation of CaM kinase IV in the NAc.

Topics: Alcohol Drinking; Animals; Behavior, Animal; Body Weight; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Central Nervous System Depressants; Ethanol; Naloxone; Narcotic Antagonists; Nucleus Accumbens; Rats; Rats, Sprague-Dawley

Many similarities exist between the overconsumption of food, which results in obesity, and drug addiction. The present study investigated the effects of anorectic drugs on responding maintained by high incentive, but nutritionally unnecessary, food reinforcers using an FI15(fixed-ratio 10:S) schedule of reinforcement, similar to that used in studies on the incentive properties of drugs of abuse. Rats were trained to respond on a lever to gain access to two high incentive foods--chocolate chip cookies and cheese. Under the FI15(FR10:S) schedule, every 10th response (fixed-ratio 10) delivered a tone and light conditioned stimulus. The first ratio completed 15 min after the start of the session produced the conditioned stimulus and opened a door to give access to a piece of cookie. After 5 min to consume the high incentive food, a second 15-min interval was started, terminating in access to a second reinforcer, cheese. Once trained, the rats were given free access to laboratory chow in the home cage. They continued to work for the high incentive foods for a period of over 1 year, showing a pattern of responding appropriate to an FI(fixed-ratio) schedule. Naloxone (1.0 mg/kg), fenfluramine (1 and 2 mg/kg), D-amphetamine (0.25 and 0.5 mg/kg), and rimonabant (3 mg/kg) significantly reduced responding, especially in the second interval. In contrast, complete removal of the high incentive food from the test procedure did not immediately reduce the rate of responding, tending to increase it in the second of the intervals. Apparently, the drugs did not reduce responding by reducing the experienced magnitude of the high incentive food, but more probably by reducing the animals' motivation.

Topics: Animals; Appetite; Appetite Depressants; Appetitive Behavior; Body Weight; Dextroamphetamine; Dose-Response Relationship, Drug; Energy Intake; Extinction, Psychological; Feeding Behavior; Fenfluramine; Male; Motivation; Naloxone; Piperidines; Pyrazoles; Rats; Rats, Long-Evans; Reinforcement Schedule; Rimonabant

Chronic pain resulting from metastasis into skeleton of certain neoplastic diseases remains poorly understood and relatively resistant to analgesic treatment. Opioids are the principal axis in drug therapy for this type of pain, especially at the end stage of cancer. Our aim was to examine whether, fentanyl as well as morphine, two potent analgesic opioids commonly used to treat cancer pain, would inhibit pain and bone lesion-related responses in a murine model of bone cancer pain. Repeated administration of equianalgesic doses of fentanyl (0.16 mg/kg s.c. once a day) and morphine (20 mg/kg s.c. once a day) initiated at day 1 (prophylactic treatment) or at day 7 (curative treatment) after tumor cell inoculation in the femoral cavity consistently decreased bone pain symptoms and tumor growth-induced bone destruction (micro-CT bone structure parameters). Both fentanyl and morphine treatments resulted in clear antinociceptive properties as well as reductions in cancer cell-induced bone lesions. The present results demonstrate that fentanyl, and to some lesser degree morphine, has potential benefits in the treatment and development of bone cancer pain. As such, chronic administration of high doses of certain opioids like fentanyl may have clinical utility in the management of bone cancer pain.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Body Weight; Bone and Bones; Bone Neoplasms; Femur; Fentanyl; Male; Mice; Mice, Inbred C3H; Morphine; Naloxone; Narcotic Antagonists; Neoplasm Transplantation; Osteosarcoma; Pain Measurement; Pain, Intractable; Postural Balance; Tomography, X-Ray Computed; Tumor Cells, Cultured

The present study was designed to examine sex differences in complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia and sex differences in opioid antinociception and anti-hyperalgesia. Female rats developed inflammation and hyperalgesia faster and exhibited greater peak hyperalgesia than male rats. In arthritic (CFA-treated) rats, lower thresholds were observed during estrus and proestrus, and in nonarthritic (vehicle-treated) rats, lower thresholds were observed during proestrus. Morphine and oxycodone were more potent in male than female arthritic rats, and butorphanol was more potent and effective in male than female arthritic rats. The potency of morphine was increased in arthritic rats, although to a greater magnitude in males. The potency of oxycodone was increased in male but not female arthritic rats. The potency of butorphanol was increased in arthritic male rats and the maximal antinociceptive effect of butorphanol was increased in arthritic female rats, but it did not result in greater than 20% antinociception. Morphine, oxycodone, and butorphanol all produced antihyperalgesic effects (returning thresholds of arthritic rats to the thresholds of nonarthritic rats) with greater potency in males than females. The peripherally acting opioid agonist loperamide produced intermediate levels of antinociception in male and female arthritic rats and no antinociception in nonarthritic rats. Loperamide was more potent in male than female arthritic rats at producing antihyperalgesia. These data demonstrate sex differences in arthritis-induced hyperalgesia and responsiveness to opioid analgesics. In arthritic rats, the antinociceptive effects of opioid agonists are most probably mediated by both central and peripheral opioid receptors, whereas their antihyperalgesic effects are mediated primarily by actions at peripheral opioid receptors.

Topics: Analgesics, Opioid; Animals; Arthritis, Experimental; Body Weight; Butorphanol; Dose-Response Relationship, Drug; Estrous Cycle; Female; Foot; Freund's Adjuvant; Hyperalgesia; Loperamide; Male; Morphine; Naloxone; Narcotic Antagonists; Nociceptors; Oxycodone; Pain Measurement; Pressure; Rats; Rats, Inbred Lew; Sex Characteristics

RGS proteins are negative regulators of signaling through heterotrimeric G protein-coupled receptors and, as such, are in a position to regulate a plethora of biological phenomena. However, those have just begun to be explored in vivo. Here, we describe a mouse line deficient for Rgs4, a gene normally expressed early on in discrete populations of differentiating neurons and later on at multiple sites of the central nervous system, the cortex in particular, where it is one of the most highly transcribed Rgs genes. Rgs4(lacZ/lacZ) mice had normal neural development and were viable and fertile. Behavioral testing on mutant adults revealed subtle sensorimotor deficits but, so far, supported neither the proposed status of Rgs4 as a schizophrenia susceptibility gene (by showing intact prepulse inhibition in the mutants) nor (unlike another member of the Rgs family, Rgs9) a role of Rgs4 in the acute or chronic response to opioids.

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Cell Differentiation; Conditioning, Classical; Fear; Female; Gene Deletion; Male; Mice; Mice, Knockout; Morphine; Naloxone; Narcotics; Neurologic Examination; Neurons; Pain Threshold; Phenotype; Reflex, Startle; RGS Proteins; Schizophrenia; Substance Withdrawal Syndrome

The purpose of the present study is to compare the capacity of opioid antagonists to elicit withdrawal jumping in mice following two acute pretreatment doses of the opioid agonist morphine. Antagonists that precipitate vigorous withdrawal jumping across both morphine treatment doses are hypothesized to be strong inverse agonists at the mu-opioid receptor, whereas antagonists that elicit withdrawal jumping in mice treated with the high but not the low dose of morphine are hypothesized to be weak inverse agonists. Male, Swiss-Webster mice (15-30 g) were acutely treated with 56 or 180 mg kg(-1) morphine 4 h prior to injection with naloxone, naltrexone, diprenorphine, nalorphine, or naloxonazine. Vertical jumping, paw tremors, and weight loss were recorded. Naloxone, naltrexone, and diprenorphine produced withdrawal jumping after 56 and 180 mg kg(-1)morphine pretreatment. Nalorphine and naloxonazine produced moderate withdrawal jumping after 180 mg kg(-1) morphine pretreatment, but failed to elicit significant withdrawal jumping after 56 mg kg(-1) morphine pretreatment. Nalorphine and naloxonazine blocked the withdrawal jumping produced by naloxone. All antagonists produced paw tremors and weight loss although these effects were generally not dose-dependent. Taken together, these findings reveal a rank order of negative intrinsic efficacy for these opioid antagonists as follows: naloxone=naltrexone> or =diprenorphine>nalorphine=naloxonazine. Furthermore, the observation that nalorphine and naloxonazine blocked the naloxone-induced withdrawal jumping provides additional evidence that nalorphine and naloxonazine are weaker inverse agonists than naloxone.

Topics: Animals; Behavior, Animal; Body Weight; Brain; Diprenorphine; Dose-Response Relationship, Drug; Male; Mice; Morphine; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Substance Withdrawal Syndrome; Tremor

The authors developed an animal model of binge eating where history of caloric restriction with footshock stress (R + S) causes rats to consume twice the normal amount of palatable food. The authors tested the hypothesis that binge eating is mediated by changes in opioid control of feeding by comparing rats' anorectic and orexigenic responses to naloxone and butorphanol, respectively, and by testing the ability of butorphanol to elicit binge eating of chow when palatable food was absent. Mu/kappa opioid-receptor blockade and activation had exaggerated responses in the R + S rats with naloxone suppressing binge eating to control levels, and although butorphanol did not trigger chow binge eating, it enhanced binge eating of palatable food. These responses in sated normal-weight rats strengthen evidence that reward, over metabolic need, drives binge eating.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Behavior, Animal; Body Weight; Bulimia; Butorphanol; Caloric Restriction; Disease Models, Animal; Electroshock; Energy Intake; Feeding Behavior; Female; Food Preferences; Naloxone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Time Factors

Codeine analgesia is dependent on metabolism to morphine. Metabolic capability is genetically determined in rats and humans, and individuals can be classified as extensive or poor metabolizers, as determined by the extent of production of morphine. Codeine is often given to infants and children. The aim of this study was to investigate the effects of developmental age on codeine analgesia in rats.. The effects of codeine were compared with those of morphine using withdrawal reflex responses to mechanical stimuli (with and without inflammation) and to noxious heat in two strains of rats (Sprague-Dawley and Dark Agouti) that have been used to model human metabolic phenotypes because of marked differences in enzyme activity. Effects of the opioids were compared at 3, 10, and 21 days of age and in adult rats.. Consistent age-related changes in the efficacy of codeine relative to morphine were noted for both strains of rats. For the extensive metabolizer (Sprague-Dawley) strain, codeine efficacy was substantially lower at 3 days of age (P < 0.001), but there was no difference between the effects of codeine and morphine for 10- and 21-day-old rats and adults (P > 0.05). Poor metabolizers (Dark Agouti strain) also had comparatively low efficacy for codeine compared with morphine in 3-day-old rats and in adults (P < 0.001). In 10- and 21-day-old Dark Agouti rats, there was no difference between either drug (P < 0.05).. Codeine analgesia is developmentally regulated, with low efficacy in the early postnatal period. Effects in the adult rat were not predictive of efficacy in development in either strain, which has important implications for further study and, possibly, for clinical use.

Topics: Aging; Analgesics, Opioid; Animals; Body Weight; Carrageenan; Codeine; Dose-Response Relationship, Drug; Female; Hot Temperature; Inflammation; Morphine; Naloxone; Narcotic Antagonists; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Species Specificity

Opiate dependence in laboratory animals is commonly induced by two methods: (1) subcutaneous (s.c.) insertion of morphine pellets, and (2) daily injections of increasing doses of opiates. While both of these methods reliably induce opiate dependence, they do not allow one to discontinue, and subsequently reestablish steady state opiate plasma levels with minimal invasive procedures. We developed an "ON-OFF" gating device for repeatedly and non-invasively turning ON or OFF opiate delivery by standard osmotic minipumps. The reliability of this "device" was tested utilizing naloxone (NAL)-precipitated somatic signs of withdrawal, and body mass index (BMI) as measures of withdrawal. Rats were implanted with osmotic minipumps equipped with the gating device, containing heroin (2.66 mg per day). Three days after surgery, somatic signs of withdrawal were precipitated every 48 h by NAL (0.3mg/kg), with minipumps gated ON or OFF. For BMI, spontaneous withdrawal was repeatedly (three times) induced by turning OFF and ON the gating devices every 48 h. Body weights were measured every 4h from 06:00 to 22:00 h daily. Results show that NAL precipitated intense somatic signs of withdrawal when gating devices were ON. This effect was almost abolished when gating devices were OFF. BMI rapidly decreased after the gating devices were turned OFF with maximum weight loss occuring 12 h post-OFF position, and gradually returning to baseline values after gating devices were turned back ON. These results demonstrate the validity of the "ON-OFF" gating device for non-invasively and repeatedly inducing physical dependence to opiates over a prolonged time.

Topics: Analysis of Variance; Animals; Body Mass Index; Body Weight; Drug Administration Schedule; Drug Delivery Systems; Equipment Design; Male; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Rats; Rats, Wistar; Reproducibility of Results; Substance Withdrawal Syndrome; Time Factors

We tested Mg2+ influence on experimental morphine-induced pharmacodependence in rats. Morphine-induced pharmacodependence model consists of progressively increased doses of morphine (M) (5 mg/kg i.p. until 90 mg/kg i.p.) during 10 days. Withdrawal syndrome was induced by naloxone (N) administration (1 mg/kg, s.c.) on the 11th day, 2 h after the last morphine administration. We evaluated and statistically interpreted symptoms from withdrawal syndrome. 2 groups received magnesium acetate (MgAc) 0.5 mEq/kg/day i.p. and 0.1 mEq/kg/day MgAc i.p. respectively during all 11 days of morphine-induced pharmacodependence. Serum magnesium levels were determined by spectrophotometry. Data obtained show that MgAc significantly decreases symptoms from withdrawal syndrome (grooming 19.9 +/- 2.1 in M + MgAc 0.5 mEq/kg/day vs. 33 +/- 2.85 in M group, p < 0.01).

Topics: Acetates; Analgesics, Opioid; Animals; Body Weight; Dose-Response Relationship, Drug; Magnesium; Male; Models, Biological; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Time Factors

We previously demonstrated an increase in Fos expression in the heart during morphine withdrawal. In the present study we examined the role of beta- and alpha-adrenoceptors in naloxone-precipitated increases in Fos expression in the heart. Dependence on morphine was induced by 7-day chronic subcutaneous implantation of six morphine pellets (75 mg). Morphine withdrawal was precipitated by administration of naloxone (5 mg/kg subcutaneously) on day 8. Using immunohistochemical staining of Fos, the present results indicate that morphine withdrawal induced marked Fos immunoreactivity (Fos-IR) within the cardiomyocyte nuclei. Moreover, Western blot analysis revealed a peak expression of c-fos in the right and left ventricles after naloxone-precipitated withdrawal in parallel with an increase in noradrenaline (NA) turnover. In the second study, the effects of the administration of adrenoceptor antagonists on withdrawal-induced Fos expression in the heart were studied. Pretreatment with the beta antagonist, propranolol (3 mg/kg intraperitoneally) or alpha1-adrenoceptor antagonist, prazosin (1 mg/kg intraperitoneally) did not block the marked Fos-IR or the hyperactivity of catecholaminergic neurons observed in the heart during withdrawal. However, pre-treatment with alpha2-adrenoceptor antagonist, yohimbine (1 mg/kg intraperitoneally), 20 min before naloxone administration to morphine-dependent rats antagonized Fos expression and the enhancement of NA turnover in the heart. Collectively, these results suggest that noradrenergic neurons in the heart are active during morphine withdrawal, and that activation of transcriptional responses mediated by Fos are dependent upon cardiac alpha2-adrenoceptor.

Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Blotting, Western; Body Weight; Drug Administration Schedule; Drug Therapy, Combination; Gene Expression; Genes, fos; Heart Ventricles; Immunohistochemistry; Injections, Subcutaneous; Male; Morphine; Myocytes, Cardiac; Naloxone; Normetanephrine; Prazosin; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Substance Withdrawal Syndrome; Time Factors; Yohimbine

Nociceptin/orphanin FQ (noci/OFQ), the endogenous ligand for the orphan ORL1 (opioid receptor-like1), has been shown to be anti- or pronociceptive and modify morphine analgesia in rats after central administration. We comparatively examined the effect of noci/OFQ on hyperalgesia and morphine analgesia in two experimental models of neuropathic pain: diabetic (D) and mononeuropathic (MN) rats. Noci/OFQ, when intrathecally (i.t.) injected (0.1, 0.3, or 1, to 10 microg/rat) was ineffective in normal rats, but reduced and suppressed mechanical hyperalgesia (paw-pressure test) in D and MN rats, respectively. This spinal inhibitory effect was suppressed by naloxone (10 microg/rat, i.t.) in both models. Combinations of systemic morphine with spinal noci/OFQ resulted in a strong potentiation of analgesia in D rats. In MN rats, an isobolographic analysis showed that the morphine+noci/OFQ association (i.t.) suppressed mechanical hyperalgesia in a superadditive manner. In summary, the present findings reveal that spinal noci/OFQ produces a differential antinociception in diabetic and traumatic neuropathic pain according to the etiology of neuropathy, an effect possibly mediated by opioid receptors. Moreover, noci/OFQ combined with morphine produces antinociceptive synergy in experimental neuropathy, opening new opportunities in the treatment of neuropathic pain.

Topics: Animals; Behavior, Animal; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Hyperalgesia; Male; Mononeuropathies; Morphine; Naloxone; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Sciatic Nerve; Streptozocin; Time Factors; Vocalization, Animal

The adipose tissue-derived hormone leptin may be a primary mediator linking nutritional status and reproduction. The present study used the leptin-resistant obese female Zucker rat to investigate whether leptin signalling is required for normal pulsatile luteinizing hormone (LH) secretion and/or generation of the LH surge. For the pulsatile LH secretion study, an indwelling atrial catheter was implanted and a low dose of oestrogen given as a subcutaneous implant to lean and obese ovariectomized (OVX) Zucker rats. One week following OVX, blood samples were collected every 10 min for 3 h during the morning. Plasma LH concentrations were measured by radioimmunoassay. For the LH surge study, lean and obese OVX rats were given a high dose of oestrogen as a subcutaneous implant. Two days later, rats were given progesterone at 09.00 h to induce a proestrus-like LH surge. Blood samples were collected from an indwelling atrial catheter throughout that and the following day and plasma LH concentrations were measured by radioimmunoassay. LH pulse amplitude and mean LH secretion were profoundly attenuated in obese Zucker rats compared with lean littermates, whereas LH pulse frequency was not significantly different between phenotypes. The opioid receptor antagonist naloxone did not affect the pattern of pulsatile LH secretion in obese rats, suggesting that leptin does not exert its facilitatory effects on LH secretion through an opioidergic pathway. Both lean and obese rats showed characteristic steroid-induced LH surges. It therefore appears that a leptin signal is required for generation of a normal pattern of pulsatile LH secretion, but is not a necessary component of the steroid-induced LH surge.

Topics: Animals; Body Weight; Estrogens; Female; Leptin; Luteinizing Hormone; Naloxone; Narcotic Antagonists; Obesity; Opioid Peptides; Pulsatile Flow; Rats; Rats, Zucker

Acute uterine cervical distension (UCD) forms the basis for obstetric and some gynecologic pain. Systemic morphine inhibits the visceromotor response to UCD in rats by an action in the central nervous system, but the effect of morphine is blocked by exposure to estrogen. The purpose of the present study was to determine whether this estrogen blockade of the action of morphine reflects a spinal mechanism.. Virgin Sprague-Dawley rats received estrogen or placebo treatment for 1 week after ovariectomy. Rats were then anesthetized, and the electromyographic response in the rectus abdominis muscle to UCD was recorded in the absence and presence of cumulative dosing with intrathecal morphine.. Estrogen treatment did not alter the stimulus- response relationship between UCD and reflex muscle contraction. Intrathecal morphine reduced the visceromotor reflex response to UCD in a dose-dependent manner that was unaffected by estrogen treatment.. These data suggest that intrathecal morphine is effective in reducing the visceromotor response to UCD and that the reduction in efficacy of systemic morphine in this model is unlikely to reflect a reduction of the efficacy of morphine at the spinal level. These data agree with clinical studies that indicate that systemic morphine, in doses that reduce acute postoperative pain, have minimal to no effect in women in labor, yet intrathecal injection of opioids provides rapid, complete analgesia.

Topics: Analgesics, Opioid; Animals; Blood Pressure; Body Weight; Cervix Uteri; Dose-Response Relationship, Drug; Electromyography; Estradiol; Estrogens; Female; Injections, Spinal; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Ovariectomy; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Uterus

Although the phenomenon of opioid tolerance and dependence has been widely investigated, neither opioid nor non-opioid mechanisms are completely understood. In view of the modulation of 5-HT transport into presynaptic terminals in the brain by nitric oxide (NO) via cGMP, and the existence of a tonic 5-HTergic inhibition of dopamine release, the present study investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor, and NO modulators L-N(G)-nitroarginine methyl ester (L-NAME; NO synthase inhibitor) and L-Arginine (substrate for nitric oxide synthase) alone or in combination against morphine tolerance and dependence. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg s.c. twice daily) on day 3 and the degree of tolerance was further enhanced on days 9 and 10. The development of tolerance to the antinociceptive effect of morphine was delayed by prior administration of fluoxetine (10 mg/kg i.p, twice daily for 9 days) and L-NAME (10 mg/kg i.p. twice daily for 9 days) alone or in combination. It was accentuated by L-Arginine (50 mg/kg i.p. twice daily for 9 days) alone or in combination with fluoxetine (10 mg/kg i.p. twice daily for 9 days). Similarly, fluoxetine (10 mg/kg i.p.) or L-NAME (10 mg/kg i.p.), when administered acutely on day 10, reversed morphine-induced tolerance. L-Arginine (50 mg/kg i.p.) however, when administered acutely on day 10, accentuated morphine tolerance. Fluoxetine (10 mg/kg i.p. twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg i.p.)-precipitated withdrawal jumps. This suppression of dependence was potentiated by L-NAME (10 mg/kg i.p. twice daily for 9 days) and reversed by L-Arginine (50 mg/kg i.p. twice daily for 9 days), respectively. Acute administration of the respective drugs on day 10 modulated morphine dependence in a similar fashion. L-Arginine also reversed fluoxetine-induced weight loss in morphine-dependent animals. The present study demonstrated that fluoxetine suppressed the dependence and development of tolerance to the antinociceptive effect of morphine. Fluoxetine-induced suppression was potentiated by L-NAME and accentuated by L-Arginine. The results therefore suggest that a complex phenomenon such as morphine tolerance and dependence might involve close interplay of the NO-c GMP/5-HT/DA receptor system. To the best of the authors' knowledge, this is the first report to suggest targeting this cascade for ame

Topics: Animals; Arginine; Body Weight; Cyclic GMP; Depression, Chemical; Diarrhea; Dopamine; Drug Interactions; Drug Tolerance; Female; Fluoxetine; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Selective Serotonin Reuptake Inhibitors; Serotonin; Substance Withdrawal Syndrome

Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Here we show that mice subjected to an intermittent fasting diet (IFD) display markedly reduced responses in models of thermal and visceral pain compared with mice fed ad libitum (AL). Pharmacological analyses suggest that a change in the endogenous kappa-opioid system underlies IFD-induced analgesia. The levels of prodynorphin mRNA and kappa-opioid receptors in the spinal cord are higher in IFD than in AL mice. Furthermore, in spinal cord nuclear protein extracts, the activity of the transcriptional repressor DREAM (downstream regulatory element antagonist modulator), the main regulator of prodynorphin expression, is lower in IFD than in AL mice. Finally, c-Fos expression in dorsal spinal cord after noxious stimulation is significantly lower in IFD than in AL animals, indicating that dynorphin could block nociceptive information at the spinal cord. These results suggest that dietary restriction together with administration of kappa-opioid agonists could be useful as a new therapeutic approach for pain relief.

Topics: Analgesia; Animals; Behavior, Animal; Body Weight; Enkephalins; Fasting; Male; Mice; Motor Activity; Naloxone; Narcotic Antagonists; Pain Measurement; Protein Precursors; Reaction Time; Receptors, Opioid, kappa; Spinal Cord

Prolonged reduction in energy intake in beef heifers has been reported to suppress ovulation but the mechanisms involved are poorly understood. The objective of this study was to examine whether changes in the pattern of LH secretion following each of three different tests predicted the functional state of the hypothalamo-pituitary-ovarian (H-P-O) axis. Test 1 examined the ratio of LH secretion during the 1h before and 2h after naloxone (NAL) administration. The other two tests assessed the LH surge following an exogenous oestradiol positive feedback signal (Test 2) or exogenous progesterone priming (Test 3). In phases 1 and 3, each of 8 weeks duration, the heifers were fed 100% of their maintenance energy requirements. In phase 2, of 9 weeks duration, they were fed 50% of their maintenance energy requirements. Oestrus was induced in all heifers by PG administration at the start of the experiment. Heifers were administered a naloxone challenge of 50, 100, 200 or 400mg naloxone hydrochloride i.v. (one dose per heifer) during the mid-luteal period of phase 1 and all four naloxone treated heifers received 400mg naloxone hydrochloride at the end of phases 2 and 3. Doses of 10, 20 or 40 mg oestradiol benzoate (EB) i.m. were each administered to two of the remaining heifers during the mid-luteal period of phase 1. One heifer on each dose of oestradiol benzoate in phase 1 had the same dose administered at the end of phases 2 and 3. The progesterone challenge was administered to three heifers by insertion of a PRID for 12 days starting in the middle of phase 2. In Test 1, the ratio of LH secretion before and after naloxone administration in phase 1 was 1:1 (50mg), 1:4 (100mg), 1:4 (200mg) and 1:9 (400mg) (50mg versus 100mg and 100mg versus 200mg doses, P<0.05); 50mg versus 400mg doses, P<0.001). In phase 2, this ratio was 1:1 and there was no response to 400mg dose of naloxone in any of the four heifers. In phase 3, the ratio depended on the ovarian activity in the heifer and ranged from 1:1 to 1:4 (P<0.05). In Test 3, a positive oestradiol feedback signal was detected in cyclic heifers in phases 1-3 but not in the acyclic heifer in phase 2. Heifers challenge with exogenous progesterone did not have oestradiol or LH values above threshold levels. We conclude that all three tests successfully predicted the functional state of the hypothalamo-pituitary-ovarian axis. In nutritionally undernourished beef heifers onset of ovarian acyclicity is either preceded or accom

Topics: Animals; Body Weight; Cattle; Estradiol; Estrus Synchronization; Female; Food Deprivation; Luteinizing Hormone; Naloxone; Narcotic Antagonists; Ovary; Ovulation; Progesterone

To investigate the effect of naloxone, an opioid receptor antagonist, on the release of growth hormone (GH) induced by the growth hormone-releasing hormone (GHRH) in normal-weight and obese women with PCOS in relation to feeding.. Prospective clinical study.. Academic research center.. Seventeen women with PCOS (10 who were normal weight and 7 who were obese) and 14 control women (7 who were normal weight and 7 who were obese).. A GHRH test (50 microg i.v.) and, on a different day, a GHRH test during a naloxone infusion (1.6 mg/h) during fasting. The same tests were repeated after a standard meal.. GH response to GHRH (expressed as the area under the curve [AUC]) in different experimental conditions.. All normal-weight women showed a significantly higher AUC-GH compared with obese women in the fasting state. Normal-weight controls had a decrease in GH response to GHRH after feeding, and naloxone did not reverse the decrease. In obese controls, feeding increased the GH response but naloxone induced a decrease in the AUC. In fasting, normal-weight women with PCOS, naloxone significantly decreased the AUC-GH; in these patients, food intake induced an inhibition of GH response to GHRH, reversed by naloxone infusion. In obese PCOS patients, GH levels did not increase significantly after GHRH stimulation, either in the fasting state or after a meal, and naloxone did not affect these responses.. Factors other than obesity and insulin may be involved in disruption of GH secretion in women with PCOS.

Topics: Adult; Area Under Curve; Body Weight; Eating; Fasting; Female; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Naloxone; Narcotic Antagonists; Obesity; Polycystic Ovary Syndrome; Prospective Studies; Reference Values

1. Mild stress plus mild pain (solvent injection) applied daily to neonatal mice induces hormonal, behavioural and metabolic changes perduring in the adult life. 2. We investigated whether daily mild stress to neonatal mice induces also long-term defined changes of immune response, and whether immune changes are prevented through repeated administration of the opioid antagonist naloxone. 3. Mild stress plus solvent injection administered from birth to the 21st postnatal day causes not only behavioural and metabolic changes, but also long-term (up to 110 days of life) splenocytes modifications, consisting in: increased release of the Th-1 type cytokines interleukin-2 (IL-2) (from an average of 346 to 788 pg ml(-1)), interferon-gamma (from 1770 to 3942) and tumour necrosis factor-alpha (from 760 to 1241); decreased release of the Th-2 type cytokines IL-4 (from 49.1 to 28.4) and IL-10 (from 1508 to 877). Moreover, enhanced natural killer-cell activity; enhanced proliferative splenocytes properties in resting conditions and following phytohemoagglutinin and concanavalin-A stimulation are observed. Immunological, behavioural and metabolic changes are prevented by the opioid antagonist (-)naloxone (1 mg kg(-1) per day s.c., administered instead of solvent) but not by the biologically inactive enantiomorph (+)naloxone. 4. In conclusion, endogenous opioid systems sensitive to naloxone are involved in long-lasting enhancement of the Th-1 type cytokines and cell-mediated immunological response caused by repeated mild stress administered postnatally.

Topics: Animals; Animals, Newborn; Body Weight; Cytokines; Leptin; Male; Mice; Mice, Inbred Strains; Naloxone; Narcotic Antagonists; Pain Threshold; Spleen; Stress, Physiological; Th1 Cells

Vibration, being a consequence of motion during transport, may impair the welfare of pigs. Therefore, the primary objectives of this study were 1) to evaluate during transport simulation the use of ACTH and cortisol plasma levels, which are part of a basic adaptation mechanism of pigs and 2) to define comfort conditions for pigs related to the frequency and acceleration of vibration. Pigs with a body weight between 20 and 25 kg were vibrated in the vertical direction for 2 h at 2, 4, 8, and 18 Hz, in combination with root mean square acceleration magnitudes of 1 or 3 m/s2. Blood was sampled at regular intervals before, during, and after vibration as the pig's behaviors were recorded. Data on ACTH, cortisol, and behavior could be collected from 104 vibrated pigs and 21 controls. In addition, eight animals (3 controls, 5 vibrated) were treated with 0.1 mg of dexamethasone/kg BW, eight animals (3 controls, 8 vibrated) with 0.1 mg naloxone/kg BW, and six (2 controls, 4 vibrated) with a physiological salt solution. Blood samples were taken and products were administrated via an intravenous catheter. The pigs spent less time lying during both hours of vibration treatment than during control conditions. Compared with 2 and 4 Hz, time spent lying was 10 times shorter at 8 Hz and 18 times shorter at 18 Hz. At 1030, ACTH levels were significantly higher than basal levels in animals vibrated at 2 (P < 0.0001), 4 (P < 0.002), and 18 Hz (P < 0.0006). After 1 h, levels returned to basal values. Cortisol levels increased very rapidly after the beginning of vibration (P < 0.0001) and remained higher until 1 h after cessation of vibration (P < 0.003). An inferrence of the lines of equal responses for ACTH and cortisol indicated that, in the beginning of vibration exposure, pigs were extremely susceptible to vibrations at lower frequencies (2 and 4 Hz), whereas at the end of vibration exposure the responses were higher at 18 Hz. The application of dexamethasone and naloxone underpinned the emotional component of the response strategy of pigs to vibration. Hence, vibration during transport should be minimized in order to enhance the adaptive capacities of pigs.

Topics: Adaptation, Physiological; Adrenocorticotropic Hormone; Animals; Body Weight; Dexamethasone; Hydrocortisone; Naloxone; Stress, Physiological; Swine; Swine Diseases; Transportation; Vibration

We investigated the effects of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), which is reported to accelerate glutamate uptake, on the development of morphine tolerance and physical dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10-45 mg/kg, s.c.) for 5 days. First, co-administration of MS-153 (12.5 mg/kg, s.c.) did not affect the morphine's potency for its acute antinociceptive effect (1 and 3 mg/kg, s.c.). Next, co-administrations of MS-153 (1, 3 and 12.5 mg/kg, s.c.) during repeated morphine treatments significantly attenuated the development of tolerance to the antinociceptive effect of morphine (3 mg/kg, s.c.) and suppressed the naloxone (10 mg/kg, i.p.)-precipitated withdrawal signs (jumps and body weight loss). The inhibitory effect of MS-153 on the withdrawal signs was due to the attenuation of the development of dependence rather than that of expression of withdrawal signs. These results suggest that MS-153, a glutamate transporter activator, has an inhibitory effect on the development of morphine tolerance and physical dependence.

Topics: Amino Acid Transport System X-AG; Analgesics, Opioid; Animals; Area Under Curve; ATP-Binding Cassette Transporters; Body Weight; Drug Tolerance; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Neuroprotective Agents; Nicotinic Acids; Pain Measurement; Pain Threshold; Time Factors

Anxiety-like effects may be universal to withdrawal from drugs of abuse. The study of withdrawal would benefit from the acoustic startle response (ASR), a discrete, cross-species reflex which is increased by fear-related states. However, existing reports of opiate-related effects on baseline ASR have not validated ASR as a measure of drug-related motivation.. The effects of opiate treatment and withdrawal were examined using fear-potentiated startle, a startle test more sensitive to fear than baseline changes.. Fear-conditioned rats were treated with Alzet osmotic pumps delivering 0.25 mg/kg per day fentanyl or placebo pumps. Experiment I examined changes before and during opiate treatment on locomotor activity and baseline, prepulse inhibition, and fear-potentiated startle. Experiment 2 examined the same responses during withdrawal precipitated after 4-7 days of treatment using IV naloxone.. Experiment 1 revealed an attenuated fear-potentiated startle on the first test after the start of fentanyl treatment (4 h); this was not seen on subsequent tests and suggested tolerance to this acute effect. Experiment 2 found an enhancement of fear-potentiated startle precipitated in fentanyl-treated rats after injection of 0.025 and 0.16 mg/kg naloxone; this was not seen at 1 mg/kg naloxone, even though more physical withdrawal signs were most prevalent at this dose. In neither experiment did locomotor activity, baseline ASR, or prepulse inhibition of the ASR show any treatment effect.. Fear-potentiated startle may provide a specific and valid measure of anxiety-like effects of drug withdrawal. Discussed were conditions needed to see this effect and the relevance of the findings for different mechanisms of withdrawal discomfort.

Topics: Acoustic Stimulation; Analgesics, Opioid; Animals; Anxiety; Behavior, Animal; Body Weight; Fear; Fentanyl; Injections, Intraventricular; Male; Motivation; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Reflex, Startle; Substance Withdrawal Syndrome

The opioid system has been implicated in ethanol self-administration. Morphine, an opiate agonist, can sometimes increase the amount of ethanol consumed, and opiate antagonists such as naloxone and naltrexone decrease the amount of ethanol consumed in both animals and humans. The objective of this study was to examine the effect of naloxone on appetitive (or seeking) and consummatory behaviors by using an operant model developed to separate these two phases of self-administration.. Intraperitoneal injections of naloxone (0.3-10 mg/kg) or vehicle were given before operant self-administration sessions to assess the effect on lever pressing (appetitive behavior) and subsequent consumption. Effects were measured in two groups of rats: one self-administered a 3% sucrose solution and the other a 10% ethanol solution.. Naloxone dose-dependently decreased ethanol and sucrose consumption by an earlier cessation of drinking in the session compared with vehicle injection days. There were some effects on appetitive responding after treatment with naloxone, but none was statistically significant.. Naloxone may decrease ethanol self-administration by decreasing the postingestive or pharmacological effects of alcohol. This model provides a new method for examining the effects of potential pharmacotherapeutics on alcohol self-administration behavior.

Topics: Alcohol Drinking; Animals; Body Weight; Consummatory Behavior; Dose-Response Relationship, Drug; Eating; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Long-Evans; Sucrose

The role of metabolic polymorphism in the development of physical dependence to codeine was assessed in cytochrome P450 2D2 (CYP2D2) deficient Dark Agouti and CYP2D2 intact Sprague-Dawley rats by assessment of the severity of naloxone precipitated withdrawal after codeine and morphine administration. Plasma morphine concentrations after codeine were significantly higher (P<0.01) in Sprague-Dawley than in Dark Agouti rats with metabolic ratios of 0.71 +/- 0.27 and 0.07 +/- 0.04, respectively. Withdrawal after codeine resulted in significantly greater hypothermia (3.5-4 degrees C, P<0.0001) in Sprague-Dawley animals compared to the other groups. Body weight loss was similar for all groups ranging from 6.2 +/- 0.4 to 8.2 +/- 0.6 g. When strain and treatment data were combined, a relationship between body temperature and plasma morphine concentration could be described by the inverse Hill equation (r(2)=0.76, EC(50)=556 +/- 121 ng/ml, n=2.9 +/- 1.5). These data indicate that dependence and withdrawal after codeine administration are dependent on its bioconversion to morphine.

Topics: Analgesics, Opioid; Animals; Aryl Hydrocarbon Hydroxylases; Body Temperature; Body Weight; Codeine; Cytochrome P-450 Enzyme System; Female; Genotype; Morphine; Naloxone; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Effects of adolescent nicotine exposure on illicit drug consumption and neuroendocrine functioning were examined in adult rats. Nicotine (NIC; 2 doses) or saline (SAL) was administered via osmotic minipumps to 30 male and 30 female adolescent Wistar rats for 19 days. After NIC/SAL cessation, oral opioid consumption was assessed in the home cage for 4 weeks. Plasma corticosterone and ACTH were measured at the end of the experiment. Low-NIC male rats consumed more fentanyl than did high-NIC male rats; opioid consumption among adult female rats was not altered by NIC exposure. Females consumed more fentanyl than did males, regardless of NIC history. NIC exposure increased adult corticosterone and ACTH levels in a dose-dependent manner. Results suggest important effects of adolescent NIC exposure, including altered neuroendocrine status and opioid consumption.

Topics: Adrenocorticotropic Hormone; Aging; Analgesics, Opioid; Animals; Body Weight; Corticosterone; Drinking; Eating; Female; Fentanyl; Male; Naloxone; Narcotic Antagonists; Neurosecretory Systems; Nicotine; Nicotinic Agonists; Opioid-Related Disorders; Rats; Rats, Wistar; Sex Characteristics; Substance Withdrawal Syndrome

Previous research has shown an increase in hypothalamo-pituitary-adrenal axis activity following naloxone administration to morphine-dependent rats. In the present study, we investigated the adaptive changes in the noradrenaline (NA) and dopamine (DA) systems in the hypothalamic paraventricular nucleus (PVN) during morphine dependence and withdrawal. Additionally, we examined the possible change in 3',5'-cyclic adenosine monophosphate (cAMP) levels in that nucleus under the same conditions. Rats were made dependent on morphine by morphine or placebo (naïve) pellet implantation for 7 days. On day 8, rat groups received an acute injection of saline or naloxone (1 mg/kg subcutaneously) and were decapitated 30 min later. NA and DA content as well as their metabolite production in the PVN were estimated by HPLC/ED. Both plasma corticosterone levels and cAMP concentration in the PVN were measured by RIA. Naloxone administration to morphine-dependent rats (withdrawal) induced a pronounced increase in the production of both the NA metabolite MHPG and the DA metabolite DOPAC and an enhanced NA and DA turnover. Furthermore, an increase in corticosterone secretion was observed in parallel to the changes in catecholamine turnover. However, no alterations in cAMP levels were seen during morphine withdrawal. These results raise the possibility that catecholaminergic afferents to the PVN could play a significant role in the alterations of PVN functions and consequently in the pituitary-adrenal response during morphine abstinence syndrome. These data provide further support for the idea of adaptive changes in catecholaminergic neurons projecting to the PVN during chronic morphine exposure.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Behavior, Animal; Body Weight; Chronic Disease; Corticosterone; Cyclic AMP; Dopamine; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Norepinephrine; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

The objective of this study was to determine whether the opiate mu receptor antagonist naloxone would prevent atrophy of the gut in 24-h-fasted rats.. Male Sprague-Dawley rats (n = 76, body weight 200-225 g) were catheterized in the jugular vein on Day 0. The rats were fed standard rat chow for 4 days. On Day 4, the diet was changed to the standard liquid diet, and the rats were allowed free access to the liquid diet. On Day 7, the rats were randomized into five groups: (1) free fed, (2) free fed plus naloxone, (3) pair fed, (4) fasting, (5) free fed plus morphine, (6) fasting plus naloxone. Either naloxone (0.16 mg/kg/h) or morphine (0. 21 mg/kg/h) was continuously infused via venous catheter for 24 h. On Day 8, 24 h after fasting or free feeding, the animals were sacrificed.. Twenty-four hours of fasting caused atrophy of the jejunum and elevated morphine levels in the brain (free fed, 931. 3 +/- 122.3 fmol/g, vs fasting, 1419.0 +/- 150.0, P < 0.05). Morphine infusion reduced villus height, mucosal weight, and protein content in jejunum as compared with the free fed rats receiving saline. Administration of naloxone caused an increase in villus height (fasting, 587.0 +/- 25.8 microm, vs fasting plus naloxone, 670.0 +/- 17.4, P < 0.05), mucosal weight (fasting, 17.4 +/- 1.8 mg/cm, vs fasting plus naloxone, 22.6 +/- 1.9, P < 0.05), and protein content (fasting, 13.5 +/- 0.7 microg/cm, vs fasting plus naloxone, 16.7 +/- 0.6, P < 0.05) in jejunum.. Mucosal atrophy of the jejunum is caused by endogenous opioid in fasting rats.

Topics: Animals; Atrophy; Body Weight; Corticosterone; Fasting; Intestinal Mucosa; Jejunum; Leucine; Male; Morphine; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

This study examined the possibility that cadmium, a toxicant in high concentration in all tobacco products, may alter the stimulus properties of morphine. Adult male rats were exposed to regular laboratory chow (Group Control) or chow containing 100 ppm added cadmium chloride (Group Cadmium). Following an initial 30 day exposure period, control and cadmium-exposed animals were trained to discriminate between i.p. injections of 3.00 mg/kg morphine sulfate and vehicle (distilled water) in a two-choice drug discrimination task. Subsequently, the morphine dose-effect generalization function (0.75-6.00 mg/kg) was determined for control and cadmium-exposed animals. Additional substitution tests were conducted with increasing doses of the high efficacy mu agonist fentanyl (0.0016-0.04 mg/kg), the intermediate efficacy mu agonist (-)-metazocine (0.60-5.00 mg/kg), and the kappa agonist (+/-)-bremazocine (0.03-0.12 mg/kg). Also, increasing doses of the selective mu antagonist naloxone (0.0008-0.50 mg/kg) were presented against the training dose of morphine (3.00 mg/kg) and 0.02 mg/kg fentanyl. Finally, training was discontinued, and control and cadmium-exposed animals were injected with 8.00 mg/kg morphine in the home cage every 12 hr for 2 weeks, prior to redetermining the morphine dose effect function. Following a 1 week recovery period where morphine injections were discontinued, a final determination of the morphine dose-effect function was made. The results of the investigation indicated that cadmium exposure, without affecting the rate-changing properties of the drugs, slowed initial acquisition of the morphine discrimination, decreased the potency of selective doses of naloxone with respect to antagonizing the stimulus effects of morphine and fentanyl, and blocked the development of tolerance to morphine. Morphine, fentanyl, and (-)-metazocine generalized (substituted) equally across both groups, while (+/-)-bremazocine failed to substitute for the morphine stimulus in either group. These findings add to the growing literature on the interaction between metal poisoning and drug selection/abuse.

Topics: Animals; Body Weight; Cadmium; Cadmium Poisoning; Diet; Discrimination Learning; Discrimination, Psychological; Drug Tolerance; Eating; Generalization, Stimulus; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley

Obesity in normal animals has been demonstrated to be associated with a decrease in sensitivity to leptin especially as it relates to leptin's capacity to increase sympathetic nerve activity and enhance cardiovascular dynamics. In normal animals leptin has been demonstrated to exert significant regulatory responses by its capacity to increase proopiomelanocortin (POMC) expression and especially the increase in alpha melanocyte stimulating hormone (alphaMSH). These responses to leptin are blocked by a melanocortin-4 (MC-4) receptor antagonist. In this study we investigated the responsiveness of the sympathetic nervous system and cardiovascular system of high fat fed obese animals to the intracerebroventricular (ICV) administration of the POMC products alphaMSH and beta-endorphin (beta-END). We further investigated these responses in obese animals following leptin administration in the presence of MC-4 receptor and opioid receptor blockade. The ICV administration of leptin resulted in an increase in lumbar sympathetic nerve activity (LSNA) and mean arterial pressure (MAP) in normals but decreased it in the obese. The ICV administration of alphaMSH increased the LSNA and MAP in normal animals but to a lesser degree in obese animals. On the other hand beta-endorphin decreased the LSNA and MAP in normal animals but increased it in obese animals. Additionally ICV leptin administration in obese animals in the presence of MC-4 or opioid receptor blockade resulted in an increase in sympathetic activity and a pressor response. From these studies we conclude that obesity in high fat fed animals is characterized by a decreased sensitivity to alphaMSH and a paradoxical response to beta-endorphin and this altered responsiveness may be a factor in the altered leptin resistance characteristic of obese animals.

Topics: Agouti Signaling Protein; alpha-MSH; Animals; beta-Endorphin; Blood Pressure; Body Weight; Dietary Fats; Drug Resistance; Electrophysiology; Female; Heart Rate; Injections, Intraventricular; Intercellular Signaling Peptides and Proteins; Leptin; Naloxone; Narcotic Antagonists; Obesity; Pressoreceptors; Pro-Opiomelanocortin; Proteins; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Opioid; Splanchnic Nerves

In previous studies, large-dose fentanyl produced electrographic seizure activity and histologically evident brain damage. We assessed whether fentanyl-induced brain damage is attenuated by using anticonvulsant drugs. Using halothane/nitrous oxide anesthesia, 40 Sprague-Dawley rats underwent tracheal intubation, arterial and venous cannulation, and insertion of biparietal electroencephalogram electrodes and a rectal temperature probe. Halothane was discontinued. The dose of IV fentanyl shown previously to cause maximal brain damage was given to all animals and N(2)O was discontinued. Control rats were given fentanyl only. Rats in the three study groups also received midazolam, phenytoin, or N(2)O/naloxone. After characteristic seizure activity began with fentanyl loading the study drug was started. After a 2-h infusion, wounds were closed, and animals recovered overnight and underwent cerebral perfusion-fixation. Neuropathologic alterations were ranked on a scale of 0-5 for both neuronal death (0 = normal, 5 = more than 75% neuronal death) and for malacia. Significantly fewer rats in the N(2)O/Naloxone, Phenytoin, and Midazolam Groups sustained any brain damage compared with controls. Protection against opioid neurotoxicity is achieved with midazolam, naloxone, and phenytoin. If opioid neurotoxicity is clinically relevant, a small change in anesthetic practice might reduce any potential neurologic morbidity.. Narcotics in large doses can cause brain damage in rats. This brain damage is attenuated by a narcotic antagonist, a sedative, and an antiepileptic drug.

Topics: Analgesics, Opioid; Animals; Anticonvulsants; Blood Gas Analysis; Body Weight; Brain Diseases; Electroencephalography; Fentanyl; GABA Modulators; Male; Midazolam; Naloxone; Narcotic Antagonists; Phenytoin; Rats; Rats, Sprague-Dawley

The immunomodulatory effects of dihydroetorphine were systematically investigated in subchronically treated mice. In a dose-dependent fashion, dihydroetorphine (total doses at 444.5, 889 and 1778 microg/kg) lowered the increase of body weight, decreased the weight of the spleen and thymus, weakened the delayed-type hypersensitivity, reduced the generation of antibody-forming cells, inhibited splenic lymphocyte proliferation induced by concanavalin A and lipopolysaccharide, suppressed the production of interleukin-2 in the supernatant of splenocytes induced by concanavalin A, and depleted the ratio of CD4+ and CD8+ subpopulations. Moreover, the physical dependence on dihydroetorphine was also evaluated to confirm that the immunosuppression was concomitant with the addiction to the drug. These results demonstrate that subchronic treatment with dihydroetorphine dose dependently suppresses both humoral and cell-mediated immune function, and that the immunosuppressive effects of dihydroetorphine are much more potent than those of morphine.

Topics: Analgesics, Opioid; Animals; Antibody-Producing Cells; Body Weight; Cell Division; Dose-Response Relationship, Drug; Etorphine; Female; Hypersensitivity, Delayed; Immunosuppressive Agents; Lymphocyte Count; Lymphocyte Subsets; Lymphocytes; Lymphokines; Mice; Mice, Inbred C57BL; Naloxone; Opioid-Related Disorders; Organ Size; Spleen; Substance Withdrawal Syndrome; Thymus Gland

Intake of palatable solutions can enhance the anorectic potency of opioid antagonists. This experiment examined the relative contributions of orosensory experience and body weight gain to the enhanced anorectic potency of naloxone (0.125, 0.25, 0.5, and 1.0 mg/kg i.p.). Four groups of male hooded Lister rats (Charles River) were maintained on separate feeding regimes for 3 months. S-ADLIB rats were nondeprived with free access to lab chow and 20% (w/v) sucrose solution. S-RESTRICT rats received limited sucrose (50 ml/day) and chow (15 g/day) access, yoking their body weights to ADLIB rats receiving free access to lab chow only. RESTRICT rats received approx. 15 g of chow/day to maintain their body weights at 90% of the ADLIB rats. Fifteen-minute sucrose intake tests revealed marked differences between naloxone sensitivity of chronic sucrose drinkers and sucrose-naive groups. Intakes of S-ADLIB and S-RESTRICT were suppressed at all doses (max suppression >60%). In comparison to animals given sucrose, ADLIB and RESTRICT animals were significantly less sensitive (maximum suppression = 35%). Naloxone potency was independent of body weight differences. The data demonstrate that overconsumption of palatable ingesta, and not diet-induced weight gain, is sufficient to enhance antagonist potency. The study confirms that orosensory stimulation can induce plasticity in opioid systems, supporting an important role for opioids in intake regulation and general reward processes.

Topics: Animals; Anorexia; Body Weight; Diet; Dietary Sucrose; Dose-Response Relationship, Drug; Eating; Male; Naloxone; Narcotic Antagonists; Rats

Previous findings show that rats with electrolytic or excitotoxic lesions in the dorsomedial hypothalamic nucleus (DMN) are hypophagic and hypodipsic and have reduced ponderal and linear growth but normal body composition. DMN-lesioned (DMNL) rats also show altered ingestive responses to naloxone. The present study investigated the intrahypothalamic nerve pathways involved in these DMNL effects and the response of the pathways to deprivation challenges by placing knife cuts posterior (Post), lateral (Lat), ventral (Vent), dorsal, or anterior to the DMN or by administering sham operations. One major finding was that rats with Post or Vent were hypophagic (P < 0. 05) and had reduced body weight but responded normally to deprivation challenges. Post and Lat groups were hypodipsic (P < 0. 05), but plasma Na+, K+, and osmolality and 24-h post-water-deprivation drinking responses were similar in all groups. Naloxone did not suppress the intake of Post rats. It appears that the hypophagia and the reduced body weight after DMNL involve fibers entering or leaving the DMN from ventral and posterior directions, and they may be part of an opioid feeding system.

Topics: Animals; Body Weight; Denervation; Dorsomedial Hypothalamic Nucleus; Drinking; Eating; Electrolytes; Feeding and Eating Disorders; Food Deprivation; Male; Naloxone; Narcotic Antagonists; Neural Pathways; Rats; Rats, Sprague-Dawley; Water Deprivation

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.

Topics: Analgesia; Animals; Arteries; Blood Pressure; Body Temperature; Body Weight; Brain; Chronic Disease; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Our previous report suggested that antagonists acting at NMDA receptors attenuate discriminative stimulus effects of naloxone in morphine dependent rats. Nitric oxide (NO) is a putative second messenger which mediates NMDA receptor activation. The present study evaluated behavioral effects of NO synthase inhibitor, 7-nitroindazole in morphine-dependent rats trained to discriminate 0.1 mg/kg naloxone from saline. 7-Nitroindazole did not significantly affect naloxone's discriminative stimulus effects but decreased naloxone-induced weight loss and abolished expression of several withdrawal signs--diarrhea, scream on touch, tremor and 'wet dog'-like shaking suggesting different mechanisms for subjective and somatic components of opioid withdrawal.

Topics: Analgesics, Opioid; Animals; Body Weight; Discrimination Learning; Drug Interactions; Enzyme Inhibitors; Indazoles; Male; Maze Learning; Morphine; Naloxone; Narcotic Antagonists; Nitric Oxide Synthase; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Substance-Related Disorders

The effect of naloxone, a potent and specific opioid antagonist, on cerebral glucose utilization was investigated in conscious rat. For quantitative evaluation of the functional activity in brain, the regional cerebral metabolic rate for glucose (rCMRglc) was measured by the double tracer technique, using [14C]2-deoxyglucose and [3H]3-o-methylglucose. Intravenous administration of naloxone significantly increased rCMRglc in the medulla and thalamus at a dose of 1 or 10 mg/kg, and in the cerebral cortex, midbrain and cerebellum at a dose of 10 mg/kg. Our findings strongly suggest that naloxone by itself affects the cerebral functional activity within 10 min of administration.

Topics: Animals; Body Temperature; Body Weight; Brain Chemistry; Dose-Response Relationship, Drug; Female; Glucose; Hematocrit; Hydrogen-Ion Concentration; Injections, Intravenous; Kinetics; Naloxone; Narcotic Antagonists; Phosphorylation; Rats; Rats, Wistar

Our previous work has demonstrated that 100-Hz electroacupuncture (EA) or 100-Hz transcutaneous electrical nerve stimulation (TENS) was very effective in ameliorating the morphine withdrawal syndrome in rats and humans. The mechanism was obscure. (1) Rats were made dependent on morphine by repeated morphine injections (5-140 mg/kg, s.c., twice a day) for eight days. They were then given 100-Hz EA for 30 min 24 h after the last injection of morphine. A marked increase in tail flick latency (TFL) was observed. This effect of 100-Hz EA could be blocked by naloxone (NX) at 20 mg/kg, but not at 1 mg/kg, suggesting that 100-Hz EA-induced analgesia observed in morphine-dependent rats is mediated by kappa-opioid receptors. (2) A significant decrease of the concentration of dynorphin A (1-17) immunoreactivity (-ir) was observed in the spinal perfusate in morphine-dependent rats, that could be brought back to normal level by 100-Hz EA. (3) 100-Hz EA was very effective in suppressing NX-precipitated morphine withdrawal syndrome. This effect of EA could be prevented by intrathecal administration of nor-BNI (2.5 micrograms/20 microliters), a kappa-opioid receptor antagonist, or dynorphin A (1-13) antibodies (25 micrograms/20 microliters) administered 10 min prior to EA. In conclusion, while the steady-state spinal dynorphin release is low in morphine-dependent rats, it can be activated by 100-Hz EA stimulation, which may be responsible for eliciting an analgesic effect and ameliorating morphine withdrawal syndrome, most probably via interacting with kappa-opioid receptor at spinal level.

Topics: Animals; Body Weight; Dynorphins; Electroacupuncture; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Pain Measurement; Rats; Rats, Wistar; Receptors, Opioid, kappa; Substance Withdrawal Syndrome

The effect of herbal preparation Qingjunyin (QJY) on the animal model of drug dependence was studied. After the morphinistic models of white rats and mice were made by ever increasing doses of morphine each time, the animals were divided into large dosage QJY group, small dosage QJY group, sustained morphine group and control group. The withdrawal symptoms were observed after naloxone was given to the animals intraperitoneally. The results showed that QJY groups withdrawal symptoms of the addicted white rats were alleviated, the number of jumps of the addicted mice was reduced, the scores of the principal symptoms of the animals were decreased, while the body weights of the animals were gained, comparing with the control group, the difference was significant (P < 0.01). The effects of QJY enhanced in the large dosage group, which suggests QJY has abstinence effects.

Topics: Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Female; Male; Mice; Morphine Dependence; Naloxone; Phytotherapy; Rats; Rats, Wistar; Substance Withdrawal Syndrome

We have previously reported the increase of preproenkephalin (PPE) mRNA in the caudal periaqueductal gray (PAG) of rats during morphine withdrawal. In this study, it was further evidenced that PPE mRNA in the caudal PAG was not increased by various kinds of stressor, suggesting that the increase in PPE mRNA in the caudal PAG is specific to morphine withdrawal. In order to investigate the physiological significance of the increase of PPE mRNA in the caudal PAG, we compared the time course of the increase of PPE mRNA in the caudal PAG with that of naloxone-precipitated or spontaneous morphine withdrawal signs. The increase of plasma corticosterone (PCS: 52 and 52 microg/100 ml; control group, 18 and 15 microg/100 ml) and body weight loss (-6 and -9%; control group, 0 and -1%) were observed but PPE mRNA increase was not detected 1 and 2 h after naloxone in morphine treated rats. PPE mRNA increased by 37 to 56%, while PCS elevation and body weight loss gradually diminished 4 h to 2 days after naloxone. A total of 12 h after spontaneous withdrawal, PCS was prominently increased (51 microg/100 ml; control group, 12 microg/100 ml), but body weight and PPE mRNA were not affected. One day after spontaneous withdrawal, PCS elevation (38 microg/100 ml; control group, 8 microg/100 ml) and body weight loss (-5%; control group, +3%) were observed and PPE mRNA also increased by 42%. Two to 3 days after the final morphine injection, PCS recovered to control level and body weight loss gradually disappeared, while PPE mRNA was still increased by 74 to 46%. These results suggest that PPE gene expression in the caudal PAG is stimulated in the recuperative phase of these morphine withdrawal signs.

Topics: Animals; Body Weight; Corticosterone; Enkephalins; Gene Expression Regulation; Injections, Subcutaneous; Male; Morphine; Naloxone; Periaqueductal Gray; Protein Precursors; Rats; Rats, Sprague-Dawley; Stress, Physiological; Substance Withdrawal Syndrome; Time Factors

Several lines of evidence have suggested that the opioid control of gonadotropin secretion in the male rat is altered with aging. Because neural control of gonadotropins is mediated through luteinizing hormone releasing hormone (LHRH) secreting neurons, we examined the postulated changes in the opioid control of gonadotropins more directly by studying isolated hypothalamic fragments in vitro. Hypothalami from young (75-90 days) and old (18-20 months) males were examined for their ability to release LHRH when incubated with increasing doses of naloxone in a semi-static culture system. Serum concentrations of testosterone and luteinizing hormone (LH) in the donor animals were both significantly lower in old male rats compared with young males. Basal secretion of LHRH was similar in both age groups. Two-way repeated measures ANOVA indicated that naloxone stimulated a significant dose-dependent increase in the release of LHRH into the media. ANOVA also indicated a significant effect of age. We conclude that the changes in the endogenous opioid systems reported to occur with aging are, in fact, linked to differences in LHRH secretion and thus to differences in the dynamic relationship between testosterone and LH in older male rats.

Topics: Aging; Analysis of Variance; Animals; Body Weight; Dose-Response Relationship, Drug; Gonadotropin-Releasing Hormone; Hypothalamus; Luteinizing Hormone; Male; Naloxone; Organ Culture Techniques; Organ Size; Prostate; Rats; Rats, Sprague-Dawley; Testosterone

The endogenous opioid peptides have been implicated in the control of the suckling-induced PRL rise during lactation. This study examined the role of the endogenous opioid peptides in suppressing tuberoinfundibular dopaminergic neuronal activity during lactation. In the first experiment, lactating rats were constantly exposed to pups. Naloxone (NAL; 60 mg/kg x h; i.v.), an opioid receptor antagonist, or saline was infused for 12 h. Blood was collected before and at 2-h intervals during the infusion. NAL suppressed circulating PRL levels to less than 36% of control values at 4, 6, 8, and 12 h after the onset of the infusion. Tyrosine hydroxylase (TH) activity in the stalk-median eminence and TH messenger RNA signal levels in the arcuate nucleus were determined at the end of the NAL infusion. TH activity and TH messenger RNA signal levels were increased 2.5- and 2.7-fold, respectively, after the 12-h NAL infusion. Even though the time spent with their pups was similar between the two groups, the pups in the NAL-treated group failed to gain weight during the 12-h NAL infusion period, whereas the control litters (8 pups) gained 5 g. In a second experiment, pups were removed from the dams before the 12-h NAL infusion and were returned after 11 h. Blood was collected before the infusion, at 3-h intervals during the pup separation period, and at 15-min intervals after reunion with the pups. Plasma PRL in control and NAL-treated rats was low (1-15 ng/ml) and similar during the separation period. The suckling-induced PRL surge in NAL-treated rats was markedly attenuated to 9-25% of control levels (350-650 ng/ml). After a 1-h suckling episode, TH activity in the stalk-median eminence of NAL-treated rats was 4.5-fold greater than controls. Litter weight gains were significantly less in NAL-treated rats during the 1-h suckling episode. These data indicate that the endogenous opioid peptides are an integral component for increasing PRL release in response to suckling and they act to decrease tuberoinfundibular dopaminergic neuronal activity during lactation, in part, by suppressing TH gene expression.

Topics: Animals; Animals, Suckling; Arcuate Nucleus of Hypothalamus; Behavior, Animal; Body Weight; Cells, Cultured; Dopamine; Endorphins; Female; Naloxone; Narcotic Antagonists; Neurons; Prolactin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tyrosine 3-Monooxygenase

Treatment of opiate addiction is generally directed at the suppression of withdrawal symptoms through maintenance of the 'addicted' state with methadone. Yet relatively little is known regarding the neural substrates that contribute to, and maintain the prolonged state of withdrawal experienced by addicts. Opiates can profoundly alter the dynamics of brain and peripheral cholinergic systems, and central administration of anticholinergic drugs in dependent rats has been shown to decrease the expression of precipitated withdrawal symptoms. The purpose of this study was to determine whether the adaptive changes to M2 muscarinic receptors in autonomic centers are linked to the expression of withdrawal phenomena. During the peak period of withdrawal, there was a significant increase in both the expression of M2 muscarinic receptors and its corresponding mRNA within the rostral ventrolateral medulla, a primary vasomotor region. That most of these changes in receptor expression were adaptive in nature was suggested by the fact that when the acetylcholinesterase inhibitor DFP was co-administered with morphine, both the increased mRNA expression and the appearance of withdrawal symptoms were inhibited. Thus, interference with morphine-induced M2 muscarinic receptor adaptation in critical brain regions was correlated with a reduction in the development of physical dependence.

Topics: Animals; Behavior, Animal; Blood Pressure; Body Weight; Disease Models, Animal; Infusions, Intravenous; Injections, Subcutaneous; Isoflurophate; Male; Morphine; Morphine Dependence; Naloxone; Pirenzepine; Rats; Rats, Wistar; Receptor, Muscarinic M2; Receptors, Muscarinic; Substance Withdrawal Syndrome; Vasomotor System

The role of endogenous opioids and nutrition on the inhibition of luteinizing hormone (LH) secretion during the postpartum period was investigated in a Spanish breed of sheep lambing in the mid-late breeding season. Two groups of adult Rasa Aragonesa ewes housed in individual pens and lambing on 30 December were fed during the suckling period to provide maintenance requirements and the production of 1.1 (M; n = 8) or 0.55 (L; n = 8) kg of milk per day. On days 10, 20 and 30 after lambing, the effect of a treatment with the opiate receptor antagonist naloxone (1 mg/kg at four hourly intervals) on LH secretion was assessed in half of the ewes of each group, the remaining females receiving four saline injections. After weaning, animals were fed to provide requirements for maintenance of liveweight. Blood samples were collected twice a week from day 20 postpartum until the end of March, and assayed for progesterone and prolactin. Although underfed ewes showed significantly lower mean plasma concentrations during the control period on day 20 postpartum, nutrition did not seem to modify LH secretion before naloxone or saline injections. Moreover, no differences between nutritional groups in the response to naloxone injections on pattern of LH secretion were found. In fact, naloxone treatment induced an increase of mean LH concentrations on days 10, 20 and 30 postpartum (at least, P < 0.05), of LH pulse frequency on days 20 and 30 (P < 0.05), and of LH pulse amplitude on days 10 and 20 (P < 0.05). Underfed ewes during the postpartum period showed a slower decline in plasma prolactin levels, with significant differences on days 29, 36 and 39 after lambing (P < 0.05). Only 3 M ewes ovulated before the onset of the seasonal anoestrus period. It is concluded that endogenous opioids are involved in the inhibition of LH secretion during the early suckling period of a reduced seasonality breed of sheep without any influence of nutrition on the response to naloxone treatment; however, ewes underfed before weaning failed to reactivate their cyclicity prior to the onset of the seasonal anoestrus.

Topics: Animal Nutritional Physiological Phenomena; Animals; Animals, Suckling; Body Weight; Enzyme-Linked Immunosorbent Assay; Estrus; Female; Lactation; Luteinizing Hormone; Naloxone; Narcotics; Nutritional Status; Postpartum Period; Pregnancy; Progesterone; Radioimmunoassay; Random Allocation; Sheep; Spain; Statistics, Nonparametric

There is an early rise in secretion of luteinizing hormone (LH) in bull calves between 6 and 20 weeks of age. This study was designed to examine the involvement of opioidergic and dopaminergic neuronal systems in the control of this early rise in gonadotrophin secretion. Four groups of five bull calves were bled every 15 min for 10 h and administered one of the following treatments i.v. at 6, 14 and 24 weeks of age: a) saline; b) 1 mg naloxone/kg body weight every hour for 10 h; c) 0.8 mg pimozide/kg body weight as a single injection, after the first blood sample; d) 1 mg naloxone + 0.8 mg Pimozide/kg body weight. The early rise in LH secretion had started by 6 weeks of age, was at a peak at 14 weeks of age and was complete by 24 weeks of age (P<0.05). Naloxone (an opioid antagonist) treatment resulted in increased basal and mean serum concentrations of LH and LH pulse frequency at 14 weeks of age, increased mean serum LH concentrations of LH pulse frequency at 24 weeks of age, decreased FSH pulse amplitude at 14 weeks of age and increased mean serum concentrations of FSH at 24 weeks of age compared to control calves (P<0.05). Pimozide (a dopamine antagonist) decreased LH pulse amplitude at 24 weeks of age compared to all other groups of calves (P<0.05). Naloxone and pimozide in combination resulted in LH secretory patterns similar to naloxone treated calves or intermediate to naloxone and control calves at 14 weeks of age but similar to control calves at 24 weeks of age. In calves given the combination treatment, parameters of FSH secretion resembled those in the other groups of calves except for basal and mean serum concentrations of FSH at 24 weeks of age, which were similar to control or pimozide treated calves, but lower than in naloxone treated calves (P<0.05). At 14 weeks of age mean serum concentrations of testosterone were greater in calves given naloxone and pimozide in combination compared to controls, but at 24 weeks of age they were greater in the naloxone treated calves and lower in pimozide treated calves compared to the control calves (P<0.05). We concluded that an opioidergic inhibition of LH secretion was seen from the middle of the early rise in LH secretion (14 weeks of age) onwards but inhibition of FSH secretion was only seen at 24 weeks of age. A dopaminergic drive for LH and FSH secretion developed after the completion of the early rise in gonadotrophin secretion (24 weeks of age). Opioidergic inhibition of gonadotrophin secretion

Topics: Aging; Animals; Body Weight; Cattle; Dopamine; Dopamine Antagonists; Follicle Stimulating Hormone; Luteinizing Hormone; Male; Naloxone; Narcotic Antagonists; Neurons; Opioid Peptides; Pimozide; Scrotum; Testis; Testosterone

At Imphal (24 degrees 44' N) testes of lal munia, Estrilda amandava, began in June/July, peaked in September/ October, and thereafter declined to a minimum in December/January. Daily im treatments of 2.5-10 mg/kg/ bird/30 days of naloxone during progressive phase suppressed testicular growth, but without effects during quiescent, peak, and regression phases. Daily morphine (5 mg/kg/bird) during progressive and peak phases stimulated testicular growth, but without effects during quiescent and regression phases. Daily morphine (10 mg/kg/bird) during progressive phase stimulated the testes, an effect reversed by daily im treatments of an equivalent dose of naloxone. Seasonal changes in body weight closely correlated with testicular size. Daily im naloxone (5 and 10 mg/kg/bird/30 days) during progressive phase inhibited the increased body weight, but had no effects during quiescent, peak, and regression phases. Morphine (5 mg/kg/bird/day) during progressive and peak phases increased body weight, but had no effects during quiescent and regression phases. Morphine (10 mg/kg/bird/day) during progressive phase increased body weight, an effect which was reversed by equivalent dose of naloxone. Plumage color increased progressively between May and August/September, was maintained during October, and thereafter declined to reach dull-brown henny feathers by December. Daily im naloxone (2.5-10 mg/kg/bird/30 days) regardless of the reproductive states did not affect plumage color cycle. Morphine (5 mg/kg/ bird/day) accelerated plumage pigmentation between June and August, but had no effect during progressive or peak phases. Postnuptial decline in plumage color was inhibited by morphine (5 and 10 mg/kg/bird/day) and naloxone failed to reverse this effect. It is concluded that in the lal munia, endogenous opioid peptides are important constituents of the neuroendocrine mechanisms that influence development of the testes and body weight.

Topics: Animals; Birds; Body Weight; Central Nervous System Agents; Feathers; Male; Morphine; Naloxone; Organ Size; Pigmentation; Seasons; Testis

Concentrations of morphine and its 3- and 6-glucuronide metabolites (M3G and M6G) in plasma, brain, and urine of rats exposed to morphine for either 24 or 48 h were measured using high-performance liquid chromatography. In another group of morphine-treated rats, the intensity of naloxone-precipitated withdrawal behaviours was monitored at 24 and 48 h. The behavioural effects of M3G in opiate-naive and opiate-dependent rats were also investigated. Morphine was present in plasma, urine, and brain at 24 and 48 h, whereas M3G was detected in plasma and urine only. M6G was not present in detectable quantities in either plasma, urine, or brain. Although plasma concentrations of M3G were similar in both time groups, rats treated for 48 h had significantly larger quantities of M3G in their urine than did the other treatment groups. The incidence of withdrawal behaviour was significantly higher in animals exposed to morphine for 48 h than in those with only 24 h of exposure, M3G had no behavioural effects in the opiate-naive rats and did not precipitate an opiate-abstinence syndrome in morphine-dependent rats. From these results, it was concluded that although M3G is the major product formed by morphine breakdown in rats, it is unlikely that it is involved in the development of morphine dependence in this species.

Topics: Animals; Body Weight; Brain; Defecation; Female; Morphine; Morphine Dependence; Morphine Derivatives; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Substance Withdrawal Syndrome

The effects of diltiazem, a Ca2+ channel blocker, on naloxone-precipitated and spontaneous morphine withdrawal were studied in male Sprague-Dawley rats. In naloxone-precipitated withdrawal, body weight loss and plasma corticosterone elevation were dose dependently inhibited by diltiazem injected 4 or 2 and 4 h before naloxone, respectively. Three administrations of diltiazem (17, 11 and 5 h before naloxone) did not reduce the above withdrawal signs. Diarrhea was dose dependently inhibited by all schedule of diltiazem treatments. In spontaneous withdrawal, body weight loss and plasma corticosterone elevation were dose dependently inhibited by two (6 and 12 h) or three (6, 12 and 18 h after the last morphine) treatments with diltiazem at 6-h intervals after the last morphine, but not by a single diltiazem injected 18 h after the last morphine.

Topics: Animals; Body Weight; Calcium Channel Blockers; Corticosterone; Diarrhea; Diltiazem; Drug Interactions; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Lewis rats are more likely to self-administer various drugs of abuse than Fischer rats. Here these two strains of rats were compared with regard to basal brain opioid peptide levels and the response to chronic morphine treatment and to naloxone-precipitated withdrawal. Lewis rats had lower basal dynorphin peptides in the substantia nigra, striatum (not Leu-enkephalinArg6) and VTA (not dynorphin B) and the pituitary gland. Leu-enkephalinArg6 levels were also lower in these structures (with the exception of striatum which had higher levels) and in the nucleus accumbens. There were also strain differences in the response to chronic morphine treatment; in the nucleus accumbens, morphine treatment increased dynorphin A levels in Fischer rats only, in the ventral tegmental area effects were opposite with increased dynorphin levels in Fischer and decreased levels in Lewis rats, in the hippocampus dynorphin levels were markedly reduced in Lewis rats only. In Fischer rats, chronic morphine strongly affected peptide levels in the substantia nigra and striatum, whereas Lewis rats responded less in these areas. Leu-enkephalin, which derives from both prodynorphin and proenkephalin, and Met-enkephalin, which derives from proenkephalin, were affected by chronic morphine mainly in Fischer rats, increasing levels in most of the brain areas examined. The results in this study show (1) strain differences in basal levels of prodynorphin-derived opioid peptides, (2) the prodynorphin system to be differently influenced by morphine in Lewis rats than in Fischer rats and 3) the proenkephalin system to be influenced by chronic morphine in brain areas related to reward processes only in Fischer rats.

Topics: Amino Acid Sequence; Animals; Body Weight; Brain Chemistry; Drug Tolerance; Dynorphins; Enkephalins; Female; Male; Molecular Sequence Data; Morphine; Naloxone; Narcotic Antagonists; Rats; Rats, Inbred F344; Rats, Inbred Lew; Species Specificity; Substance Withdrawal Syndrome

The development of morphine physical dependence in the contrasting brain states of the nonhibernating (NH) vs. the hibernating (H) condition was measured in the ground squirrel hibernator Citellus lateralis. Morphine was infused continuously into the lateral ventricle (3.44, 6.88 and 13.75 micrograms/hr for periods of 1, 3 and 6 days) in NH and H animals, followed by measurement of the naloxone (1 mg/kg s.c.) evoked abstinence syndrome during the NH state (i.e., H animals were tested after arousal to the NH state). The results showed that morphine treatment during the NH state resulted in significant naloxone-evoked abstinence and an overall dose- and duration-related increase in the strength of the abstinence syndrome. By contrast, morphine treatment during hibernation resulted in significantly reduced abstinence compared with that observed after treatment during the NH state, with no significant morphine dose-response or duration-response trends evident. However, H-state morphine treatment did produce a dose-related reduction of hibernation bout duration. The reduction in the strength of dependence during the H state was associated with a qualitative change in the abstinence syndrome, as revealed by exploratory factor analysis. This change was reflected by an approximate reversal of the rank order of abstinence signs. These results demonstrate that hibernation-related changes in central nervous system function significantly reduce the liability for and change the character of the development of morphine dependence.

Topics: Animals; Body Temperature; Body Weight; Cerebral Ventricles; Female; Hibernation; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Sciuridae

The effect of pretreatment with a delta opioid receptor antagonist, naltrindole (NTI), on the development of physical dependence on morphine was investigated in mice. Several withdrawal signs, an increase in cortical noradrenaline (NA) turnover and a decrease in dopamine (DA) turnover in the limbic forebrain were observed following naloxone challenge in morphine-dependent mice. Pretreatment with NTI (0.3-5 mg/kg, s.c.) during chronic morphine treatment dose-dependently suppressed the behavioral and biochemical changes after withdrawal. The blocking effects of NTI suggest that delta opioid receptors may play a significant role in modulating the development of physical dependence on morphine.

Topics: Animals; Behavior, Animal; Body Weight; Male; Mice; Mice, Inbred Strains; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid; Sodium Chloride; Time Factors

The effect of anandamide, a putative endogenous ligand of the cannabinoid receptor, has been studied in a naloxone-precipitated morphine withdrawal syndrome in mice. Animals were chronically treated with increasing doses of morphine (from 8 to 45 mg/kg) over 5 days or implanted with morphine pellets (72 hr). Typical signs of withdrawal (jumping and body weight loss) were examined after naloxone administration (1 mg/kg). In these conditions, anandamide (5 mg/kg, i.v.) decreased both the number of jumps, measured over 30 min (81.2% +/- 3.15 and 92.2% +/- 3.5 decrease in chronically administered morphine and pellet implanted mice, respectively), and the body weight loss at 30 and 60 min (30 min: 2.6% +/- 0.4 vs 4.4% +/- 0.2 and 3.7% +/- 0.4 vs 5.3% +/- 0.4; 60 min: 3.2% +/- 0.5 vs 5.0% +/- 0.4 and 4.1% +/- 0.5 vs 6.0% +/- 0.5 in chronically treated morphine and pellet implanted mice respectively) after naloxone administration. This suggests, as shown in the case of delta 9-tetrahydrocannabinol, a modulation by anandamide of pathways involved in the expression of physical signs of opioid dependence and support its role as an endogenous cannabinoid agonist.

Topics: Animals; Arachidonic Acids; Body Weight; Dose-Response Relationship, Drug; Dronabinol; Endocannabinoids; Male; Mice; Mice, Inbred Strains; Morphine; Naloxone; Polyunsaturated Alkamides; Substance Withdrawal Syndrome

10 patients with renovascular hypertension (HRV) and 12 healthy persons were examined under water immersion (WI) conditions without and after blockade of opioid receptors with 2 mg of naloxone. Blood pressure, body mass, change of plasma volume, plasma molality, PRA, and serum values of AVP, aldosterone and catecholamines were evaluated. There were no significant changes between the two examined groups before and after WI. It seems that the drop in blood pressure induced by WI is not only the result of diminished activation of RAAS. The role of opioid receptors in controlling blood pressure and other evaluated parameters is likely in both examined groups.

Topics: Adult; Aldosterone; Body Height; Body Weight; Case-Control Studies; Catecholamines; Female; Humans; Hypertension, Renovascular; Immersion; Male; Naloxone; Narcotic Antagonists; Osmolar Concentration; Plasma Volume; Renin-Angiotensin System; Vasopressins

Pregnant Long-Evans hooded rats were dosed with 1, 5, or 10 mg/kg per day naloxone from gestational day 7 (GD7) through GD20. The control groups included both uninjected animals and injected animals pairfed to the 10-mg dose animals. At birth, all litters were culled to four males and four females, and fostered to undosed surrogate dams. Prenatal naloxone exposure produced changes in body weight development, pain sensitivity, and motor behavior in the offspring. Five and 10 mg/kg naloxone increased adult body weights in females only, as did the pairfeeding condition. The 10 mg/kg naloxone altered pain sensitivity (in males only) as measured by the tail flick test. Animals in the 1 mg/kg dose condition habituated more rapidly than uninjected (UN) subjects in the open field, and showed less activity than UNs as they matured. Bar pressing rates were reduced in the 10 mg/kg dose males in a visual discrimination task, while 10 mg/kg males and females showed reduced bar pressing rates on differential reinforcement of low rates of responding (DRL). These findings confirm that prenatal exposure to naloxone alters some aspects of neurobehavioral development in the rat, and are consistent with the hypothesis that 1 mg/kg prenatally may increase opiate function in offspring, while 10 mg/kg prenatally may decrease opiate functioning in the offspring.

Topics: Animals; Behavior, Animal; Body Weight; Cognition; Dose-Response Relationship, Drug; Female; Male; Motor Activity; Naloxone; Narcotic Antagonists; Pain Measurement; Pregnancy; Prenatal Exposure Delayed Effects; Psychomotor Performance; Rats; Reflex

Acute administration of long-acting general opioid antagonists reduces body weight and food intake in rats. In contrast, chronic administration of short-acting general opioid antagonists produces transient effects. The present study evaluated whether chronic central administration of selective long-acting antagonists of mu (beta-funaltrexamine, BFNA, 20 micrograms), mu1 (naloxonazine, 50 micrograms), delta1 ([D-Ala2,Leu5,Cys6]-enkephalin, DALCE, 40 micrograms), delta2 (naltrindole isothiocyanate, NTII, 20 micrograms) or kappa (nor-binaltorphamine, NBNI, 20 micrograms) opioid receptor subtypes altered weight and intake of rats exposed to a palatable diet of pellets, fat, milk and water, relative to pellet-fed and diet-fed controls. Diet-fed rats receiving chronic vehicle injections significantly increased weight (7-10%) and intake over the 11-day time course. Weight was significantly reduced over the time course in rats administered either BFNA (9%), naloxonazine (12%), DALCE (7%) or NTII (6%). Initial weight reductions failed to persist following chronic NBNI. All antagonists chronically reduced fat intake, but did not systematically alter total intake, pellet intake or milk intake relative to the pattern of weight loss. These data indicate that central mu, mu1, delta1, delta2, and, to a lesser degree, kappa receptors mediate long-term opioid modulation of weight even in animals maintained on diets that ultimately result in dietary obesity.

Topics: Animals; Body Weight; Dietary Fats; Eating; Male; Naloxone; Naltrexone; Narcotic Antagonists; Obesity; Rats; Rats, Sprague-Dawley; Time Factors

Effects of indomethacin, N omega-nitro-L-arginine (NNA) and naloxone, and of pretreatment with cyclophosphamide (CY), on the interleukin (IL)-1 beta induced inhibition of exocytotic noradrenaline release were investigated in the isolated, vascularly perfused spleen of the rat. Neurotransmitter release was evoked by perivascular electrical stimulation (4 Hz) and the overflow of endogenous noradrenaline was determined by HPLC with electrochemical detection. Perfusion of the spleen with Tyrode's solution containing IL-1 beta (100 pg/ml) for 90 min caused an inhibition of the stimulation-evoked noradrenaline overflow which persisted for at least 20 min after washout of the IL. The evoked overflow was reduced in the presence of NNA 30 mumol/l, but remained unaffected by indomethacin 3 mumol/l, naloxone 0.1 mumol/l or treatment of the rats with CY (250 mg/kg). The opioid agonist etorphine 10 mumol/l inhibited the evoked overflow of noradrenaline and this effect was prevented by naloxone 0.1 mumol/l. The inhibition of evoked overflow by IL-1 beta was not affected by indomethacin but was reduced or even prevented in the presence of NNA or naloxone, or after lymphocyte depletion of spleens by CY. The results are compatible with the idea that in the rat spleen exocytotic noradrenaline release is accompanied by a concomitant secretion of a nitric oxide (NO)-like compound which, in turn, reinforces noradrenaline release, and that the release can be inhibited via prejunctional opioid receptors. The IL-1 beta induced inhibition of evoked release appears to be a complex process which involves as one of many steps a decrease of the facilitatory NO-like compound and the release of endogenous opioids probably from spleen lymphocytes.

Topics: Animals; Arginine; Body Weight; Cyclophosphamide; Electric Stimulation; In Vitro Techniques; Indomethacin; Interleukin-1; Lymphocytes; Male; Naloxone; Nitric Oxide; Nitroarginine; Norepinephrine; Organ Size; Rats; Rats, Wistar; Receptors, Opioid; Spleen

1. The opioid activity of the amphibian peptide, [Lys7]dermorphin, was studied in rats and mice. When administered intracerebroventricularly (i.c.v.), intravenously (i.v.) or subcutaneously (s.c.) it produced a long lasting analgesia. Its antinociceptive potency exceeded that of morphine 290 times by i.c.v. injection, and 25-30 times by peripheral administration. 2. The dose-response curves of [Lys7]dermorphin antinociception were shifted to the right by the pretreatment with naloxone (0.1 mg kg-1, s.c.) or with the mu 1-selective antagonist, naloxonazine (10 mg kg-1, i.v. 24 h before peptide injection). 3. The peptide also displayed potent antinociceptive effects in a chronic inflammatory pain model (rat Freund's adjuvant arthritis). In this pain model, systemic administration of the peptide raised the nociceptive threshold more in inflamed than in healthy paw. 4. High central and peripheral doses of [Lys7]dermorphin in rats produced catalepsy. The cataleptic response was antagonized by naloxone but left unchanged by naloxonazine pretreatment. 5. In rats and mice, central or peripheral administration of [Lys7]dermorphin induced a significantly slower development of tolerance to the antinociceptive effect than did morphine. 6. Upon naloxone precipitation of the withdrawal syndrome, [Lys7]dermorphin-dependent mice made fewer jumps and lost less weight than the morphine-dependent animals. Withdrawal hyperalgesia did not develop in [Lys7]dermorphin-dependent mice. 7. In conclusion, [Lys7]dermorphin seems to be a unique opioid peptide having a high penetration into the blood-brain barrier despite its low lipid solubility. This peptide causes fewer side-effects than other opioids and appears less likely than morphine to cause physical dependence in rats and mice.

Topics: Analgesics, Opioid; Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mice; Morphine; Naloxone; Nociceptors; Oligopeptides; Opioid Peptides; Rats; Rats, Wistar; Receptors, Opioid, mu; Substance-Related Disorders

Plasma morphine concentration and naloxone-precipitated withdrawal body weight loss and plasma corticosterone (PCS) increase were determined at 12, 18 and 24 hr after i.v. infusion of morphine at a constant rate of 10 mg/kg/hr for 4 hr in Sprague-Dawley rats. Plasma morphine concentration declined 98.0% within 12 hr and further declined 58.8% during 12-24 hr after morphine infusion. There was a significant difference between plasma morphine concentrations at 12 and 24 hr after the morphine infusion. Naloxone (0.5 and 2.0 mg/kg)-precipitated withdrawal, but not spontaneous withdrawal, was elicited at 12-24 hr after the morphine infusion, and the severity of withdrawal precipitated by 2.0 mg/kg naloxone was the same at 12-24 hr after the morphine infusion. Furthermore, there was no significant correlation between plasma morphine concentration and body weight loss or PCS increase. The results suggest that a constant degree of morphine dependence is sustained during 12-24 hr after the morphine infusion and the severity of naloxone-precipitated withdrawal is not related to the plasma morphine concentration at the time of naloxone injection, that is, the rate of morphine removal from its receptor sites.

Topics: Animals; Body Weight; Corticosterone; Dose-Response Relationship, Drug; Male; Morphine; Naloxone; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Time Factors

The intensity of opiate withdrawal syndrome in rats is usually quantified on the basis of selected physical signs or global scores. However, the selection criteria of signs and scores have not been subjected to an ethological discussion, hence they appear to be somewhat arbitrary. The objectives of this study were thus: i) to analyse the rat's behaviour during the naloxone-precipitated morphine withdrawal syndrome, ii) to evaluate the validity of classic methods, and iii) to design a new "etho-score". Ten rats were implanted with morphine pellets (75 mg x 2, SC), all receiving different naloxone doses following a within-subject design (0, 0.01, 0.05, 0.1, 0.5, 1 mg/kg SC). Twenty unexperienced rats and 20 with placebo pellets were injected with either saline or naloxone. Behaviour was videotaped and later analysed by computer-based ethological techniques. The ethogram encompassed 16 patterns displayed by rats during morphine withdrawal. Frequency, duration and latency of each pattern was measured, and a cluster analysis allowed discerning the structure of behaviour. Several physical signs and the Gellert-Holtzman score were also evaluated. The data revealed that writhing responses linearly changed in a dose-related fashion, and mastication was also enhanced after naloxone. Wet-dog shakes and jumping changed following an U-shaped curve. Significant changes in weight loss were found to be dose-dependent, and highly correlated to diarrhea. Learning effects were found to reliably affect exploration, writhing responses and some physical signs. The Gellert-Holtzman score was gradually enhanced after naloxone, being affected by learning as well. Naloxone affected lying and self-care responses in placebo rats. To sum up, the data indicated that: i) classic signs are useful, although most of them are disrupted by high naloxone or affected by learning effects, ii) the Gellert-Holtzman score was validated in this study, and iii) mastication and weight loss are good indicators of naloxone-precipitated morphine withdrawal, representing the basis of an "etho-score" which is herein proposed.

Topics: Animals; Behavior, Animal; Body Weight; Cluster Analysis; Dose-Response Relationship, Drug; Drug Implants; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Rats; Rats, Wistar; Substance Withdrawal Syndrome

The effects of benzodiazepine receptor ligands with different intrinsic activity profiles were studied on voluntary ethanol consumption in the selectively bred alcohol-preferring AA (Alko, Alcohol) rat line, and compared to those of an opiate antagonist, naloxone, and a serotonin uptake inhibitor, citalopram. The rats were first allowed to develop a strong preference for 10% (v/v) ethanol solution in tap water over plain water until their ethanol consumption stabilized. Thereafter, the period when ethanol solution was available for the rats was gradually reduced to 4 h, 3 times a week, every second working day. The acute effects of positive allosteric modulators (agonists) of the gamma-aminobutyric acid type A (GABAA)/benzodiazepine receptor [midazolam, abecarnil, ethyl 5-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (ZK 91296), bretazenil, and 2,5-dihydro-2-(4-methylphenyl)-3H-pyrazolo[4,3-C]quinolin-3(5H)-on e (CGS 9895)] and of negative allosteric modulators [inverse agonists, ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5- a][1,4]benzodiazepine-3-carboxylate (Ro 15-4513) and t-butyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]thieno[2,3- f][1,4]diazepine-3-carboxylate (Ro 19-4603)] were tested after i.p. injections of three different drug doses using saline injections as a control treatment. The benzodiazepine agonists had rather modest effects on ethanol intake, measured 1 and 4 h after the injections, whereas the inverse agonists and naloxone strongly decreased ethanol consumption. Acute citalopram had no clear effect on ethanol drinking, but it slightly decreased the consumption of novel food during the 4-h session, as did all other benzodiazepine agonists except bretazenil. Neither the inverse agonists nor naloxone had any significant effect on food intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alcohol Drinking; Animals; Anti-Anxiety Agents; Azepines; Azides; Benzodiazepines; Benzodiazepinones; Body Weight; Drug Administration Schedule; Eating; Food Preferences; Injections, Intraperitoneal; Ligands; Male; Naloxone; Pyrazoles; Rats; Receptors, GABA-A

Elevation of plasma corticosterone (PCS) has been used as an indicator of morphine withdrawal, but it is not clear whether the magnitude of elevation is related to the intensity of the dependence. The dose-dependent effects of naloxone on PCS and body weight were studied in male Sprague-Dawley rats rendered physically dependent on morphine by injecting increasing doses of 40-120 mg/kg/day, s.c. twice daily for 1-6 days. Naloxone (0.01-2.0 mg/kg, s.c.) was administered 3 hr after the last morphine administration. Naloxone elevated PCS levels in a dose-dependent manner in all groups treated with morphine, and the elevation was correlated with the number of days of morphine treatment. Naloxone also reduced dose-dependently the body weight in all groups treated with morphine; in this case, a reverse correlation was obtained between the body weight changes and the PCS levels. It was confirmed that PCS elevation is a quantitative sign of naloxone-precipitated morphine withdrawal and that the elevation is indicative of the degree of morphine physical dependence.

Topics: Analysis of Variance; Animals; Body Weight; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Subcutaneous; Male; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

1. Physical dependence was induced in mice by repeated injections of increasing doses of morphine for either 4 or 7 days. 2. Withdrawal symptoms induced by naloxone (1 mg/kg, i.p.) given 3 hr postmorphine were more severe in mice treated for 7 than for 4 days. 3. In mice that developed a similar degree of dependence, various doses of naloxone (0.1-10 mg/kg) given 3 hr postmorphine produced withdrawal symptoms of different intensities. 4. Withdrawal jumping was maximal at naloxone (1 mg/kg) but declined with further increases in the dose of the antagonist. 5. "Wet dog" shakes progressively increased with increasing doses of naloxone (0.1-10 mg/kg). 6. Variation in the temporal time interval between the last dose of morphine and that of naloxone (1 mg/kg) influenced the intensity of withdrawal symptoms. 7. In male and female mice that developed a similar degree of dependence, no major differences were observed in the severity of withdrawal symptoms-induced by naloxone (1 mg/kg) given 3 hr postmorphine.

Topics: Animals; Body Weight; Drug Administration Schedule; Female; Male; Mice; Morphine; Naloxone; Sex Factors; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

We measured neuropeptide Y (NPY) concentration in microdissected hypothalamic nuclei, by radioimmunoassay, and NPY mRNA in the hypothalamus in rats treated systemically with the nonspecific opioid antagonist, naloxone, to produce mild anorexia. Twenty rats were treated with daily SC injections of naloxone (7.5 mg/kg); 20 were treated with vehicle alone. Naloxone produced a 7% reduction in food intake (p < 0.01) and a reduction in weight gain (p < 0.002). Neuropeptide Y concentrations were increased specifically in the dorsomedial nucleus of the hypothalamus (DMN) in rats treated with naloxone (6.8 +/- 0.7 fmol/micrograms protein vs. 3.1 +/- 1.0 fmol/micrograms protein, p < 0.05, n = 10 per group). Total hypothalamic NPY mRNA was unchanged. Neuropeptide Y-opioid interactions may be important in the control of food intake.

Topics: Animals; Anorexia; Body Weight; Eating; Feedback; Hypothalamus, Middle; Insulin; Male; Naloxone; Neuropeptide Y; Opioid Peptides; Random Allocation; Rats; Rats, Wistar; RNA, Messenger

The general and sexual activity of food restricted male broiler breeder poultry was assessed for evidence of behavioural changes associated with musculoskeletal lesions. The activity and fertility of male birds given betamethasone (an anti-inflammatory steroid) or saline were compared in a two-period crossover experiment. Behavioural changes occurred and the birds' mating activity and fertility were decreased when they were given the steroid, but these effects were not associated with the presence of lesions. In a second experiment, there were no differences in sexual motivation between birds either with or without leg disorders. The birds were trained to walk down an alley for their food and the speed of walking was compared in a two-period crossover experiment. Betamethasone decreased their walking speed in period one and the carryover effect was significant in period two. Naloxone decreased the walking speed of birds with lesions more than of those without lesions. This effect was taken as evidence for analgesia by endogenous opioids and may help to explain the lack of response of the birds to the analgesic agent. The evidence that these food restricted male broiler breeder birds experienced pain was equivocal.

Topics: Animals; Betamethasone; Body Weight; Chickens; Cross-Over Studies; Food Deprivation; Male; Musculoskeletal Diseases; Naloxone; Organ Size; Pain; Poultry Diseases; Sexual Behavior, Animal; Testis

We studied the effects of two different ATP-sensitive K+ channel openers on naloxone-precipitated withdrawal in morphine-dependent mice. The i.c.v. administration of cromakalim and diazoxide (both at 5-40 micrograms/mouse) dose-dependently inhibited several signs of morphine withdrawal (number of jumps and episodes of forepaw tremors, and body weight loss). At present it is impossible to specify the exact mechanism(s) involved in this effect. However, considering that morphine opens K+ channels in neurons, it is tempting to suggest that K+ channel openers can mimic the effects of morphine on neuronal K+ currents, and as a consequence can act as substitutes for this drug during morphine withdrawal.

Topics: Adenosine Triphosphate; Animals; Behavior, Animal; Benzopyrans; Body Weight; Cromakalim; Diazoxide; Dose-Response Relationship, Drug; Female; Injections, Intraventricular; Injections, Subcutaneous; Mice; Mice, Inbred Strains; Morphine; Naloxone; Potassium Channels; Pyrroles; Substance Withdrawal Syndrome

The present study examined the effects of the opiate antagonist naloxone on spatial acquisition and retention in a water-maze task by adult, nonbreeding, male and female meadow voles (Microtus pennsylvanicus). Voles were required to learn the position of a hidden, submerged platform using distal visual cues. There were four trials per day for 6 days. Daily pretraining (15 min before first trial) systemic administrations of naloxone (1.0 mg/kg, IP) significantly facilitated spatial acquisition in female, but not in male, voles in a water-maze task on days 2, 3, and 4. There were two probe tasks given 1 day and 1 week after the last training trial. All groups acquired the spatial task by the end of the fifth day with no significant effects of naloxone on retention of the spatial task. There were also no significant sex differences in acquisition of the spatial task and task retention in control, nonbreeding adult voles. It is suggested that the lack of sex differences in basal spatial performance may be related to the low levels of testosterone in male nonbreeding voles. The obtained sex differences in the effects of naloxone on spatial acquisition are considered in relation to sex differences in stress, opiate responses, and gonadal steroid levels.

Topics: Animals; Arvicolinae; Body Weight; Cues; Female; Learning; Male; Naloxone; Sex Characteristics; Space Perception; Testosterone

Topics: Body Weight; Drinking; Drug Administration Schedule; Humans; Naloxone; Schizophrenia; Schizophrenic Psychology

Morphine-6-beta-D-glucuronide (M6G) is a metabolite of morphine with opioid activity in adults. No data are available, however, on the developmental pharmacology of M6G including investigation of the respiratory effects of M6G in the neonate. A randomized, placebo-controlled study comparing the time-action, dose-response and potency of the respiratory effects of M6G to morphine was done using a nonanesthetized neonatal guinea pig model and a noninvasive computerized plethysmograph technique. Respiration was measured while the neonate breathed room air followed by 5% CO2 in air. M6G (0.5-5.0 mg/kg) and morphine (1.5-15 mg/kg) administered subcutaneously decreased ventilation in 3-, 7- and 14-day-old neonatal guinea pigs given a 5% CO2 challenge. During CO2 inhalation, time-to-peak action for M6G occurred 21 min later than for morphine. At maximal ventilatory depression on day 3, a dose of 1.5 mg/kg morphine or M6G decreased minute ventilation while breathing 5% CO2 by 30% compared to placebo. Ventilation also decreased as a function of age in both placebo and drug-treated animals. The percent respiratory depression relative to placebo remained constant for a given dose of morphine as the neonate aged, but not for M6G, which increased in potency. M6G was equipotent to morphine on day 3 after birth, but was 8-fold more potent by day 7. This increase in potency persisted through day 14. The increased potency of M6G that accompanies aging may be caused by either a change in M6G disposition or a change in opioid receptors during development of the neonatal guinea pig.

Topics: Animals; Animals, Newborn; Body Weight; Female; Guinea Pigs; Male; Morphine; Morphine Derivatives; Naloxone; Random Allocation; Respiration; Sex Ratio; Time Factors

This paper has tested the hypothesis that patients with hypothalamic obesity have altered mechanisms controlling insulin secretion when compared to obese patients without hypothalamic injury. Fasting glucose and insulin values were significantly higher in the morning than in the afternoon in the six control obese patients, but there was no diurnal difference in the six patients with hypothalamic obesity (n=6). The control obese subjects showed a diurnal variation in glucose-stimulated insulin secretion, whereas the patients with hypothalamic obesity did not, suggesting that hypothalamic injury had destroyed diurnal rhythms. Naloxone, an opioid antagonist, acutely suppressed fasting insulin in the six patients with essential obesity but had little effect on fasting insulin in the three patients with hypothalamic obesity or in five normal-weight controls. Naloxone increased insulin sensitivity in the obese control patients, but did not affect either insulin secretion or insulin sensitivity in patients with hypothalamic obesity or in normal weight subjects. Our results support the conclusion that hypothalamic obesity disrupts diurnal rhythms, with the suggestion that opioid peptides affect insulin secretion differently in patients with essential obesity as compared to normal weight subjects or those with hypothalamic obesity.

Topics: Adolescent; Adult; Blood Glucose; Body Height; Body Mass Index; Body Weight; Carbohydrates; Case-Control Studies; Circadian Rhythm; Female; Glucose; Glucose Tolerance Test; Humans; Hypothalamic Diseases; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Male; Naloxone; Narcotic Antagonists; Obesity; Time Factors

The effect of morphine on tumor growth of EL-4 leukemia in C57BL/6 mice and of Sarcoma 180 carcinoma in ddY mice was studied. Local subcutaneous tumor growth was enhanced by morphine (10 mg/kg, s.c.) given daily for 10d. This effect was inhibited by preadministration of the opioid antagonist naloxone. However, naloxone alone had no significant effect on tumor growth. Morphine also enhanced tumor growth in C57BL/6 mice inoculated i.p. with P388 as well as Meth-A cell in Balb/c mice. However, incubation of morphine with cultures of EL-4, P388, MM-46 and Meth-A cells failed to enhance tumor growth. Mice given morphine displayed marked atrophy and reduced cellularity of the spleen and thymus. The humoral response to sheep erythrocytes and T- and B-cell responses to foreign antigens were suppressed, and the lymphocyte proliferative response to T- and B-cell mitogens (concanavalin A and bacterial lipopolysaccharide, respectively) was attenuated. Morphine exerted an inhibitory effect on the immune response which was antagonized by the concomitant administration of naloxone. These data suggest that the enhancement of tumor growth by the administration of morphine is the result of a overall immunosuppressive effect. The significance of the immunomodulatory effect of morphine is discussed in this report.

Topics: Animals; Antibody Formation; Body Weight; Immunosuppressive Agents; Lipopolysaccharides; Lymphocyte Activation; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred Strains; Morphine; Naloxone; Neoplasm Transplantation; Neoplasms, Experimental; Organ Size; Tumor Cells, Cultured

The profile of actions of dihydroetorphine (DHE) concerning antinociception, tolerance and dependence was compared with those of morphine in mice. DHE at 1, 5, 10 or 20 micrograms/kg produced an antinociceptive effect in a dose dependent manner and 10 micrograms/kg was nearly equipotent to that of 10 mg/kg of morphine. The antinociceptive effect of both drugs was completely suppressed by 1 mg/kg of naloxone, while neither 10 mg/kg of naltrindole nor 1 mg/kg of nor-binaltorphimine had any suppressive effect. Mice tolerant to morphine antinociception were tolerant to DHE and vice versa. The naloxone-sensitive, locomotor accelerating activity was progressively enhanced by daily administration of DHE and morphine and a cross reverse tolerance developed between these compounds, suggesting that common mechanisms, especially mediating opioid receptors, underlay the activity enhancement. The development of physical dependence as evidenced by naloxone precipitated withdrawal signs, however, was not observed with daily treatment with DHE, 10, 20 and 100 micrograms/kg for 6 d. Thus, we demonstrated that DHE produces the antinociceptive effect mediated through mu opioid receptors without causing development of a physical dependence, suggesting that it is safe to use in the clinical therapy of patients suffering severe pain such as that accompanying cancer.

Topics: Analgesics; Animals; Body Weight; Drug Tolerance; Etorphine; Male; Mice; Mice, Inbred Strains; Morphine; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Substance-Related Disorders

The present study examined the dose-dependent (0.25-5 mg/kg) effects of systemic naloxone upon deprivation-induced intake and high-fat intake as functions of age (4, 8, 14, and 20 months), gender, and gonadectomy in rats. Significant increases in body weight were observed as functions of age and gonadectomy. Whereas aging significantly reduced basal deprivation-induced intake, it generally failed to alter basal high-fat intake. Whereas age, gender, and gonadectomy failed to alter the decreases in deprivation-induced intake following low (0.25-2.5 mg/kg) naloxone doses, sham males displayed significantly greater age-related and gender-related inhibition following the 5 mg/kg dose of naloxone. Young gonadectomized rats displayed significant increases in naloxone's inhibition of deprivation-induced intake as well. More dramatic changes occurred in naloxone's inhibition of high-fat intake. Naloxone's potency increased in sham female rats as a function of age, and decreased in sham males and ovariectomized females as a function of age. Whereas sham males and ovariectomized females were most sensitive to naloxone's inhibition of high-fat intake at young ages, sham females were most sensitive at older ages. These data indicate that effects of age, gender, and gonadectomy upon naloxone-induced hypophagia dissociate as a function of the type of intake. Because selective opioid antagonist studies demonstrate that deprivation-induced intake is mediated by the mu1 receptor and high-fat intake is mediated by kappa and mu2 receptors, it is postulated that the differential effects of aging, gender, and gonadectomy variables upon opioid mediation of the two forms of intake may reflect their interaction with different opioid receptor subtypes.

Topics: Aging; Animals; Appetite; Body Weight; Dietary Fats; Dose-Response Relationship, Drug; Eating; Endorphins; Female; Gonadal Steroid Hormones; Male; Naloxone; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Sex Factors; Sexual Maturation

The effect of intermittent footshock stress (0.8 mA; 0.2 s on; 40 s off on the average; for 10 min/day) on oral fentanyl (50 or 75 micrograms/ml) self-administration (SA) in operant chambers was examined in male rats. In Experiment 1, after 1 month of initiation of the fentanyl SA by partial water deprivation, animals were tested for lever-pressing for fentanyl (75 micrograms/ml) under fixed-ratio-4 (FR-4) and progressive-ratio (PR) schedules of reinforcement for 30 min/day in operant chambers. Exposure to footshock stress increased fentanyl SA under the FR-4 and PR schedules compared with a nonstress condition. When water was substituted for the drug, the operant behavior persisted before extinction. In Experiment 2, different rats were tested for lever-pressing for fentanyl (50 micrograms/ml) under FR-6 and PR schedules. This experiment further assessed the role of taste in the stress-induced fentanyl SA and examined the effect of increasing the schedule requirements (i.e., FR-3, 6, and 12) on lever-pressing for fentanyl. Exposure to footshock stress increased lever-pressing for oral fentanyl SA under the FR schedules of reinforcement. When a quinine solution (30 micrograms/ml), matched for bitter taste with the fentanyl solution, was substituted for the drug solution, an extinction of the drug-reinforced behavior occurred, indicating that the stress-induced oral fentanyl SA is not related to stress-induced changes in taste sensitivity. In both experiments, no significant stress effects were observed for water consumption in home cage and lever-pressing on the nonoperative lever.

Topics: Animals; Body Weight; Conditioning, Operant; Drinking; Electroshock; Fentanyl; Male; Naloxone; Rats; Rats, Wistar; Reinforcement Schedule; Self Administration; Stress, Psychological; Taste

Sex differences in the neurochemical mediation of swim stress-induced analgesia (SSIA) were examined in Swiss-Webster mice. Intact and gonadectomized adult mice of both sexes were tested for their analgesic response (hot-plate test) to 3 min of forced swimming in 15 degrees C and 20 degrees C water. SSIA resulting from 15 degrees C swim was previously shown to be naloxone-insensitive (i.e., non-opioid) whereas SSIA resulting from 20 degrees C swim produced an analgesia that was partially reversible by naloxone (i.e., mixed opioid/non-opioid). The non-opioid components of these SSIA paradigms were attenuated by the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). We now report that in males, but not females, dizocilpine (0.075 mg/kg, i.p.) and naloxone (10 mg/kg, i.p.) antagonized the non-opioid and opioid components of SSIA, respectively. After ovariectomy, females displayed a pattern of antagonism similar to males such that dizocilpine attenuated non-opioid SSIA, although naloxone remained ineffective in antagonizing 20 degrees C SSIA. Thus, SSIA in intact females was neither opioid- nor NMDA-mediated, yet it was of similar magnitude to the SSIA displayed by intact males. In separate experiments, estrogen replacement (estrogen benzoate; 5.0 micrograms/day, i.p.) administered to ovariectomized mice over a 6-8 day period reinstated the dizocilpine-insensitivity of 15 degrees C SSIA characteristic of intact females. However, a similar estrogen regimen administered to both intact and castrated males did not compromise the sensitivity to dizocilpine previously noted in male mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesia; Animals; Body Weight; Dizocilpine Maleate; Estrogens; Female; Male; Mice; Naloxone; Orchiectomy; Ovariectomy; Pain Measurement; Reaction Time; Sex Characteristics; Stress, Psychological; Swimming

Feeding and its regulation by opioids were studied in lean sheep and sheep in the static phase of dietary obesity. Sheep were fasted 16 h and on separate days were injected IV with 0 (saline), 0.01, 0.1, 1, or 3 mg/kg naloxone 5 min before they were allowed ad lib intake for the ensuing 32 h. All sheep were in chronic zero energy balance when not fed ad lib during naloxone treatment. After 0 mg/kg naloxone, intake rate was at least twice as fast (p < 0.05) in lean than obese sheep through the first 4 h of ad lib feeding, but was similar (approximately 0.5 g/min) in both groups of sheep after 8 h of ad lib feeding. Dose-dependent inhibitory effects of naloxone on intake were observed in lean and obese sheep through the first 4 h of ad lib feeding with maximum inhibition at +2 h. Dose-response curve for naloxone inhibition of intake was shifted leftward in obese compared with lean sheep. Dose of naloxone needed to inhibit intake by 25% was less (p < 0.05) in obese (0.13 mg/kg) than lean (0.57 mg/kg) sheep when both groups experienced similar plasma concentrations of injected naloxone. Basal concentrations of immunoreactive beta-endorphin in fasted plasma were similar in lean (33 +/- 4 pg/ml) and obese (48 +/- 9 pg/ml) sheep. Dietary obesity in sheep was associated with reduced appetite and with enhanced responsiveness to the intake-inhibitory effects of naloxone.

Topics: Animals; Appetite; beta-Endorphin; Body Weight; Dose-Response Relationship, Drug; Endorphins; Feeding Behavior; Female; Naloxone; Receptors, Opioid; Sheep

The present study was conducted to evaluate the influence of chronic kappa receptor blockade on the neuroendocrine effects of the selective kappa 1 opioid agonist U-50,488H, on the hypothalamo-pituitary-adrenocortical (HPA) axis. Male Sprague-Dawley rats were chronically treated with naloxone (3 mg kg-1 day-1 for 7 days) or distilled water by s.c. implantation of osmotic minipumps and the response of the HPA axis to U-50,488H or saline was assessed before and 24 h after pump removal. Chronic infusion of naloxone reduced body weight gain and blocked the increase in corticosterone secretion induced by U-50,488H, indicating occupation of kappa opioid receptors. Significantly higher plasma corticosterone levels after U-50,488H administration at doses of 5 or 15 mg/kg were observed 1 day after cessation of naloxone treatment compared with those in corresponding control rats. The enhanced responsiveness of the HPA axis to U-50,488H (15 mg/kg) was antagonized by norbinaltorphimine (5 mg/kg), suggesting a role for kappa receptors in mediating supersensitivity to the kappa agonist. The findings of the present study demonstrated that chronic blockade of the kappa receptor results in augmentation of kappa agonist-induced stimulation of the HPA axis activity (functional supersensitivity).

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Body Weight; Corticosterone; Dose-Response Relationship, Drug; Hyperalgesia; Hypothalamo-Hypophyseal System; Male; Naloxone; Naltrexone; Pituitary-Adrenal System; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sensitivity and Specificity; Sodium Chloride

It has been demonstrated previously that chronic treatment with opioid antagonists enhances the potency of opioid agonists (supersensitivity) and produces an increase in brain opioid binding sites (up-regulation). The objective of the present study was to examine whether chronic blockade of mu-opioid receptors with naloxone would produce functional supersensitivity to the action of selective mu- and/or kappa-opioid agonists, within the hypothalamus-pituitary-adrenocortical axis. Naloxone (0.5 mg/kg/hr) was infused s.c. to Sprague-Dawley rats via osmotic minipumps for 7 days. The increase in plasma corticosterone produced by 30 mg/kg i.p. of morphine in control rats was shown to be significantly higher in naloxone-pretreated rats, 24 hr after pump removal. Furthermore, in naloxone-pretreated rats, 10 mg/kg i.p. of morphine significantly increased corticosterone levels 24 hr after naloxone was withdrawn, whereas in control rats the concentration of corticosterone increased first after the 30-mg/kg dose. No supersensitivity could be detected to the stimulating action on corticosterone release of U-50,488H (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidynyl)cyclohexyl]ben zeneacetamide methane sulfonate; 1 or 15 mg/kg i.p.), 1 day after cessation of naloxone treatment. These data suggest that chronic blockade of the mu receptor with naloxone may induce a functional supersensitivity to the effects of mu- but not to those of kappa-agonists on the hypothalamus-pituitary-adrenocortical axis.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Body Weight; Corticosterone; Dose-Response Relationship, Drug; Hyperalgesia; Hypothalamo-Hypophyseal System; Male; Morphine; Naloxone; Pituitary-Adrenal System; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors

The purpose of the present study was to investigate the role of the locus coeruleus in the development of opiate dependence. Two groups of rats each were subjected to either a electrolytic lesion of the locus coeruleus or a sham lesion. All animals were implanted with an intracerebroventricular (i.c.v.) cannula, and made physically dependent by subcutaneous insertion of two 75-mg morphine (base) pellets. Abstinence was precipitated by i.c.v. administration of methylnaloxonium (31-1,000 ng) 72 h after pellet implantation. Methylnaloxonium administered intracerebroventricularly induced a withdrawal syndrome characterized by the appearance of teeth chattering, mastication, rearing, wet dog shakes, jumping, piloerection, hyperactivity, ptosis and eye twitch. Withdrawal observed in the electrolytic lesion groups was less severe than in sham group. The presence of mastication, rearing, piloerection, hyperactivity, ptosis and eye twitch was significantly lower. These results support the hypothesis that the locus coeruleus has an important role in the expression of the physical signs of opiate dependence.

Topics: Animals; Blepharoptosis; Body Weight; Brain Chemistry; Dose-Response Relationship, Drug; Eye Movements; Injections, Intraventricular; Locus Coeruleus; Male; Mastication; Morphine; Morphine Dependence; Motor Activity; Naloxone; Norepinephrine; Piloerection; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Substance Withdrawal Syndrome

As preliminary evidence for the implication of opioids in the increase in blood pressure due to the stress of brief social deprivation, hypertension has been shown to be antagonized by acute administration of opiate receptor blockers. As a further evidence of involvement of opioids in the hypertensive response to this type of stress, cross-tolerance ought to be capable of being demonstrated in isolated animals, treated with an opiate. When rats were treated subchronically with morphine in the drinking water throughout the isolation period (1-15 days), readings of blood pressure did not show any variation, as compared to group-housed control rats. However, 7 days after withdrawal of morphine readings of arterial pressure in the isolated rats increased above the levels of the group-housed control animals. These findings support the idea that an endogenous opioid system is implicated in the induction of readings of high blood pressure due to the stress of social deprivation.

Topics: Animals; Blood Pressure; Body Weight; Drug Tolerance; Hypertension; Male; Morphine; Naloxone; Rats; Rats, Wistar; Self Administration; Social Isolation; Stress, Psychological; Substance Withdrawal Syndrome

Opioid peptides have been implicated in reward-related components of eating, especially with fatty and sweetened foods. This study examined the effect of pre-exposure of rats to milk on the subsequent anorexic effect of naloxone in a separate daily mash intake test. Rats were given constant access to either skimmed or whole milk for 15 days, in addition to normal diet. A third (control) group received only the normal diet. Subsequently, all groups received 0, 0.125, 0.5 and 1.0 mg/kg naloxone prior to their daily mash intake test. Naloxone caused dose-dependent reductions in mash intake in all groups, but this effect was significantly greater in the group with whole milk than in controls, with the group with skimmed milk intermediate. Daily intakes of milk were similar with skimmed and whole milk, and milk intake in separate two-bottle choice tests provided no evidence for overall preferences for either solution. These results suggest that prior exposure to milk enhances opioid involvement in feeding, and possible mechanisms for this are discussed.

Topics: Animals; Anorexia; Body Weight; Dietary Fats; Drinking; Energy Intake; Male; Milk; Naloxone; Rats

It has been reported that perinatal exposure to opiates affects mRNA synthesis, body growth and brain development in mammals, including humans. We have observed that morphine administration in drinking water during the perinatal period alters peptide development in the striatum of the rat. There is a marked increase in substance P and met-enkephalin content, the latter is maintained even at 30 days postnatally. The transient increase or earlier maturation of substance P content is correlated by a more precocious axon terminal organization as revealed by immunocytochemical staining. The increased metenkephalin content is correlated by a higher abundance of preproenkephalin A mRNA and this correlation is particularly evident at 15 days postnatally. At earlier times both northern blotting and in situ hybridization techniques fail to show any significant difference between control and morphine exposed rats, likely because the peptide content is not very different in the two groups or at least the gap is not as wide as at later times.

Topics: Animals; Blotting, Northern; Body Weight; Corpus Striatum; Endorphins; Enkephalin, Methionine; Enkephalins; Female; Growth; Immunohistochemistry; In Situ Hybridization; Morphine; Naloxone; Naltrexone; Protein Precursors; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Substance P

Development of physical dependence is observed after treatment with opioid agonists, but not after chronic i.c.v. administration of mixed inhibitors of enkephalin-degrading enzymes. The aim of this study was to investigate further this promising result of repeated administration of the systemically active mixed inhibitor prodrug RB101, N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopro pyl]- L-phenylalanine benzyl ester. In a comparative study, the naloxone-evoked withdrawal syndrome was quantified in mice chronically treated with i.p. administered morphine or RB101 (6 and 160 mg/kg, respectively) for 5 days, twice daily. After administration of naloxone (5 mg/kg s.c.) on the sixth day, large behavioral changes (jumps, paw shakes, wet-dog shakes, tremor, teeth chattering) and body weight losses occurred in the morphine-treated mice. In contrast, no significant behavioral signs of physical dependence, or body weight changes were observed in the RB101-treated mice. The difference between morphine and RB101 could be partially due to a very low tonic release of enkephalins in the locus coeruleus, a brain region critically involved in the development of physical dependence. These results confirm the potential of mixed inhibitors of enkephalin-degrading enzymes as new non-addictive analgesics.

Topics: Animals; Behavior, Animal; Body Weight; Disulfides; Injections, Intraventricular; Male; Mice; Morphine; Naloxone; Phenylalanine; Prodrugs; Substance Withdrawal Syndrome; Substance-Related Disorders

The present experiments were performed to investigate the effects of the selective mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on the physical dependence liability of butorphanol (a mixed agonist/antagonist opioid analgesic). Butorphanol (26 nmol/microliter/h) was continuously infused via osmotic minipumps into the lateral cerebral ventricle of male Sprague-Dawley rats for 72 h. beta-FNA (12, 24, and 48 nmol/5 microliter/rat) was administered ICV 3 h prior to and 48 h after initiation of the butorphanol infusion. Treatment with beta-FNA significantly diminished naloxone-induced escape behavior, hypothermia, and loss of body weight in a dose-dependent manner, while naloxone-induced teeth-chattering, forepaw tremors, and urination were also reduced, but in a dose-independent manner. These results suggest that the mu opioid receptor is partially involved in the development of physical dependence upon butorphanol.

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Butorphanol; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Reinforcement Schedule; Substance Withdrawal Syndrome; Substance-Related Disorders

Opioids were administered to female Long Evans rats in their drinking water. Maintenance doses of 0.8 and 0.4 mg/ml for morphine and methadone, respectively, were achieved using an ascending dosage schedule. Rats were decapitated 0, 20, or 60 min after naloxone (10 mg/kg, IP) or saline. Brain met-enkephalin-like immunoreactivity (ME-LI) was determined by radioimmunoassay (RIA). In morphine-drinking animals, ME-LI in all regions of the brain was unaltered following saline administration; however, 20 min after naloxone injection ME-LI had increased in the striatum, hypothalamus, midbrain, and pituitary. By 60 min, ME-LI was no longer elevated. In both methadone- and water-drinking rats, ME-LI did not deviate from normal. These elevated levels of ME-LI, 20 min after naloxone-precipitated withdrawal in morphine-dependent rats, coincided with the peak of behavioural signs in the precipitated withdrawal syndrome. The milder behavioural disturbances observed in the withdrawal of methadone-drinking rats were consistent with the unaltered ME-LI in these animals.

Topics: Animals; Behavior, Animal; Body Weight; Brain Chemistry; Drinking; Enkephalin, Methionine; Female; Methadone; Morphine; Morphine Dependence; Naloxone; Radioimmunoassay; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

Chronic opioid antagonist administration increases opioid binding sites and potentiates behavioral responses to morphine. Conversely, chronic opioid agonist administration attenuates behavioral responses to morphine, though this is not necessarily accompanied by a parallel loss of binding sites. We examined the possibility that the in vivo affinity of the mu receptors might be altered as a consequence of the continuous administration of either naloxone or morphine. Rats were implanted sc with naloxone- or morphine-filled osmotic pumps; control animals were implanted with sham pumps. One week later, 24 hr after removing the osmotic pumps, cumulative dose-response curves for fentanyl analgesia were generated in the presence of 0.0, 0.03, 0.1, or 0.3 mg/kg naltrexone, using a tail-flick procedure. The analgesic ED50 (with 95% C. L.) of fentanyl in sham implanted animals, following saline pretreatment was 0.027 mg/kg (0.019, 0.039). The potency of fentanyl was decreased in rats infused with morphine, ED50 = 0.051 mg/kg (0.028, 0.093), and increased in rats that received naloxone, ED50 = 0.018 mg/kg (0.015, 0.022). The mean apparent pA2 value for naltrexone (with 95% C.L.) in the control group was 7.7 (7.5, 7.9). No differences were detected in animals that had received either naloxone or morphine for 7 days, pA2 = 7.8 (7.5, 8.1) and 7.4 (7.3, 7.6), respectively. Our results indicate that there is no change in the apparent affinity of the mu-receptor following continuous exposure to either an opioid agonist or antagonist, at a time when the analgesic potency of the agonist is decreased or increased, respectively.

Topics: Analysis of Variance; Animals; Body Weight; Dose-Response Relationship, Drug; Drug Interactions; Fentanyl; Male; Morphine; Naloxone; Naltrexone; Pain Measurement; Rats; Rats, Inbred Strains

We have investigated the effects of the local administration into the periaqueductal gray matter of thiorphan, a selective inhibitor of endopeptidase 24.11 "enkephalinase", kelatorphan, (R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)- L-alanine, and RB 38 A, (R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)-L-phenylalanine, two almost complete inhibitors of enkephalin metabolism, on the naloxone-precipitated morphine withdrawal syndrome in rats. Local administration of these inhibitors decreased the severity of the withdrawal syndrome. Jumping, chewing, diarrhea, piloerection, salivation and hypothermia were decreased by all drugs. Lacrimation and weight loss were reduced by kelatorphan and RB 38 A whereas teeth chattering, tremor, eye twitch and rhinorrhea were decreased only by RB 38 A. The rise in plasma corticosterone levels was only slightly reduced by the three inhibitors. Wet dog shakes and ptosis remained unchanged. These results indicate that during the morphine withdrawal syndrome in rats there is a tonic or/and naloxone evoked release of opioid peptides, presumably enkephalins, into the periaqueductal gray matter and that inhibition of their degradation strongly decreases the severity of the withdrawal syndrome.

Topics: Analgesics; Animals; Behavior, Animal; Body Temperature; Body Weight; Corticosterone; Dipeptides; Enkephalins; Hydroxamic Acids; Male; Morphine; Morphine Dependence; Naloxone; Neprilysin; Periaqueductal Gray; Phenylalanine; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Thiorphan

Experiments were conducted to test the hypothesis that chronic administration of an opioid receptor antagonist, naloxone, would affect the outcome of the developmental phase of hypertension in Dahl salt-sensitive (S/JR strain) rats. Accordingly, S/JR rats were maintained on either a low-salt (0.45% NaCl) or a high-salt (7% NaCl) diet for 4 wk. Half of the animals of each dietary group were treated with naloxone (100-130 micrograms/h) by osmotic minipump. Food and water intakes of the high-salt animals were measured for the first 25 days, and blood pressure was measured at the end of the 4 wk via an indwelling femoral arterial catheter. Naloxone treatment slightly but significantly reduced the level of hypertension attained in the high-salt animals (158 +/- 2 mmHg in naloxone-treated animals vs. 168 +/- 3 mmHg in control animals; P less than 0.05) and also attenuated food (and hence salt) and water intakes. Naloxone did not affect the blood pressure of the low-salt animals. To determine whether the slight attenuation of hypertension might be secondary to a reduction of salt intake, a group of control S/JR animals were fed a moderately high-salt diet (2% NaCl), and naloxone-treated S/JR animals were salt-intake matched to this group by daily adjustment of the dietary salt content. Blood pressures after 4 wk of treatment were not different between these two groups. Finally, acute administration of 1 and 30 mg/kg of naloxone failed to lower blood pressure of animals with established hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Body Weight; Diet; Drinking; Eating; Hypertension; Male; Morphine; Naloxone; Rats; Rats, Mutant Strains; Sodium Chloride

One day after intraplantar inoculation of Mycobacterium butyricum into the right hind-paw, unilaterally inflamed and control rats were implanted subcutaneously with osmotic mini-pumps delivering naloxone at 0.16 or 3.0 mg/kg/h or vehicle. As determined three days after implantation, 0.16 mg/kg/h of naloxone completely antagonized the antinociceptive action of the mu-agonist, morphine, but did not affect antinociception evoked by the kappa-agonist, U69,593. In contrast, at 3.0 mg/kg/h, naloxone blocked both morphine- and U69,593-induced antinociception. Thus, 0.16 mg/kg ("low dose") and 3.0 mg/kg ("high dose") of naloxone block mu, or mu- plus kappa-opioid receptors, respectively. Pumps were removed one week following their implantation. Inoculation was associated with a sustained hyperalgesia of the inflamed paw to noxious pressure, and elevation in resting core temperature, a loss of body weight, hypophagia, hypodipsia and a reduction in mobility. These parameters were differentially modified by the high as compared to the low dose of naloxone. Two days following implantation of pumps delivering the high dose of naloxone, the hyperalgesia of the inflamed paw was potentiated: by six days, this effect was lost. Further, one day after removal of pumps yielding the high dose, the inflamed paw showed a normalization of thresholds, that is a "rebound antinociception". One day later, this effect had subsided. In distinction, at no time did the low dose of naloxone modify nociceptive thresholds. The high dose of naloxone enhanced the reduction in body weight and food intake shown by unilaterally inflamed rats whereas the low dose was ineffective. Neither dose affected the reduction in water intake or hypothermia of unilaterally inflamed animals. The high dose of naloxone reduced the mobility of unilaterally inflamed rats whereas the low dose was ineffective. Finally, by 10 days following pump removal, pathology had transferred to the contralateral paw. In rats which had received the high but not the low dose, this transfer was blocked. It is concluded that blockade of kappa-opioid receptors with a high dose of naloxone experts pronounced functional effects in unilaterally inflamed rats. In distinction, selective blockade of mu-receptors with a low dose is ineffective. The changes seen include not only an enhancement of the hyperalgesia of the inflamed tissue, but also an exacerbation of variables (body weight, food intake and motility) which reflect pain states.

Topics: Analgesics; Animals; Behavior, Animal; Benzeneacetamides; Body Temperature; Body Weight; Inflammation; Male; Morphine; Naloxone; Nociceptors; Pain; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

In order to test the hypothesis that endogenous opiates are at least partially responsible for hyperinsulinaemia in patients with polycystic ovarian disease (PCOD), the effect of naloxone (an opiate receptor blocker) on the insulin response to oral glucose load (OGTT) was studied in 20 women with PCOD and 17 control subjects at days 5-8 of their follicular phase. After fasting overnight for 10-12 h, each woman received an i.v. bolus injection (2 mg) of naloxone or an equal volume of saline infusion followed by a constant infusion of naloxone or saline solution at a rate of 8 ml/h (1 mg/h of naloxone) for 5 h. OGTT (75 g) was performed 1 h after the bolus injection. The naloxone study was performed 48 h after the saline study. Naloxone did not modify the insulin response to OGTT in either group. When the data were related to the insulin response, in PCOD hyperinsulinaemic patients, naloxone significantly reduced (P less than 0.02) the insulin response to OGTT without any change in glycaemic response curves. In control and PCOD normoinsulinaemic patients, naloxone did not change significantly either the glycaemia or the insulin levels after OGTT. No change of gonadotrophin and steroid secretion was found in any patient receiving naloxone. In conclusion, endogenous opiates may play a significant role in hyperinsulinaemia in PCOD.

Topics: Adolescent; Adult; Blood Glucose; Body Weight; Endorphins; Female; Glucose Tolerance Test; Humans; Insulin; Naloxone; Narcotic Antagonists; Polycystic Ovary Syndrome

In a previous study, we found that the kappa opioid agonist U50,488H (U50) suppresses both appetitive and consummatory components of drinking behavior in rats trained to negotiate water in a straight runway. U50 also activates diuresis. Kappa opioid mechanisms could therefore play a dissipative role in the body's water balance. Since naloxone inhibits diuresis, but not hypodipsia produced by U50, these effects are probably mediated also by nonopioid mechanisms. In rats trained to negotiate water in a straight runway, we have studied the influence on the hypodipsic effects of U50 of the selective alpha-1 adrenoceptor antagonist dapiprazol (DAP), which we found to inhibit U50-mediated diuresis. When given alone, DAP (3 and 6 mg/kg IP) influenced neither running for water nor water intake; neither did it prevent the suppression of water intake produced by U50 (8 mg/kg IP) across the test. However, it did antagonize the U50-mediated slowing of running for water. Alpha-1 adrenoceptors thus appear to play a role in U50's effects on diuresis and the appetitive, but not consummatory, aspects of drinking.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic alpha-Antagonists; Animals; Body Weight; Depression, Chemical; Diuresis; Drinking Behavior; Male; Naloxone; Piperazines; Pyrrolidines; Rats; Rats, Inbred Strains; Triazoles

In these studies, the physical dependence liability of butorphanol, a mixed 'agonist/antagonist' opioid analgesic, was compared to that of morphine. Male, Sprague-Dawley rats received i.c.v. infusions of saline (1 microliter/h), or an equimolar dose of butorphanol or morphine (52.3 nmol/h) for 3 days. The physical dependence liabilities of these two compounds were then compared by assessing both behavioral withdrawal signs and weight loss following naloxone-precipitated withdrawal. Body weight loss was also evaluated following abrupt (cessation of infusion) withdrawal from butorphanol or morphine. In animals receiving i.c.v. infusions of butorphanol or morphine, naloxone administration (5 mg/kg s.c.) induced an equivalent degree of body weight loss compared to saline-treated animals. In addition, the ED50 of naloxone to produce wet shakes, escape behavior, teeth chattering, urination and defecation was equivalent in rats receiving butorphanol or morphine. Infusions of butorphanol or morphine also produced an equivalent degree of weight loss in animals undergoing abrupt withdrawal. These results demonstrate then that a substantial degree of physical dependence had developed in rats which received a large dose of butorphanol.

Topics: Animals; Behavior, Animal; Body Weight; Butorphanol; Injections, Intraventricular; Male; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Substance-Related Disorders

This study assessed the relationship between autotomy and opioid systems following brachial nerve sections in the rat. Morphine, buprenorphine and/or naloxone were self-administered orally to rats following nerve sections. Oral morphine and buprenorphine increased the severity of autotomy. Naloxone alone had no effect, but reversed oral morphine effect on autotomy. These results suggest that mu-receptor activation by morphine and buprenorphine can increase the severity of autotomy.

Topics: Administration, Oral; Animals; Body Weight; Brachial Plexus; Buprenorphine; Denervation; Dose-Response Relationship, Drug; Drug Administration Schedule; Male; Morphine; Naloxone; Pain; Rats; Rats, Inbred F344; Self Mutilation

This investigation was carried out to study the development of physical dependence on spinally administered morphine, and it was determined if this phenomenon is associated with altered levels of [Met5]enkephalin. Morphine was infused continuously into the intrathecal space of rats for three or six days. In morphine-dependent animals, an intrathecal naloxone challenge produced increased reaction to nociceptive stimuli, hypertension, hyperthermia, decreased urinary output, and loss of body weight. Chronic spinal infusion of morphine alone failed to alter levels of [Met5]enkephalin in sacral and lumbar spinal cord. However, 24 h after the naloxone challenge, there was a significant increase in spinal enkephalin levels in morphine-dependent animals. It is concluded that spinal morphine treatment leads to the development of physical dependence. Certain characteristics of this phenomenon, as reflected in the naloxone-precipitated withdrawal signs, differ from those associated with dependence on systemic morphine.

Topics: Analgesics; Animals; Behavior, Animal; Blood Pressure; Body Temperature; Body Weight; Brain Chemistry; Drug Tolerance; Enkephalin, Methionine; Injections, Spinal; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Spinal Cord; Substance Withdrawal Syndrome; Urodynamics

The effects of naloxone on the development of hypertension were studied in unilaterally nephrectomized rats implanted with deoxycorticosterone acetate (DOCA; 200 mg/kg) and given saline to drink. Intraperitoneal (i.p.) infusion of naloxone at 150 micrograms/hr significantly lowered systolic blood pressure (SBP) compared to rats not receiving naloxone, (135 +/- 4.4 vs 158 +/- 5.9 mmHg on day 16). IP infusion of naloxone at 300 micrograms/hr produced the same reductions of SBP as that at 150 micrograms/hr in DOCA-salt treated rats. In other experiments intracerebroventricular (i.c.v.) infusion of naloxone at 7 micrograms/hr also significantly attenuated the DOCA-salt hypertension. The same dose given i.p. had no effect on the development of hypertension. Naloxone had no effect on plasma renin activity (PRA), plasma atrial natriuretic peptide (ANP), or concentrations of Na+ and K+ in plasma. The present data demonstrate that naloxone significantly attenuates the development of hypertension in rats given DOCA and fed a high salt diet. The attenuation of blood pressure could not be associated with the changes in PRA or plasma ANP. These results imply that the central opiate receptors play an important role in the pathogenesis of this model of hypertension.

Topics: Animals; Blood Pressure; Body Weight; Desoxycorticosterone; Heart Rate; Hypertension; Naloxone; Rats; Rats, Inbred Strains; Sodium Chloride

To assess the role of opioid receptors in the spinal cord in regulation of functions of the intestinal mucosa in a secretory model, we evaluated the ability of i.t. administered mu (PL017), delta (DPDPE) and kappa (U50,488H) selective opioid agonists to inhibit diarrhea produced in mice by an injection of prostaglandin E2 (PGE2) (200 micrograms/mouse, i.p.). I.t. PL017 and DPDPE inhibited diarrhea in a dose-related fashion. U50,488H had only minimal antidiarrheal effects. The i.t. doses of PL017 and DPDPE required to inhibit diarrhea were higher than the doses required to produce antinociception and inhibit gastrointestinal transit. Spinally administered PL017 and DPDPE were considerably less potent in the diarrhea model than after i.c.v. administration but far more effective than after peripheral (s.c.) dosing. The antidiarrheal effects of spinally administered opioids were antagonized by concurrently administered naloxone. These data indicate that opioid chemosensitive sites in the spinal cord can modulate diarrhea produced by PGE2, and that the receptor specific opioids, PL017 and DPDPE, and to a lesser extent U50,488H, all possess antidiarrheal activity when administered i.t.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Antidiarrheals; Body Weight; Diarrhea; Dinoprostone; Endorphins; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Gastrointestinal Transit; Male; Mice; Mice, Inbred ICR; Naloxone; Narcotics; Pyrrolidines; Spinal Cord

Chronic treatment of rats with naloxone for 5 days increased the analgesic threshold (hot plate latency). Further, when rats were treated with morphine-admixed food for 3 days after the chronic naloxone treatment the withdrawal signs precipitated by naloxone were significantly greater in the naloxone-pretreated rats than in saline-pretreated rats. These results suggest that paradoxical analgesia and enhancement of the morphine withdrawal signs induced by chronic naloxone treatment may be associated mainly with up-regulation of mu- and delta-opioid binding sites in the central nervous system.

Topics: Analgesia; Animals; Body Weight; Male; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Up-Regulation

Chronic treatment with naloxone (Nx) or naltrexone (Ntx) induces paradoxical analgesia. In the present study, the effects of chronic treatment with opioid receptor antagonists, such as nor-binaltorphimine (nor-BNI) for kappa and naltrindole (NTI) for delta receptors, on analgesic response using the hot plate test and on morphine physical dependence in rats were examined. The hot plate latency was significantly increased by pretreatment with Nx (5 mg/kg, s.c.), nor-BNI (20 mg/kg, i.p.) or NTI (20 mg/kg, i.p.) for 5 days. After chronic pretreatment with these antagonists, the rats were treated with morphine-admixed food (0.5 mg/g of food) for 3 days. Chronic pretreatment with Nx and NTI significantly increased Nx precipitated body weight loss in morphine dependent rats, while chronic pretreatment with nor-BNI produced small increase. These results indicate that chronic treatment with nor-BNI or NTI as well as with Nx induces obviously paradoxical analgesia, and that chronic blockade of mu or delta may enhance the development of physical dependence on morphine.

Topics: Animals; Body Weight; Indoles; Male; Morphinans; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pain Measurement; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Substance-Related Disorders

Reduction of renal perfusion is followed by increases in plasma renin activity (PRA) and arterial pressure. The present experiments were designed to determine if an opiate antagonist would alter pressor or renin responses to acute reduction of renal arterial pressure (RAP) in anesthetized rats. Male Sprague-Dawley rats were anesthetized with Inactin, and an adjustable constrictor device was placed around the abdominal aorta proximal to the renal arteries. One-half of the animals were pretreated with the opiate antagonist naloxone (2 mg/kg iv), and the other one-half were pretreated with saline vehicle. The abdominal aorta was then constricted to reduce RAP by 25% (measured as femoral arterial pressure) in one-half of the animals in each pretreatment group. Compared with vehicle pretreatment, naloxone pretreatment did not alter the PRA response to aortic constriction; however, naloxone did attenuate the pressor response. We conclude that 1) the PRA response to acute reduction of renal arterial pressure is not dependent on an opiate mechanism in the rat, and 2) attenuation of the pressor response to aortic constriction by naloxone in intact rats is not secondary to a suppression of the PRA response.

Topics: Analysis of Variance; Animals; Blood Pressure; Body Weight; Heart Rate; Hypotension; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Renal Circulation; Renin

The physical dependence potential of Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399), a novel enkephalin analog with a potent analgesic effect, was assessed in rats. The animals were given EK-399 (0.008, 0.032, 0.125, or 0.5 mg/kg), morphine (0.125, 0.5, or 2 mg/kg), pethidine (2 or 8 mg/kg), or pentazocine (2 or 8 mg/kg) every hour through an implanted intravenous cannula. After 3 days of treatment, precipitated withdrawal tests were conducted: naloxone (5 mg/kg) was administered subcutaneously. Rats treated with morphine showed withdrawal signs such as hyperirritability, salivation, diarrhea, and weight loss. Rats treated with pethidine, pentazocine, or EK-399 showed similar signs, but they were less evident than those in morphine-treated rats. In abrupt withdrawal tests after 7 days of treatment, rats treated with morphine, pethidine, or pentazocine showed weight loss, whereas rats treated with EK-399 showed little or no weight loss. In substitution tests, EK-399 suppressed the withdrawal signs in morphine-dependent rats, and vice versa. These results show that EK-399 has a morphine-like physical dependence potential that is weaker than that of morphine, pethidine, or pentazocine in rats.

Topics: Animals; Body Weight; Enkephalins; Infusions, Intravenous; Male; Meperidine; Morphine; Naloxone; Opioid-Related Disorders; Pentazocine; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

It is well known that the immune function can be compromised by stress. To investigate immune function in mice stressed by experimental restraint or unavoidable and opioid dependent stress, we evaluated the changes in total body weight and in organ weights (liver, spleen and thymus) of these animals, as well as the phagocytic activity of macrophages, the cytotoxicity of T cells and inhibitory effects on tumor growth and changes in T cell subset populations. At the same time we evaluated the effects of Neurotropin (NSP), a substance extracted from the inflamed skin of rabbits inoculated with the vaccinia virus and which appears to possess neuroimmunomodulating activity. The experimentally stressed group exhibited a reduction of phagocytic activity of macrophages, cytotoxicity of T cells and inhibitory effects on tumor growth. In addition there were changes in the population of T cell subsets. In those animals pretreated with NSP, the immunosuppression induced by stress was ameliorated. As compared with several agents which influence phagocytosis, neurotropin exhibited effects similar to that of agents that blocked the adrenaline receptor and an opioid antagonist rather than tranquilizer (diazepam) and a cholinergic receptor blocker. The pharmacologic effects of neurotropin support a relationship between the actions of the central nervous system and the immune system.

Topics: Animals; Atropine; Body Weight; Cytotoxicity, Immunologic; Diazepam; Female; Immune Tolerance; Killer Cells, Natural; Lymphoma; Macrophages; Mice; Mice, Inbred AKR; Mice, Inbred C3H; Naloxone; Organ Size; Phagocytosis; Polysaccharides; Propranolol; Reference Values; Restraint, Physical; Stress, Psychological; T-Lymphocyte Subsets

Adult male Han/Wistar rats were treated with 1000 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg body weight and allowed to restabilize their body weight at a lower level. Therefore, their feeding or drinking responses were determined to the following ip challenges: NaCl (1 M, 10 ml/kg body weight); 2-deoxy-D-glucose (2DG; 400 mg/kg); sodium mercaptoacetate (MA; 800 mumol/kg); 2DG + MA (200 mg/kg + 400 mumol/kg); insulin (10 U/kg). In addition, the suppressive effects of naloxone (10 mg/kg), glucose (1.36 mg/kg) and fructose (1.36 mg/kg) on feed intake stimulated by 24-hr food deprivation were examined. After the restabilization, the body weights of TCDD-treated rats followed the course of body changes in control rats. The responses to NaCl were also similar in TCDD-treated and control rats. However, marked differences were observed in all other responses studied. Pretreatment with TCDD abolished 2DG-induced feeding, attenuated the effects of insulin and naloxone, caused an aberrant decrease in feed intake following MA, and resulted in hypersensitivity to the satiating effects of glucose and fructose. These data show that exposure to a high dose of TCDD leads to notable distortions in responses to metabolic challenges in Han/Wistar rats, which are present even when they have seemingly recovered from the acute toxicity. The results also indicate that the central nervous system plays a crucial role in TCDD toxicity, and suggest hypersensitivity to peripheral satiety signals coupled with hyporesponsiveness to metabolic cues of energy deficit to be important mechanisms in the pathogenesis of the wasting syndrome.

Topics: Animals; Body Weight; Deoxyglucose; Drinking; Drug Interactions; Eating; Food Deprivation; Fructose; Glucose; Insulin; Male; Naloxone; Polychlorinated Dibenzodioxins; Rats; Rats, Inbred Strains; Sodium Chloride; Thioglycolates

To study the regulation of nociceptive sensitivity/behavioral reactivity in animals during aversive states of different nature, the changes of vocalization thresholds and tail-withdrawal latencies were investigated in rats in free behavior, during restraint stress, after acute trauma to an extremity and under intraperitoneal acetic acid administration. To understand opioid peptide involvement in mediation of the changes obtained, this analysis was also done during opiate receptor blockade by naloxone. The data on the modification of vocalization and movement reactivity as well as on the changes of suprarenal weight and gastric ulceration, produced in normal and naloxone-treated rats by innoxious stressogenic, noxious somatic and visceral stimulation are discussed in relation with: 1. the peculiarities of sensitivity and responsivity of animals to external stimuli in aversive environment; 2. the role of these changes in maintenance of an animal's adaptive activity produced by environmental threat and their mediation by endogenous opioids; 3. the functional significance of the activation of endogenous opioidergic neurotransmission in organization, realization and modification of an animal's adaptive activity, directed on behavioral escape from aversive environment as well as on satisfaction of actual biological and zoosocial needs, in regulation of precise conformity among homeostasis, behavior and variable environment.

Topics: Acetates; Acetic Acid; Animals; Avoidance Learning; Behavior, Animal; Body Weight; Endorphins; Female; Male; Naloxone; Nociceptors; Noise; Pain; Rats; Restraint, Physical; Stomach Ulcer; Stress, Psychological; Vocalization, Animal

Endogenous opioid systems (i.e., endogenous opioids and opioid receptors) act in the trophic regulation of biological development. Opioid antagonist paradigms have served to elucidate the nature of this relationship. If growth is mediated at the level of the opioid receptor, one would expect that this interaction would be stereospecific. This study shows that daily injections of 20-60 mg/kg (-) naloxone, given chronically throughout the preweaning period, depress body weight when monitored at Day 21. Opioid challenge experiments using nociceptive measures show that these dosages of (-) naloxone invoked an opioid receptor blockade for no more than 10-12 hr/day. A dosage of 100 mg/kg (-) naloxone, which blocked the opioid receptor for 12-16 hr/day, did not alter body weight in comparison to control levels. In subsequent experiments, 40 mg/kg (-) naloxone depressed body weight of 21-day-old rats, and the wet weights of the liver, spleen, thymus, heart, and triceps surae muscle from these animals were subnormal. A dosage of 40 mg/kg (+) naloxone did not alter growth. These results show that opioid action in regard to growth is stereospecific and dependent on the duration of opioid receptor blockade, providing additional evidence that endogenous opioid systems play an important role in developmental events.

Topics: Animals; Animals, Newborn; Body Weight; Dose-Response Relationship, Drug; Female; Male; Naloxone; Organ Size; Pain Measurement; Rats; Rats, Inbred Strains; Reaction Time; Receptors, Opioid; Stereoisomerism

This study examines the effect of sustained sucrose consumption on the development of tolerance to morphine analgesia (20 mg/kg IP injections) and subsequent, naloxone-precipitated withdrawal (2 mg/kg IP). Food intakes are also measured. Sprague-Dawley rats were allowed ad lib access to a 20% sucrose solution in addition to their normal diet. Pain thresholds and intakes were monitored for two weeks, then morphine tolerance was induced, followed by precipitated withdrawal. Tolerance was assayed by the tailflick method, and withdrawal was gauged by weight loss. The animals given access to sucrose developed lowered pain thresholds prior to tolerance induction relative to those of control animals, but they failed to exhibit any differences from controls in tolerance development of severity of withdrawal. The induction of tolerance first decreased, then increased sucrose consumption and steadily decreased chow consumption. Naloxone-precipitated withdrawal decreased chow consumption, but failed to affect the ingestion of the sucrose solution. It is concluded that changes in opioid function caused by sustained sucrose-feeding are insufficient to affect the development of tolerance to morphine analgesia; however, tolerance induction biphasically alters sucrose consumption.

Topics: Analgesia; Animals; Body Weight; Dietary Carbohydrates; Drug Tolerance; Feeding Behavior; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Sucrose; Time Factors

The effects of a single morphine pellet (75 mg) implanted in developing male rats at 27 days of age on reproductive endocrine parameters were compared to those found in adult (65-day-old) animals after the same treatment. The pellets were left in place to provide the release of morphine during critical phases of puberty and sexual maturation and to prevent an abrupt withdrawal syndrome upon pellet removal which would confound our results. Developing rats were sacrificed at representative intervals after pellet insertion to assess the development of key indices of reproductive endocrinology; adult rats were sacrificed at the same time intervals to permit an evaluation of age-related differences in the sensitivity to opiate-induced endocrine disturbances. Our results showed that morphine markedly influenced a number of endocrine parameters associated with the maturation of the hypothalamic-pituitary-gonadal axis in developing rats for prolonged periods of time, whereas the effects of the opiate in the adult rat were relatively modest and transient. In the developing rat, serum luteinizing hormone (LH), testosterone, the wet tissue weights of the seminal vesicles and testes and hypothalamic LH-releasing hormone (LHRH) levels were substantially depressed immediately after pellet implantation and these effects persisted for up to 4 weeks when compared to placebo-implanted, age-matched controls. In contrast to these results, adult rats showed only transient effects (less than 1 week) of morphine on certain reproductive endocrine parameters (e.g., serum LH, testosterone and the weights of the seminal vesicles) and no effects on others (e.g., testes weights and hypothalamic LHRH).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Age Factors; Animals; Body Weight; Gonadotropin-Releasing Hormone; Hypothalamo-Hypophyseal System; Luteinizing Hormone; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Seminal Vesicles; Testis; Testosterone

Beef cows were used to determine if suckling influences release of LH via endogenous opioids at 28 +/- 4 d after parturition. Cows of similar weight and body condition (6.8 +/- .1, 1 = emaciated, 9 = obese) were assigned randomly to five groups (n = 6 to 7): 1) control-suckled/saline (suckled 15 min every 6 hr for 48 hr); 2) control-suckled/naloxone; 3) calf-removal/saline (calf removal for 52 hr); 4) calf-removal/naloxone; and 5) control-suckled/GnRH (Gonadotropin-Releasing Hormone). At 0 hr, saline was administered to all cows. This treatment was continued at 6 hr intervals for 24 hr. Either naloxone (0.5 mg/kg), GnRH (40 ng/kg) or saline was administered to cows in their respective groups every 6 hr during the ensuing 24-hr period in calf-removal groups, or immediately preceding each suckling episode in the control-suckled groups. Blood samples for analysis of luteinizing hormone (LH) were collected at 15-min intervals for 1 hr prior to and 3 hr after treatment at 0, 24, 36 and 48 hr. Cows were observed for estrus twice daily. All cows in the control-suckled/GnRH group released LH (P less than .05) in response to exogenous GnRH, indicating the presence of releasable quantities of the gonadotropin. Mean concentrations of LH were not effected (P greater than .05) by the control-suckled regime. However, calf-removal alone, or in combination with naloxone, increased (P less than .05) mean concentrations of LH by 48 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anestrus; Animals; Body Weight; Cattle; Endorphins; Female; Gonadotropin-Releasing Hormone; Kinetics; Lactation; Luteinizing Hormone; Naloxone; Postpartum Period; Pregnancy; Radioimmunoassay; Reference Values

Recent studies suggest that opioid peptides may influence the secretion of pituitary gland hormones. Since obese patients often show impaired growth hormone (GH), prolactin (PRL) and cortisol responses to stimuli and raised beta endorphin levels, the opioid regulation of such hormone secretion could be different from that in normal weight subjects. In order to verify this hypothesis we studied the effect of iv naloxone, an opiate receptor antagonist, on GH, PRL and cortisol response to insulin-induced hypoglycemia in 9 obese female subjects. Seven normal weight females were used as control group. A control test using saline showed that the PRL and GH responses to insulin stress were impaired in obese subjects, whereas no difference was seen in the cortisol response. Naloxone did not modify the PRL and GH response but provoked a rise in the cortisol response in both obese and normal weight subjects. These findings suggest that while the opioid peptides do not play an important role in regulating the GH and PRL response to insulin hypoglycemia, they influence the cortisol response. In obese patients the impairment in GH and PRL response to stimuli cannot be related to alterations in opioid peptide regulation.

Topics: Adolescent; Adult; Blood Glucose; Body Weight; Female; Growth Hormone; Humans; Hydrocortisone; Insulin; Middle Aged; Naloxone; Obesity; Prolactin

Various alterations of the immune system have recently been reported to attenuate the severity of morphine withdrawal. The effect of the immunosuppressive agent ciclosporine A on the naloxone-induced morphine withdrawal syndrome in the chronically dependent mouse was investigated. Ciclosporine A significantly suppressed stereotyped behaviour such as jumping and forepaw treading while wet shakes were potentiated. Withdrawal diarrhoea was diminished as a consequence of a promotive action of ciclosporine A on the intestine. A ciclosporine derivative, which is devoid of immunosuppressive activity, had no influence on withdrawal signs. The attenuating effect of ciclosporine A was observed at a dose of 20 mg/kg i.p., which is not regarded as immunosuppressive in the mouse. It was also effective in animals lacking an intact immune system as a result of a genetic T-cell defect (nude mouse) or after selective ablation by whole body irradiation. Nude mice and irradiated normal mice developed dependence on morphine to the same extent as normal animals, as could be derived from the severity of their withdrawal signs. These results suggest that an intact immune system is not a necessary prerequisite for ciclosporine A to attenuate morphine withdrawal and that its action may be attributable to mechanisms other than immunosuppression. It is possibly a result of a direct effect of ciclosporine A on the central nervous system structures involved in the behavioural expression of the opiate withdrawal syndrome.

Topics: Animals; Body Temperature Regulation; Body Weight; Cyclosporins; Diarrhea; Female; Immune System; Mice; Mice, Nude; Morphine; Naloxone; Stereotyped Behavior; Substance Withdrawal Syndrome; Time Factors

We investigated the effects of thiorphan, a selective inhibitor of endopeptidase 24.11 'enkephalinase', kelatorphan ((R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)-L-alanine), and RB 38 A ((R)-3-(N-hydroxycarboxamido-2-benzylpropanoyl)-L-phenylalanine) two almost complete inhibitors of enkephalin metabolism, on the naloxone-precipitated morphine withdrawal syndrome in rats. Inhibitors administered intracerebroventricularly reduced several symptoms of the withdrawal syndrome. Jumping, chewing and tooth chattering were decreased by all drugs. The rise in plasma corticosterone and the hypothermia were reduced by kelatorphan and RB 38 A whereas rhinorrhea was blocked by thiorphan, tremor by kelatorphan and diarrhoea by RB 38 A. Other signs remained unchanged. These data suggest that an increase in opioid receptor occupancy by endogenous opioid peptides, protected from biotransformation specially by mixed inhibitors reduced the severity of the morphine abstinence symptoms in rats.

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Corticosterone; Dipeptides; Hydroxamic Acids; Injections, Intraventricular; Male; Morphine Dependence; Naloxone; Neprilysin; Phenylalanine; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Thiorphan

Chronic subcutaneous infusion with a low dose (0.5 mg/kg/h) of naloxone via minipumps blocked the antinociceptive action of the mu-agonist, morphine, without affecting that of the kappa-agonist, U50488H. This dose resulted in a transient suppression in the rate of body weight gain and a sustained reduction in daily food intake (FI) and water intake (WI): this decrease was seen in both the light and dark phases. Naloxone also resulted in a reduction in resting core temperature (TC) in the light but not the dark phase. It did not affect the weight loss or hypothermia which accompanied 24 h food and water deprivation. Naloxone did, however, suppress FI and WI following deprivation and inhibited the recovery of body weight thereafter. The influence of naloxone upon FI, WI, TC and body weight was dose-dependent over 0.05-0.50 mg/kg/h. Increasing the dose to 3.0 mg/kg/h eliminated the antinociceptive action of U50,488H revealing a blockade of kappa- (in addition to mu-) receptors. This higher dose was not more effective in reducing FI, WI, body weight and TC than 0.5 mg/kg/h. Further, treatment with MR 2266, an antagonist (or weak partial agonist) with a higher activity at kappa-receptors than naloxone, was not more effective than naloxone in reducing FI, WI and body weight: further, it did not affect TC. Moreover, chronic infusion of bremazocine, (a kappa-agonist and mu-antagonist) reduced WI, FI, body weight and TC by a magnitude comparable to that of naloxone. Finally, chronic infusion of the mu-agonist, sufentanyl, led to a sustained rise in TC. It is concluded, that: (1) mu-opioid receptors may play a major role in the modulation of daily FI and WI and of body weight in freely behaving rats: this action is expressed in both the light and dark phases of the cycle and maintained following deprivation. The data provide no evidence for (but do not exclude) a particular role of kappa-receptors. (2) mu-Receptors play a physiological role in the modulation of TC in the light but not the dark phase of the daily cycle.

Topics: Animals; Benzomorphans; Body Temperature Regulation; Body Weight; Circadian Rhythm; Drinking Behavior; Feeding Behavior; Fentanyl; Male; Naloxone; Pain; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, mu; Sufentanil

We have previously reported that female obese Zucker rats are hypersensitive to painful stimuli and are resistant to the analgesic effects of morphine. In continuation we hypothesized that these phenomena are possibly the result of diminished population of opioid receptors, or an overabundance of dynorphin interfering with morphine analgesia. We now report that female obese Zucker rats have decreased concentrations of mu opioid receptors in whole brain and elevated levels of Dynorphin A(1-8) (DYN) in a brain area known to be associated with responses to nociceptive stimuli.

Topics: Animals; Body Weight; Brain; Dynorphins; Female; Hypothalamic Area, Lateral; Hypothalamus, Middle; Naloxone; Peptide Fragments; Periaqueductal Gray; Radioligand Assay; Rats; Rats, Zucker; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

1. The antinociceptive effects of [D-Arg2] dermorphin tetrapeptide analogues, H-Tyr-D-Arg-Phe-Gly-NH2 and H-Tyr-D-Arg-Phe-beta-Ala-OH when administered subcutaneously (s.c.) in rats were measured by the tail-flick test. In addition, the appearance of typical withdrawal signs upon cessation of administration or on subsequent treatment with naloxone were measured after chronic administration of either peptide or morphine. 2. The dose of peptides and of morphine in the physical dependence test was determined from the AD50 to inhibit the tail-flick test in rats. Doses from 4 to 64 times the AD50 doses were employed in the s.c. administration schedules. 3. The intensity of the antinociception induced by either peptide was greater than that produced by morphine. Moreover, the antinociception induced by the peptides was of much longer duration than that produced by morphine. 4. Abrupt withdrawal after chronic administration of either peptide produced only slight loss of body weight. In contrast, morphine withdrawal produced sharp loss of body weight. 5. Naloxone precipitated withdrawal signs after chronic administration of either peptide were less intense than those after chronic morphine. 6. These results suggest that the antinociception produced by these peptides is more intense and of longer duration than that produced by morphine. It is also interesting to note that the physical dependence produced by these peptides is less marked than that produced by morphine.

Topics: Analgesics; Analgesics, Opioid; Animals; Body Weight; Drinking; Eating; Male; Morphine Dependence; Naloxone; Oligopeptides; Rats; Rats, Inbred Strains; Reaction Time; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

The effects of 60 min pretreatment with the enkephalinase inhibitor acetorphan were assessed on naloxone-precipitated (2.5 mg/kg IP) abstinence in chronically morphinized rats. In addition, the antinociceptive activity of the compound was investigated in mice. Intraperitoneal injection (50 mg/kg) in rats attenuated some aspects of the opioid withdrawal syndrome such as burrowing, wet dog shakes, squeal on touch hostility, tachypnoea, ptosis and rough hair, whereas jumping and escape behaviour were significantly increased in acetorphan-treated animals. No effect was observed on withdrawal hypothermia or acute weight loss. Similarly, chronic dosing with acetorphan after withdrawal produced no significant effect on body weight. Acetorphan (50 mg/kg IP) failed to produce any antinociceptive activity in the mouse tail immersion test, but potentiated the antinociceptive effect of D-Ala2-D-Leu5-enkephalin. These results are discussed in terms of acetorphan crossing the blood-brain barrier before being hydrolysed to thiorphan, thus yielding opioid withdrawal relieving effects.

Topics: Amino Acids, Sulfur; Analgesics; Animals; Body Temperature; Body Weight; Male; Metalloendopeptidases; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Neprilysin; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Thiorphan; Tiopronin

We have studied effects of an opioid antagonist, naloxone (NLX) on rat brain development. Newborn rats were given daily subcutaneous injection of 1 or 50 mg/kg NLX from birth until weaning (day 21). The 28 day-old rats were examined their brain development. Both doses of NLX reduced the cerebral and cerebellar weights of rats but the body weight loss was significant only in the higher dose (50 mg). However, there were neither morphological changes in the central nervous system nor movement disorders such as abnormal gait and involuntary movements in naloxone treated rats (NLX-rats). We found that serotonin content was decreased significantly in the cerebral cortex and medulla while it was significantly increased in the pons and striatum of NLX-rats. Noradrenaline was decreased significantly in the medulla while it was increased in the pons of the NLX-rats. In contrast, the concentrations of these monoamines did not show any changes in cerebellum and hippocampus of NLX-rats. On the other hand, thyrotropin-releasing hormone (TRH) was significantly decreased in cerebellum and hippocampus of NLX-rats, while it did not show any changes in cerebral cortex, medulla and pons of NLX-rats. These observations suggest that the neurotransmitters influencing the brain development, which are modulated by endogenous opioid systems, may play an important role in the development of rat brain; monoaminergic neurons play a significant role in the development of the cerebrum while TRH containing neurons may be involved in that of the cerebellum.

Topics: Animals; Body Weight; Brain; Cerebellum; Medulla Oblongata; Naloxone; Norepinephrine; Organ Size; Pons; Rats; Rats, Inbred Strains; Serotonin; Thyrotropin-Releasing Hormone

Clonidine, an alpha-2-adrenergic agonist, suppresses signs of opiate withdrawal in animals and in man. Electrical or chemical stimulation of the nucleus locus coeruleus (LC) increases noradrenergic activity and brain concentration of the noradrenergic metabolite MHPG, and produces many signs of opiate withdrawal. Thus, clonidine's ability to attenuate withdrawal might be due to the reduction of noradrenergic neuronal activity originating in the LC, but additional alpha-2-adrenergic receptors throughout the body and other mechanisms may also play a role. The present study explored the neuroanatomical and pharmacological selectivity of alpha-2-adrenergic receptors of the LC in the anti-withdrawal action of clonidine. Experiment 1 tested the hypothesis that behavioral and biochemical measures of naloxone-precipitated withdrawal from morphine would be blocked by infusions of clonidine (0.6 or 2.4 micrograms/microliters) into the LC. Significant reductions were observed in the occurrence of diarrhea, ptosis, weight loss and wet-dog shakes. Clonidine also reversed the naloxone-precipitated increase in hippocampus MHPG concentration. In experiment 2 subjects received an LC infusion or IP injection of a non-lipophilic alpha-2-agonist (ST-91), which does not penetrate the blood-brain barrier, or of clonidine into the dorsal parabrachial nucleus (DPB) to test the selectivity of the effects of clonidine infusions into the LC. ST-91 infusions into the LC reduced several of the observed withdrawal signs and increased others (e.g., jumping). Although peripheral injections of ST-91 attenuated some of the checked signs associated with naloxone-precipitated withdrawal, the frequency of wet-dog shakes was not reduced. ST-91 infusions into the LC, but not systemic ST-91 administration, prevented the withdrawal-induced increase in hippocampus MHPG concentration. Clonidine infused lateral to the LC into the DPB did not significantly attenuate withdrawal or reduce hippocampus MHPG levels. These results provide behavioral and biochemical evidence to support the suggestion that clonidine significantly attenuates naloxone-precipitated withdrawal through an interaction with noradrenergic neurons located in the vicinity of the LC.

Topics: Animals; Behavior, Animal; Body Weight; Brain Chemistry; Clonidine; Hippocampus; Injections; Locus Coeruleus; Male; Methoxyhydroxyphenylglycol; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

The effects of prenatal administration of phencyclidine (PCP) on the learning and memory processes of rat offspring were investigated at doses below the level for producing malformations. The offspring prenatally treated with PCP (10 or 20 mg/kg) on days 7 to 17, as well as on days 7 to 21 of gestation, showed disruption of the acquisition of passive avoidance response and pole-climbing avoidance response at the ages of 4 and 7 weeks, respectively. The brain weight of the offspring prenatally treated with PCP was significantly decreased. These results suggest that prenatal PCP administration impairs learning and memory processes of passive and active avoidance tasks and that more attention should be given to the developmental toxicity of PCP.

Topics: Animals; Avoidance Learning; Body Weight; Brain; Female; Learning; Memory; Naloxone; Organ Size; Phencyclidine; Physostigmine; Piperidines; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Ritanserin

The effects of two enantiomers of diltiazem (l-cis and d-cis) on naloxone-precipitated morphine abstinence after acute morphine dependence were evaluated in vivo in mice and in vitro in isolated pieces of rat terminal ileum. d-cis-diltiazem (10-40 mg/kg) produced a dose-dependent inhibition of the jumping and body weight loss induced by naloxone in acutely morphine dependent mice. By contrast, l-cis-diltiazem 40 mg/kg did not significantly inhibit jumping and produced a much lower inhibition of body weight loss than the same dose of d-cis-diltiazem. In addition, d-cis-diltiazem (0.01-1 microM) produced a concentration-dependent inhibition of naloxone-induced contracture in morphine dependent ilea, whereas l-cis-diltiazem, even at 1 microM, did not inhibit this contracture. These results suggest that calcium channels may play a similar role in naloxone-precipitated morphine abstinence in vivo and in vitro.

Topics: Animals; Body Weight; Diltiazem; Dose-Response Relationship, Drug; Female; Ileum; In Vitro Techniques; Mice; Morphine Dependence; Muscle Contraction; Muscle, Smooth; Naloxone; Rats; Rats, Inbred Strains; Stereoisomerism; Structure-Activity Relationship

To determine whether endogenous opiates mediate hyperactivity in food restricted hamsters and serotonergic fibers innervating the hippocampus mediate hypoactivity in obese hamsters, food restriction and high-fat diet supplementation were used to produce significant body fat changes (8 vs. 21%). The levels and pattern of spontaneous running were examined after IP saline or naloxone HCl (20 mg/kg) and following the infusion of vehicle and 5,7-dihydroxytryptamine creatine sulfate (4 micrograms/2 microliters) into rostromedial septum of mature female hamsters. Septum-medial preoptic area (POA), hippocampus, hypothalamus, and cortex were dissected from the three groups as well as from two additional groups of hamsters receiving vehicle or neurotoxin. Concentrations of serotonin, norepinephrine, and dopamine were measured in these tissues by HPLC method. Fat-fed hamsters were hypoactive relative to food-restricted hamsters. Naloxone had no significant effect on running behavior. Serotonin neurotoxin increased the running activity of fat-fed hamsters to the level displayed by control hamsters by increasing the number of runs, the total activity level, the speed of running and by decreasing the duration of pauses. Neurotoxin led to selective deletion of serotonin in the hippocampus (77%) and parietal cortex (50%). Serotonergic fibers innervating the hippocampus thus appear to mediate the hypoactivity that is induced by dietary obesity in mature hamsters. Since serotonin mediates some other manifestations of aging, and slow weight increases characterize mid-portion of hamster life span, we hypothesize that serotonergic mediation of hypoactivity is another manifestation of aging.

Topics: 5,7-Dihydroxytryptamine; Aging; Animals; Body Weight; Brain Chemistry; Cricetinae; Dietary Fats; Dihydroxytryptamines; Dopamine; Fasting; Female; Hippocampus; Mesocricetus; Motor Activity; Naloxone; Norepinephrine; Obesity; Serotonin

1. The cardiovascular responses to acute myocardial ischaemia were studied in opiate-dependent animals before and after 2 weeks morphine withdrawal. 2. Rats were treated with morphine sulphate in drinking water for 2, 3 or 5 weeks. The development of morphine tolerance and dependence was verified by the tail-immersion test for analgesia and the naloxone-precipitated withdrawal syndrome, respectively. 3. Acute left coronary artery ligation induced a decrease in blood pressure, a slight increase in heart rate and ventricular tachycardia or fibrillation in anaesthetized naive rats. 4. Chronic morphine treatment did not alter the haemodynamic responses to coronary artery ligation. However, a significantly lowered incidence, and prolonged time of onset, of ventricular arrhythmias was found in 3 and 5 week morphine-treated rats. This phenomenon did not occur in animals receiving morphine for 2 weeks and in a 3 week morphine-treated group which was subsequently withdrawn for 2 weeks. 5. It is suggested that the decreased occurrence of early ventricular arrhythmias resulting from acute myocardial ischaemia in chronic morphine-treated rats may be related to the degree of opiate tolerance and dependence.

Topics: Animals; Blood Pressure; Body Weight; Coronary Disease; Coronary Vessels; Drug Tolerance; Heart Rate; Hemodynamics; Male; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Tachycardia; Ventricular Fibrillation

Morphine dependence was induced by treatment with morphine-admixed food (0.25mg/g of food) for 7 days. Withdrawal was precipitated by injecting naloxone (0.5mg/kg, s.c.). Rats treated with morphine exhibited body weight loss upon the naloxone injection. When morphine-dependent rats were injected subcutaneously with morphine, codeine, meperidine and pentazocine 30 min before the naloxone injection, these drugs significantly suppressed the naloxone-precipitated loss of body weight in a dose-dependent manner. However, body weight loss induced through coadministration of naloxone and Mr-2266 BS were not suppressed by morphine pretreatment. These results suggest that opioids protect against naloxone-precipitated loss of body weight, and that mu and kappa opiate receptors play an important role in the protection against naloxone-precipitated withdrawal.

Topics: Animals; Benzomorphans; Body Weight; Codeine; Male; Meperidine; Morphine; Naloxone; Pentazocine; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

1. Acutely, opioids inhibit oxytocin secretion. To study the responses of oxytocin neurones during chronic opioid exposure, forty-five lactating rats were infused continuously from a subcutaneous osmotically driven mini-pump via a lateral cerebral ventricle with morphine sulphate solution from day 2 post-partum for 5-7 days; the infusion rate was increased 2- or 2.5-fold each 40 h from 10 micrograms/h initially up to 50 micrograms/h; controls were infused with vehicle (1 microliter/h, twenty-eight rats) or were untreated (eight rats). 2. Maternal behaviour was disrupted in 27% of the morphine-treated rats; in rats that remained maternal morphine did not affect body weight or water intake but increased rectal temperature by 0.82 +/- 0.14 degrees C (mean +/- S.E.M.) across the first 4 days. 3. Weight gain of the litters of maternal morphine-treated rats was reduced by 32% during 7 days, predominantly in the first day of treatment when milk transfer was also reduced. Observation of pup behaviour during suckling showed decreased frequency of milk ejections on only the second day of morphine treatment. Plasma concentration of prolactin after 6 days was similar in maternal morphine-treated and control rats, but reduced by 90% in non-maternal morphine-treated rats, indicating normal control of prolactin secretion by suckling in morphine-treated rats. 4. Oxytocin and vasopressin contents, measured by radioimmunoassay, in the supraoptic and paraventricular nuclei and in the neurohypophysis were similar between fourteen maternal morphine-treated, twelve vehicle-treated and eight untreated lactating rats; thus exposure to morphine did not involve increased production and storage of oxytocin. 5. Distribution of [3H]morphine infused intracerebroventricularly into six virgin female rats for 6 days was measured by scintillation counting of tissue extracts. Morphine concentration in the hypothalamus and neurohypophysis was 2.7 and 12.8 micrograms/g, respectively, and in blood plasma 0.75 micrograms/g. Tolerance was not due to failure of morphine infusion. In addition, naloxone (5 mg/kg s.c.) provoked typical withdrawal reactions ('wet dog' shakes, defaecation, burrowing) in lactating rats infused with morphine for 5 days. 6. Pups were suckled onto seven maternal morphine-infused and five vehicle-infused rats anaesthetized with urethane for recording of intramammary and arterial blood pressures after treatment for 5 days. The incidence and pattern of milk ejections, and m

Topics: Animals; Body Weight; Carbachol; Cerebral Ventricles; Drug Tolerance; Female; Infusions, Parenteral; Lactation; Maternal Behavior; Milk Ejection; Morphine; Morphine Dependence; Naloxone; Neurons; Oxytocin; Pregnancy; Rats

1. We have tested the hypothesis that the pressor action of (-) naloxone HC1 after haemorrhage is due to antagonism of endogenous opiate mechanisms that are activated by haemorrhage, rather than to some more direct vasoconstrictor action of the drug. 2. Six conscious rabbits were treated intravenously with either naloxone (4 mg kg-1, then 0.1 mg kg-1 min-1) or equivalent volumes of saline. In unbled rabbits the naloxone regimen had no effect except to cause a transient bradycardia. After each treatment the rabbits were bled at a rate of 2.45 ml kg-1 min-1 until blood pressure fell to 40 mmHg or 28 ml kg-1 of blood had been withdrawn (17-24 ml kg-1 after saline, 21-28 ml kg-1 after naloxone). 3. Throughout both episodes of bleeding there was a progressive fall of cardiac output and rise of heart rate, at rates that were constant and independent of the prior treatment. 4. After saline treatment, bleeding at first resulted in a steep and progressive fall of systemic vascular conductance and a small fall in blood pressure. However, when blood loss exceeded 12.7 ml kg-1 (approximately 28% of blood volume) there was an abrupt rise in systemic vascular conductance and an abrupt fall in blood pressure. 5. After naloxone treatment, during the entire period of bleeding systemic vascular conductance fell steeply and blood pressure fell slowly. 6. The different effects of saline and naloxone on the haemodynamic responses to acute blood loss were not explicable by differences in haematocrit or net blood volume. 7. We conclude that endogenous opiate mechanisms are responsible for the abrupt vasodilation that occurs when more than 28% of blood volume is withdrawn rapidly from conscious rabbits. We suggest that these mechanisms reside in the central nervous system.

Topics: Acute Disease; Animals; Blood Pressure; Blood Volume; Body Weight; Heart Rate; Hematocrit; Hemodynamics; Hemorrhage; Naloxone; Rabbits; Sodium Chloride; Vascular Resistance

A comparison of the effects of the short-acting opioid antagonist naloxone, with the irreversible and highly-specific mu-1 antagonist naloxonazine, has categorized the mediation of opioids in some forms of feeding into mu-1 and non-mu-1 components. The mu-1 sites have been implicated in free-feeding, deprivation-induced feeding and morphine-induced hyperphagia, based upon their sensitivity to both naloxone and naloxonazine. However, the ability of naloxone, but not naloxonazine to inhibit feeding, induced by either 2-deoxy-D-glucose glucoprivation, ethylketocyclazocine, dynorphin or (D-ala2., D-leu5.)-enkephalin implies the existence of non-mu-1 opioid receptor mechanisms in these responses. The present study compared the effects of the daily administration of naloxone and naloxonazine (10 mg/kg, i.v.) in rats in three different types of maturational or dietary situations. In adult rats, naloxonazine and naloxone significantly reduced body weight (7% and 4%, respectively) and food intake (21% and 13%, respectively) over 14 days. These effects were more pronounced in adolescent rats where naloxonazine and naloxone significantly reduced the gain in body-weight (53% and 33%, respectively) and food intake (24% and 15%, respectively) over 14 days. In the adolescent rats, the effects of naloxonazine were significantly greater than those of naloxone. In contrast, chronic treatment with neither naloxone nor naloxonazine altered body weight or food intake of rats made obese by dietary manipulations and left on that diet during treatment with antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Animals; Appetite Depressants; Body Weight; Feeding Behavior; Male; Naloxone; Rats; Rats, Inbred Strains

Environmental exposure to toxic levels of lead occurs in a number of industries with potential adverse effects on the reproductive capacity of exposed men. Using a rat model, we previously reported that dietary exposure to lead resulted in suppressed spermatogenesis and testosterone levels without significant changes in luteinizing hormone (LH). In this study, to identify more specifically the site of lead's toxic actions on the hypothalamic-pituitary-testicular axis, the response of lead-treated male rats as compared to control animals to naloxone, gonadotropin-releasing hormone (GnRH), and LH stimulation was studied. Three groups of 52-day-old Wistar rats were allowed access to either deionized distilled water containing no lead acetate or a 0.3% lead acetate solution for 30 days. In each study group, 10 control and 10 lead-treated animals were anesthetized prior to cardiac puncture and collection of serum for the measurement of lead level and baseline LH (Groups I and II) or testosterone levels (Group III). In Group I, 20 min after an i.p. injection of naloxone (1.5 mg/kg/BW), the animals were killed by decapitation, and serum was collected for LH measurement. Thirty minutes after an i.p. injection of GnRH (100 ng/100 gm BW), Group II animals were killed by decapitation, and serum was collected for LH. Sixty minutes after an injection of LH (100 mg/100 mg BW), serum was collected from Group III animals for testosterone measurement. All control animals and lead-treated animals consumed similar volumes of water. Control animals had undetectable levels of lead in their blood. Lead-treated animals had mean blood lead values of 30 micrograms/dl +/- 5 micrograms/dl.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Hypothalamo-Hypophyseal System; Lead; Luteinizing Hormone; Male; Naloxone; Organometallic Compounds; Pituitary Hormone-Releasing Hormones; Rats; Rats, Inbred Strains; Testis; Testosterone

The effect of improving diabetic control on secondary hypogonadotropic amenorrhea was investigated in patients with insulin-dependent diabetes mellitus (IDDM). Second, the hypothesis that increased central (hypothalamic) opiate inhibition may have been responsible for the suppression of gonadotropin-releasing hormone (GnRH) was tested by observing the effect of a four-hour naloxone infusion (1.4 mg/hour) on serum gonadotropin levels. All known causes of secondary amenorrhea were excluded before patients were eligible for the study. The median duration of amenorrhea was six years, and median body weight was 101 percent of ideal. After six months of improved metabolic control (n = 5) using intensified conventional therapy or continuous subcutaneous insulin infusion, the level of glycosylated hemoglobin dropped from 11.8 +/- 0.9 percent to 8.5 +/- 0.5 percent (p less than 0.005), and body weight increased from 60.5 +/- 1.8 kg to 64.7 +/- 1.4 kg (p less than 0.02). Menses did not, however, return in any patient. There was no significant change in serum levels of estradiol, progesterone, dihydroxyepiandrosterone, testosterone, prolactin, basal or GnRH-stimulated luteinizing hormone, or follicle-stimulating hormone. There was no change in the levels of luteinizing hormone or follicle-stimulating hormone during the naloxone infusion either during poor metabolic control or after six months of improved metabolic control. In conclusion, a form of secondary hypogonadotropic amenorrhea was identified in patients with IDDM that did not remit with sustained improvements in metabolic control. It did not appear to be mediated through increased central opiate tone.

Topics: Adult; Amenorrhea; Body Weight; Diabetes Mellitus, Type 1; Female; Gonadotropins, Pituitary; Humans; Naloxone; Pituitary Hormone-Releasing Hormones

Effects of the dietary carbohydrate-to-fat ratio on opiate-stimulated eating and on naloxone-, cholecystokinin- and bombesin-suppressed eating were examined. Rats were fed either a high carbohydrate (cornstarch) diet (68% of energy from carbohydrate and 12% from fat), an intermediate diet (40% carbohydrate and 40% fat) or a high fat (corn oil and lard) diet (3% carbohydrate and 77% fat). Other rats self-selected from the high carbohydrate and high fat diets. Subcutaneous administration of naloxone, an opiate antagonist, generally suppressed intake of the high fat diet to a greater extent than intake of the high carbohydrate diet. Neither cholecystokinin octapeptide nor bombesin (administered intraperitoneally) exerted preferential suppression of fat intake. The opiate agonists ketocyclazocine and butorphanol tartrate administered subcutaneously at 1000 h preferentially, although not exclusively, stimulated intake of the high fat diet in a dose-dependent manner during the 6-h feeding trial. Repeated daily subcutaneous injections of butorphanol tartrate caused rats to consume more than 50% of their daily intake during the 6-h period postinjection; intake during the normal night feeding period was suppressed to maintain total daily intake equal to that of vehicle-injected rats. We conclude that stimulation of the opioid feeding system contributes to the overeating often associated with consumption of a high fat diet.

Topics: Animals; Body Weight; Bombesin; Butorphanol; Cyclazocine; Dietary Carbohydrates; Dietary Fats; Eating; Energy Intake; Ethylketocyclazocine; Food Preferences; Male; Naloxone; Rats; Rats, Inbred Strains; Sincalide

The effects of acute and chronic morphine treatment on glucose tolerance were investigated in mice. In acute experiments, a single dose of morphine (20 mg/kg i.p.) increased the serum and muscle glucose level. After glucose loading (1.5 g/kg), the rate of increase and the peak of serum glucose concentration were significantly lowered in morphine-treated mice, while the availability and the half-life of glucose were similar to those of controls. In morphine-dependent mice, the fasting serum and muscle glucose levels were similar to those of control but the liver glucose was significantly greater. After glucose loading the rate of increase in serum glucose level was faster and the availability of glucose was 10% greater than that in naive mice. Again, there was no difference in the half-life of serum glucose between naive and morphine-dependent mice.

Topics: Animals; Blood Glucose; Body Weight; Glucose; Glucose Tolerance Test; Half-Life; Male; Mice; Mice, Inbred ICR; Morphine; Morphine Dependence; Naloxone; Substance Withdrawal Syndrome

It is well documented that opioids and sex steroids modify body temperature in the rat. We have previously reported that the temperature responses to naloxone in the morphine-dependent rat was more pronounced in the female than in the male rat. In addition, ovariectomy but not castration resulted in altered temperature responses in the morphine-dependent rat, which suggests a role for estrogen in modifying the temperature responses. This study was designed to evaluate the effect of sex steroid hormones on the surge in tail skin temperature associated with administration of naloxone to morphine-dependent female rats. Ovariectomized female rats were treated with estrogen (0.5 mg pellet), progesterone (5 mg pellet), or the combined therapy for 21 days. Administration of naloxone to these morphine-dependent rats resulted in a 5.9 +/- 0.5 degrees C rise in tail skin temperature in the placebo control rats and 5.7 +/- 0.5 degrees C in the progesterone-treated group; there was a significantly reduced elevated in tail skin temperature of 3.1 +/- 1.0 degrees C and 2.9 +/- 1.0 degrees C in the and estrogen-progesterone treated groups. Body weights also were significantly depressed in the estrogen-treated groups. In a subsequent study, the effects of several doses of chronic estrogen treatment were evaluated (0.1-50 mg pellets). The elevation of tail skin temperature in response to administration of naloxone to morphine-dependent rats was significantly reduced at all doses of estrogen when compared with placebo-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Estradiol; Female; Morphine; Naloxone; Ovariectomy; Progesterone; Rats; Skin Temperature; Substance-Related Disorders

The effects of two calcium channel blockers (verapamil and flunarizine) were evaluated on the naloxone-precipitated syndrome in morphine-dependent rats. The withdrawal signs in saline-treated rats were mainly diarrhea, body weight loss, jumping and ptosis. On i.p. administration, verapamil and flunarizine prevented diarrhea and body weight loss but not jumping. Verapamil also reduced the incidence of ptosis at the highest dose tested (40 mg/kg). Administered i.c.v., 160 micrograms verapamil reduced the body weight loss and the number of jumps without modifying diarrhea or ptosis. The results show that calcium channel blockers inhibit morphine abstinence syndrome manifestations through both peripheral and central mechanisms.

Topics: Animals; Body Weight; Brain; Calcium Channel Blockers; Clonidine; Diarrhea; Flunarizine; Injections, Intraventricular; Male; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome; Verapamil

The effects of chronic infusion of porcine relaxin on oxytocin release were studied in lactating rats. Infusion of relaxin (4.2 micrograms/h for either 4 or 6 days) suppressed reflex milk ejection and reduced litter weight gain for 48 h compared with saline-infused controls. After 2 days, neither the rate of growth nor the frequency of milk ejection were significantly different from controls. For 24 h after the infusion of relaxin ended, litters gained weight more quickly than controls but there was no difference seen in the frequency of milk ejection. The effects on oxytocin release of stopping an infusion of relaxin after 3 days were investigated. There was a significant (P less than 0.01) rise in plasma oxytocin (up to 90 pmol/l) 30 min after the infusion was stopped, followed by a sustained rise in intramammary pressure. Treatment of relaxin-infused rats with naloxone (0.1 mg/kg) when the infusion was halted caused a more rapid release of oxytocin (within 2 min), a greater release of oxytocin (up to 140 pmol/l) and a prolonged rise in intramammary pressure.

Topics: Animals; Body Weight; Female; Lactation; Mammary Glands, Animal; Milk Ejection; Naloxone; Oxytocin; Pregnancy; Pressure; Rats; Relaxin

Sexual differences in body weight of juvenile thirteen-lined ground squirrels (Spermophilus tridecemlineatus) were significant (P less than 0.05) at all weeks of age except weeks 0-4, 6, 7, 9, 20 and 24. Hibernation onset between sexes did not differ significantly. Naloxone administration did not alter weight gain nor onset of hibernation when compared to saline controls.

Topics: Animals; Body Weight; Female; Hibernation; Male; Naloxone; Sciuridae; Sex Factors; Time Factors

The dose-response relationship of neonatal (days 1-7) administration of beta-endorphin (BE) and corticotropin-releasing factor (CRF) on body weight, eye opening, response to thermal pain, and concentrations of plasma and adrenal corticosterone were measured in developing rat pups. At the highest dose (50 micrograms/pup), neonatal CRF reduced body weight, while 10 and 50 micrograms/pup accelerated eye opening. In addition, a reduction in concentration of plasma and adrenal corticosterone was correlated with the dose of neonatal CRF, whereas adrenal weights were not altered. BE produced none of these effects, but 1, 10 and 50 micrograms/pup on days 1-7 significantly reduced baseline latencies in a novel water-bath tail-flick test on day 9. These same animals showed reduced numbers of brain opiate receptors on day 14. The results indicate that peptide administration during the sensitive neonatal period can alter the development of physiological processes that will later be influenced by the peptide.

Topics: Analgesia; Animals; Animals, Newborn; Body Weight; Brain Chemistry; Corticosterone; Corticotropin-Releasing Hormone; Dose-Response Relationship, Drug; Endorphins; Male; Naloxone; Nociceptors; Rats; Rats, Inbred Strains; Receptors, Opioid

The binding of [3H]quinuclidinyl benzilate (QNB) to various brain regions was determined in rats after acute or chronic treatment with morphine. Morphine and naloxone, in vitro, inhibited the binding of [3H]QNB to striatal membranes only at high concentrations. Thirty minutes after a single injection, morphine (5 or 40 mg/kg s.c.) did not alter the Bmax or Kd values for [3H]QNB binding to striatal receptors. The binding of [3H]QNB to membranes of different brain regions was not changed in morphine tolerant-dependent rats or rats undergoing abrupt or naloxone precipitated withdrawal. The results suggest that central cholinergic muscarinic receptors are unaffected by acute or chronic treatment with morphine, or during abstinence.

Topics: Animals; Body Temperature; Body Weight; Brain Chemistry; Corpus Striatum; Drug Implants; In Vitro Techniques; Kinetics; Male; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Substance Withdrawal Syndrome

The rate of development of dependence to morphine was studied in female rats which were given increasing concentrations of morphine sulphate in their drinking fluid (5% sucrose solution). The occurrence of physical dependence was determined by the naloxone-precipitated withdrawal syndrome at various times during the 3-week experimental period. It was found that a significant degree of the withdrawal syndrome precipitated by naloxone was evident at 24 hr after starting administration of morphine; the syndrome reached its greatest intensity after the rats had received the opiate for 7 days. This study shows that dependence on morphine can be induced in rats by administration of the opiate in drinking fluid for a period shorter than 7 days.

Topics: Animals; Body Weight; Female; Injections, Intraperitoneal; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Time Factors

Spontaneously diabetic (db/db) and nondiabetic (db/m+, m+/m+) C57BL/KsJ mice were made dependent by a 9-day exposure to increasing doses of morphine-admixed food. Radioimmunoassay for morphine demonstrated that diabetic mice had significantly greater brain accumulations of morphine than nondiabetic littermates after morphine-admixed food. Despite their greater brain levels of morphine, diabetic mice showed significantly fewer behavioral signs of withdrawal after naloxone, and lost significantly less weight at 60 min after naloxone than their nondiabetic littermates. Streptozotocin-diabetic and nondiabetic rats rendered dependent by a 6-day i.p. infusion of morphine had equal brain levels of morphine, but the diabetic rats showed significantly fewer behavioral signs of withdrawal than nondiabetic rats at 24 and 48 hr after the end of the infusion. These results indicate that spontaneously diabetic mice and streptozotocin-diabetic rats were both significantly less physically dependent upon morphine than their respective nondiabetic controls and support our conclusion that the development of physical dependence upon morphine is reduced in experimental models of diabetes.

Topics: Animals; Body Weight; Brain Chemistry; Diabetes Mellitus, Experimental; Female; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

It has been reported that pregnancy produces an opioid-mediated, endogenous analgesia in the rat. In an attempt to confirm this finding, we used 5 different analgesic measures to compare the responsiveness of pregnant and non-pregnant female rats to painful stimuli. Pregnant and non-pregnant rats differed only when assessed by measures that were highly correlated with body weight. Furthermore, the reduced pain responsiveness of pregnant rats was not prevented by administration of the opioid antagonists, naloxone or naltrexone. We can find no evidence for an endogenous analgesia of pregnancy; instead, our results suggest that findings of a diminished response to painful stimuli in pregnant rats may be an artifact related to the greater body mass/weight of the pregnant animals.

Topics: Animals; Body Weight; Endorphins; Female; Naloxone; Naltrexone; Pain; Postpartum Period; Pregnancy; Pregnancy, Animal; Rats; Rats, Inbred Strains; Sensory Thresholds

The male C57BL/6 mice used in this study were the offspring either of untreated or lead treated (0.1% lead acetate (PbAc) instead of drinking water) parents. Offspring of lead treated parents were reared on 0.1% PbAc until weaning, and also given 0.5% PbAc to drink for 3 weeks prior to testing (Pb2 group). Offspring of untreated parents were either given 0.5% PbAc to drink (Pb1 group) or maintained on tap water throughout (Control group). Control (C) and lead treated mice were subdivided according to single- or group-housing; no confrontation ("unfought") or confrontation with a trained aggressor mouse ("defeated"). All the mice were then given a hot-plate pain test, in which paw-lick and escape latencies were recorded. In untreated mice, latencies were reduced after defeat. This effect was not seen in lead treated animals. Lead treatment increased latencies in most instances relative to the appropriate control group. The paw-lick latencies were less consistently affected than the escape latencies. Escape latencies, with one exception, were longer in the Pb2 group than in the Pb1 group. Treatment with naloxone of single-housed C and Pb2 was without effect, except for Pb2 treated undefeated mice: here, naloxone abolished the analgesic effect of lead treatment. Lead-induced analgesia is discussed in terms of central mechanisms of pain reception.

Topics: Animals; Body Weight; Dominance-Subordination; Endorphins; Escape Reaction; Housing, Animal; Lead; Male; Mice; Mice, Inbred C57BL; Naloxone; Organometallic Compounds; Pain; Reaction Time; Social Isolation

The plasma concentrations of morphine and glucose, the body weight, and the severity of the naloxone-precipitated withdrawal syndrome were studied in female rats in which morphine dependence was induced by administration of the opiate, with or without sucrose, in their drinking water. It was found that sucrose encouraged the animals to consume more morphine and that the initial plasma concentrations of the opiate, as well as the rate of development of physical dependence, were higher than the group not given sucrose. Plasma glucose concentrations, maximum plasma morphine levels and the maximum severity of the naloxone-precipitated withdrawal syndrome were, however, not significantly different between the two groups. The findings suggest that both regimens of administering the opiate in drinking fluid are effective in inducing morphine dependence in rats; the addition of sucrose tends to speed up the development of physical dependence, probably by increasing intake of the opiate through consuming more sucrose solution.

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Feeding Behavior; Female; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Self Administration; Substance Withdrawal Syndrome; Sucrose

Uremia results in a decrease in food intake. In the present study we investigated whether opiates known to stimulate feeding would alter food intake in rats made uremic by 1 and 5/6 nephrectomy. Morphine increased food intake in sham nephrectomized rats, but failed to alter food intake in uremic animals and depressed the ingestion of rat chow in a group of weight restricted rats. Butorphanol tartrate increased feeding in sham and uremic animals but did not alter intake in the weight restricted group. Higher doses of butorphanol were needed to stimulate feeding in the uremic rats compared to the sham group, suggesting a relative resistance to opioid-induced feeding in the uremic rats. The opiate antagonist, naloxone, suppressed food intake in the uremic and sham groups more effectively than in the weight restricted rats. These data suggest that the opioid feeding system functions in a reduced fashion in uremic rats, but probably is not the sole factor involved in producing the anorexia associated with uremia.

Topics: Animals; Anorexia; Body Weight; Butorphanol; Endorphins; Feeding Behavior; Male; Morphinans; Morphine; Naloxone; Rats; Rats, Inbred Strains; Uremia

Mice were rendered physically dependent by repeated administration of morphine, 25 mg/kg s.c., 5 times daily for 4 days, and on the 5th day, 2 h after the last morphine dose, they were challenged with a s.c. injection of either naloxone, 25 mg/kg, or the peripherally selective opioid antagonist SR 58002 C (N-methyl levallorphan mesilate), 75 mg/kg. Naloxone provoked jumping and diarrhea in all the animals; mice challenged with SR 58002 C presented no significant jumping but a high frequency of withdrawal diarrhea. When naloxone, 12 mg/kg, or SR 58002 C, 50 mg/kg, were given s.c. in combination with repeated morphine as above, mice which had received naloxone with morphine presented virtually no diarrhea or jumping upon naloxone challenge; those repeatedly treated with morphine plus SR 58002 C were substantially protected from naloxone-precipitated diarrhea, but not jumping. These results further support the remarkable selectivity for peripheral opioid receptors of SR 58002 C, even after repeated high-dose treatment, and are strongly consistent with the primary role of a local intestinal mechanism in the development and expression of opioid withdrawal diarrhea in mice. The in vivo dissociation of central and peripheral components of dependence on morphine is illustrated, apparently for the first time.

Topics: Animals; Body Weight; Diarrhea; Levallorphan; Mice; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome

The characteristics of an analog of tetrapeptide dermorphin (H-Tyr-D-Arg-Phe-Sar-OH), [D-Arg2, Sar4]-dermorphin (1-4) were examined in comparison with morphine by the appearance of typical withdrawal signs upon cessation of administration or treatment with naloxone, an opioid antagonist. The dose of [D-Arg2, Sar4]-dermorphin (1-4) or morphine in the physical dependence test can be quantified by determining the ED50 to inhibit the tail-flick response to thermal stimuli. Doses from 8 to 64 times the ED50 doses were employed in the subcutaneous injection schedules. The cessation of [D-Arg2, Sar4]-dermorphin (1-4) or naloxone treatment was largely without effect on body weight, in contrast to a marked loss of weight in morphine-dependent rats. The tetrapeptide failed to substitute for morphine in morphine-dependent rats. The physical dependence of [D-Arg2, Sar4]-dermorphin (1-4) was revealed by the behavioral signs of withdrawal precipitated by naloxone. However, the scores of lacrimation, diarrhea and urination were much lower in chronically tetrapeptide-treated rats than in morphine-treated rats, though the score of teeth chatter was higher. These findings indicate that [D-Arg2, Sar4]-dermorphin (1-4) may differ from morphine in physical dependence.

Topics: Analgesics; Animals; Body Weight; Drinking; Eating; Male; Morphine; Naloxone; Narcotics; Oligopeptides; Rats; Rats, Inbred Strains; Reaction Time; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

We have examined the effect on feeding of opioid blockade with naloxone in two species which demonstrate a marked seasonality in their feeding patterns, the racoon (Procyon lotor) and the woodchuck (Marmota monax). Naloxone suppressed food intake in the woodchuck which is a true hibernator. Naloxone failed to suppress food intake in the racoon and, in fact, enhanced intake of a preferred sucrose solution. In the racoon, ir-dynorphine concentrations were extremely high in the hypothalamus compared to the values obtained in rats and woodchucks. We suggest that possible explanations for the lack of responsiveness to opiates in racoons may be their extremely high daily food intake relatively to body mass when compared to woodchucks and rats and the high levels of ir-dynorphin may be sufficient to overcome the inhibitory effect of naloxone. These studies stress the occurrence of species diversity in the response to opioid antagonism.

Topics: Animals; Body Weight; Drinking; Eating; Endorphins; Hibernation; Male; Marmota; Naloxone; Raccoons; Receptors, Opioid; Seasons; Taste

Twenty-eight hours of endorphin receptor blockade by subcutaneous naloxone infusion produced behavioral and respiratory symptoms resembling opiate abstinence syndrome. Rats were implanted subcutaneously with two Alzet osmotic minipumps delivering 0.7 mg/kg per hour naloxone or with two control minipumps containing distilled water only. They were observed for 10 minutes under blind conditions at 16 and 28 hours post-implantation. The naloxone-infused rats showed significantly more wet dog shakes, abdominal writhes and overall abstinence-like symptoms than did the control rats. These symptoms decreased after 28 hours despite continued naloxone infusion. Acute administration of naloxone failed to produce abstinence-like symptoms, even when combined with the trauma of carrying two implanted water-filled minipumps for 28 hours. In another experiment, naloxone-infused rats showed a highly significant 53.4% elevation of O2 consumption over water-infused control rats in a pure O2 atmosphere at 28 hours after implantation. This difference disappeared at 48 hours post-implantation. In contrast to the effect of naloxone infusion, acute administration of three different doses of naloxone failed to significantly increase O2 consumption.

Topics: Animals; Behavior, Animal; Body Weight; Disease Models, Animal; Humans; Male; Naloxone; Narcotics; Oxygen Consumption; Rats; Rats, Inbred Strains; Receptors, Opioid; Substance Withdrawal Syndrome

Young and mature, genetically obese and non-obese, spontaneously hypertensive rats (SHR) were injected with saline (controls) or naloxone for 12 weeks. Naloxone stilled the hyperphagia to a normal intake in the obese SHR (Obese/SHR) so that young Obese/SHR did not develop their usual massive obesity and mature Obese/SHR that had become massively obese were reduced to leanness. The naloxone-treated young, obese and non-obese SHR (controls) exhibited marked reduction of the weight of their pituitary and adrenal glands, whereas the pituitary and adrenal glands of naloxone-treated mature, obese and non-obese/SHR were greatly increased in weight. The elevated systolic blood pressure of the obese and non-obese rats was reduced after chronic treatment with naloxone. Naloxone treatment caused reduction of blood ACTH, corticosterone, and beta endorphin levels but elevated growth hormone levels. The characteristic hyperinsulinemia, hyperlipidemia, hyperglycemia, elevated BUN levels, and the Cushingoid spectrum of degenerative changes found in Obese/SHR did not appear in naloxone-treated rats.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; beta-Endorphin; Blood Pressure; Body Weight; Corticosterone; Cushing Syndrome; Disease Models, Animal; Endorphins; Female; Growth Hormone; Male; Naloxone; Obesity; Organ Size; Pituitary Gland; Rats; Rats, Inbred SHR; Rats, Inbred Strains

The effects of thyrotropin releasing hormone (TRH) were compared with two of its analogs, L-N-(2-oxopiperidine-6-yl-carbonyl)-L-histidyl-L-thiazolidine-4-carbo xam ide (MK-771) and gamma-butyrolactone-4-carboxyl-histidyl-prolineamide (DN-1417) on the abrupt and naloxone-precipitated abstinence symptoms in morphine-dependent male Swiss-Wester mice. Mice were made physically dependent on morphine by subcutaneous implantation for 3 days of a pellet containing 75 mg morphine free base. Control mice were implanted with placebo pellets. Intracerebral administration of TRH (10 ng-10 micrograms per mouse) immediately after removal of placebo pellets had no effect on the basal temperature of mice. Mice implanted with morphine pellets exhibited a characteristic hypothermic response following the removal of the pellets. TRH at all doses employed prevented the hypothermia observed during abrupt withdrawal of morphine (pellet removal). DN-1417 and MK-771 (10 ng-10 micrograms per mouse) on the other hand produced a short lived hyperthermic response in mice from which placebo pellets had been removed. However, both TRH analogs produced long-lasting antagonism of withdrawal hypothermia in mice from which morphine pellets had been removed. TRH and its analogs had no effect on the body weight loss observed during abrupt withdrawal of morphine. Intracerebral administration of 10 micrograms TRH and its analogs inhibited the naloxone-induced jumping response as evidenced by increases in naloxone ED50 values to elicit this response. It is concluded that TRH and its analogs may be useful in combating some of the withdrawal symptoms in opiate-dependent subjects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anticonvulsants; Body Temperature; Body Weight; Male; Mice; Morphine Dependence; Naloxone; Substance Withdrawal Syndrome; Thiazolidines; Thyrotropin-Releasing Hormone; Time Factors

With the aim of examining central opioid influences on the control of luteinizing hormone (LH) secretion, we evaluated the LH response to naloxone, an opioid receptor antagonist, in patients affected by normo-, hyper-, and hypogonadotropic amenorrhea, polycystic ovarian disease and hyperprolactinemia. The results indicate that opioid influences are altered in well-defined pathologic conditions (hyperprolactinemia, obesity), in addition to being modified by gonadal steroids.

Topics: Adenoma; Adolescent; Adult; Amenorrhea; Body Weight; Female; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Luteinizing Hormone; Menstruation Disturbances; Naloxone; Oligomenorrhea; Ovary; Pituitary Neoplasms; Prolactin

The effect of several drugs on food intake has been examined in two strains of rats, one (S 5B/P1) which is resistant to developing obesity when eating a high fat diet, and one (Osborne-Mendel) which readily develops obesity when eating the same diet. Insulin and 2-deoxy-D-glucose increased food intake in a dose dependent manner in both S 5B/P1 and Osborne-Mendel rats. However, the S 5B/P1 rats showed a greater response, with a shorter latency period, to both agents than did the Osborne-Mendel rats. Conversely, d-amphetamine at the higher doses produced a dose dependent suppression of food intake with maximal suppression being similar for both strains. At a lower dose, however, d-amphetamine significantly increased food intake in the Osborne-Mendel rats, but not in the S 5B/P1 rats. The S 5B/P1 rats were also slightly more sensitive to the anorexic effects of lower dose adenosine than were the Osborne-Mendel rats whereas the reverse was true following higher dose adenosine. Naloxone suppressed food intake equally in both strains and D-glucose did not alter food intake in either strain. These studies identify three drugs, all stimulatory, to which the two strains of rat respond differently.

Topics: Adenosine; Animals; Appetite; Body Weight; Deoxyglucose; Dextroamphetamine; Eating; Female; Glucose; Insulin; Naloxone; Rats; Rats, Inbred Strains

LHRH (median eminence) and LH (pituitary and plasma) from male and female Sprague-Dawley rats were assayed 1 month after streptozotocin injection and compared with values in controls either fed ad libitum or offered a restricted diet. Plasma LH was also assayed after stimulation with exogenous LHRH or naloxone. In diabetic males, the median eminence LHRH content and the plasma LH response to exogenous LHRH were unaltered, pituitary LH was increased, and plasma LH was decreased under basal conditions and after naloxone treatment. In diabetic females, while the median eminence LHRH content and the plasma LH response to exogenous LHRH or naloxone were reduced, pituitary and plasma LH levels were not different. Measurements made in undernourished rats excluded the possibility that the alterations found in diabetic animals were nutrition dependent. In parallel experiments, hypothalami and pituitaries were examined morphologically. In diabetic animals, degenerate axons, mainly of the LHRH type, were found in the arcuate nucleus and median eminence, and LH gonadotrophs were altered and more numerous. Strong differences between control males and females were revealed by morphometry; moreover, diabetic females had higher brain weights and fewer LH gonadotroph changes than diabetic males. These studies indicate that 1) the hypothalamo-pituitary changes that occur early in our streptozotocin-treated rats are unrelated to undernourishment and are possibly caused by insulin deficiency; 2) the LHRH axonal lesions might play a primary pathogenic role in the hypothalamo-pituitary disorder; 3) some anatomical data indicate that the brain and pituitary are less severely affected by diabetes in female than in male animals; and 4) differences between control males and females may account for some of the dissimilarities between the sexes observed under diabetic conditions.

Topics: Animals; Biometry; Body Weight; Diabetes Mellitus, Experimental; Female; Food Deprivation; Gonadotropin-Releasing Hormone; Hypothalamus; Luteinizing Hormone; Male; Microscopy, Electron; Naloxone; Organ Size; Pituitary Gland; Rats; Rats, Inbred Strains; Sex Factors

Six pigeons, trained to peck a response key on a fixed-ratio 20 schedule of food reinforcement, were used to examine the effects of morphine, naltrexone, and dextrorphan, before, during, and after chronic treatment with increasing doses of morphine (10.0-100.0 mg/kg/day). Tolerance developed to the rate-decreasing effect of the daily maintenance doses of morphine within 2 days of each dose increase. A small amount of tolerance to morphine and supersensitivity to naltrexone was evident within the 1st week of morphine treatment (10.0 mg/kg/day). Continued administration of morphine (32.0-100.0 mg/kg/day) produced further tolerance to morphine and supersensitivity to naltrexone, as evidenced by a 5-fold increase in the dose of morphine, and 1,000-fold decrease in the dose of naltrexone, necessary to suppress responding. By the 4th week of treatment (100.0 mg/kg/day), a modest tolerance had also developed to the rate-decreasing effects of dextrorphan. Suppression of responding by naltrexone, but not morphine or destrorphan, was accompanied by a loss in body weight over the 1- to 2-h session in morphine-maintained pigeons; both weight loss and reduced response rates also occurred on termination of morphine treatment. Sensitivity to the rate-decreasing effects of morphine and naltrexone was near normal within 10 days following termination of morphine treatment. The dramatic changes in sensitivity to naltrexone and morphine produced by daily morphine injections, as well as the ability to generate complete dose-effect curves within a single session, indicate that this behavioral preparation may provide sensitive concurrent measures of narcotic tolerance and supersensitivity to antagonists in the pigeon.

Topics: Animals; Behavior, Animal; Body Weight; Columbidae; Conditioning, Operant; Dextrorphan; Dose-Response Relationship, Drug; Drug Tolerance; Morphinans; Morphine; Naloxone; Naltrexone; Stereoisomerism

The ontogeny of spontaneous motor and sensorimotor behaviors of preweaning rats, as well as ambulation, emotionality, and nociception at weaning (day 21), were studied in rats given chronic administration of 1 or 50 mg/kg naltrexone from birth to day 21. The age at which a specific spontaneous motor behavior or performance initially appeared and the age at which 100% of the animals demonstrated a particular behavior were accelerated in animals given 50 mg/kg naltrexone, but delayed in rats injected with 1 mg/kg naltrexone. In general, ambulation, emotionality, and nociceptive responses were not affected by naltrexone treatment, although the frequency of face-washing in both naltrexone groups and activity cage performance in the 50 mg/kg naltrexone group deviated from control levels. Observations of head-shake and wet-dog shake behaviors in naltrexone-treated animals at 2 hr and 10 hr post-drug injection were similar to controls with the exception of an abnormal increase in the 1 mg/kg naltrexone group at 10 hr. Although these results may imply that endogenous opioid systems play a role in regulating neurobehavioral development, further study is needed to distinguish whether these changes are a consequence of the somatic and morphological alterations known to occur with naltrexone administration or if the timetable of behavioral ontogeny is governed by endorphin-opiate receptor interaction.

Topics: Animals; Behavior, Animal; Body Weight; Female; Male; Motor Activity; Naloxone; Naltrexone; Nervous System; Nociceptors; Psychomotor Performance; Rats; Rats, Inbred Strains; Reflex; Time Factors; Weaning

Clonidine, an alpha 2 adrenergic agonist, has analgesic properties and recently has been used to suppress opiate withdrawal. These two properties theoretically make it a suitable analgesic substitute in patients tolerant to opioids. The objectives of this study were to see if intrathecal clonidine is analgesic and whether it can modify morphine withdrawal at the spinal level. Rats chronically implanted with catheters in the lumbar subarachnoid space were utilized. In analgesia experiments, intrathecal clonidine produced analgesia with the peak effect in the paw-lick test occurring at 200nM, and in the tail-flick test analgesia was apparent at 100 nM and peaked at 400 nM (in 10 microL Ringer's lactate). In dependency experiments, animals dependent on morphine (300 mg X kg-1) received intrathecal clonidine 25, 50, 200 nM in 10 microliter Ringer's lactate 72 h after morphine. Following this, a naloxone challenge, 3 mg X kg-1 was administered and withdrawal assessed. Clonidine-treated animals showed significant weight loss and decrease in temperature, and those treated with high doses showed marked hypothermia and hind-limb flaccidity. Intrathecal clonidine prevented the hyperalgesia associated with opiate withdrawal but did not affect the occurrence of the majority of behavioral signs (e.g., piloerection, irritability) associated with morphine withdrawal. Intrathecal clonidine prevented the naloxone-induced increase in blood pressure during withdrawal and in animals not treated with morphine-produced hypotension. Thus, intrathecal clonidine is analgesic, and part of the antiwithdrawal action of clonidine may be exerted at the spinal level.

Topics: Analgesics; Anesthesia, Spinal; Animals; Blood Pressure; Body Temperature; Body Weight; Clonidine; Humans; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

Morphine-dependent rats can be trained to discriminate between s.c. injections of saline and 0.1 mg/kg of naltrexone. The discriminative effects of naltrexone, measured by the number of trials completed on the naltrexone-appropriate choice lever in a 20-trial avoidance paradigm, derive from stimuli associated with morphine withdrawal. Opiate and nonopiate drugs were injected s.c. and examined for their ability to block naltrexone-induced discriminative effects and loss of body weight in morphine-dependent rats. Seven opiates blocked dose dependently the discriminative effects of naltrexone and loss of body weight. Potency ranged from fentanyl (330 X morphine) to meperidine (less than 1 X morphine); effects were stereoselective for levorotatory isomers. Loperamide, an opiate that does not readily enter the brain, blocked loss of body weight but not discriminative effects, suggesting that discriminative effects are mediated centrally. Nonopiate behavioral depressants, diazepam, haloperidol and pentobarbital, did not substantially affect either dependent variable, but clonidine (0.01-1.0 mg/kg) blocked discriminative effects of naltrexone partially and weight loss completely. The blockade by morphine (30 mg/kg) of naltrexone-induced discriminative effects and weight loss was surmounted by increasing the dose of naltrexone whereas the blockade by clonidine (0.1 mg/kg) was not. Thus, blockade by opiates of effects of naltrexone appears to be due to a competitive interaction at the mu opioid receptor; clonidine has a different mechanism of action. This discrimination paradigm may afford a specific animal model for studying fundamental processes underlying physical dependence on opiates and for evaluating novel pharmacologic approaches for treating opiate withdrawal in humans.

Topics: Animals; Body Weight; Clonidine; Haloperidol; Humans; Male; Morphine Dependence; Naloxone; Naltrexone; Narcotics; Rats; Rats, Inbred Strains; Stereoisomerism; Substance Withdrawal Syndrome

Relationship between withdrawal time or naloxone injection time and withdrawal signs were examined in morphine-treated rats. Sixty-five rats were treated chronically with morphine-admixed food (1 mg/g food) for 7 days and were divided into 13 groups. The rats of 4 groups were abruptly withdrawn from morphine, and the rats of another 4 groups were given naloxone (3 mg/kg, s.c.) at 20:00 on the 8 th day and 2:00, 8:00 and 14:00 on the 9 th day after the morphine administration, respectively. Withdrawal signs were observed at intervals of 2 hr. After each naloxone injection, abnormal behaviors were observed for 60 min, and body weight was measured for 3 hr at intervals of 15 or 30 min. In the withdrawal test, weight loss at 24 hr after withdrawal in each group was approximately 10%, and there was no difference between each group. However, the body weight of non-treated rats and morphine-treated rats increased during the night period (20:00-8:00) and decreased during the daytime (8:00-20:00). Therefore, body weight reached the minimum at 20:00, and then this time is appropriated for withdrawal. In the naloxone test, withdrawal signs in the night period were more potent than that in the daytime. The withdrawal signs induced by naloxone at 8:00 showed the maximum magnitude. Plasma morphine levels in rats treated with morphine-admixed food were high in the night period and low in the daytime. These results suggest that the magnitude of naloxone-precipitated withdrawal signs depends on the amount of morphine in the plasma.

Topics: Animals; Body Weight; Humans; Male; Morphine; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Time Factors

The relationship between arousal and efficiency of the brain is shown by the inverted U of the Yerkes-Dodson curve. Measuring arousal has been difficult because the three types of arousal (EEG, behaviour and autonomic) do not change in unison. From Magoun's work, arousal can be stimulated via the reticular formation or from parts of the cortex. Kyotorphin (Tyr-Arg) causes widespread excitation when applied to the cortex and may represent this mechanism: it is then inhibited only by noradrenaline. The hippocampus causes stimulation of arousal to persist after the exciting stimulus stops and can itself be stimulated into long term potentiation. The latter may be related to the onset of compulsive behaviour which appears to occur only with excessive stimulation of arousal. The opioid dynorphin is the main stimulator of the hippocampus and can cause long term potentiation. Inhibition of opioid activity by continuous naloxone infusion facilitates weight gain in anorexia and in some will abolish the compulsive drive. Other opioid antagonists need to be found for the more severe compulsive behaviour patients.

Topics: Anorexia Nervosa; Arousal; Body Weight; Brain; Compulsive Behavior; Electroencephalography; Endorphins; Energy Metabolism; Hippocampus; Humans; Naloxone; Reticular Formation; Sleep Stages

We have previously found that saline drinking increases fighting in male pairs and decided to test this treatment (0.9% NaCl for 24 hours before test day 1; SAL) on social behaviour of both males and females. Paired C57BL/6 mice (same-sex pairs) were observed in the open field in daily sessions for three days. One member of each pair (test mouse) was given either SAL treatment, a control injection of saline (SI), an injection of naloxone (1 mg/kg IP; NLX) or a combination of both treatments (NLX + SAL). NLX alone had previously been found to increase aggression in resident/intruder tests at the dose used. Open field testing is not associated with aggressive encounters in our experience. SAL had little effect on (unaggressive) social behaviour in males, but increased social contact seeking in females. The NLX and NLX + SAL treatments had essentially the same effects, irrespective of sex; the treated animals showed behavioural inhibition (reduced social and ambulatory behaviour), while their untreated partners showed significantly more than normal interest in the naloxone treated mice. The results are discussed in terms of opioid involvement in social behaviour.

Topics: Animals; Body Weight; Electrolytes; Female; Male; Mice; Mice, Inbred C57BL; Motor Activity; Naloxone; Sex Factors; Social Behavior; Sodium Chloride

Preweaning rats receiving daily injections of 20, 50, or 100 mg/kg naltrexone, a potent opiate antagonist, had body and brain weights that were increased 16-22% and 6-13%, respectively, from control levels on day 21 (weaning). All of these dosages of naltrexone blocked the opiate receptor for 24 hr/day as measured in opiate challenge experiments. Dosages of 0.1, 1, and 10 mg/kg naltrexone, which blocked the opiate receptor for less than 12 hr/day, inhibited growth. Repetitive administration of low dosages (3 mg/kg naltrexone, 3 times daily), which blocked the receptor 24 hr/day, increased body and brain development by 31% and 10%, respectively, whereas a cumulative dosage of 9 mg/kg naltrexone given once daily retarded growth. These results show that developmental events are dictated by the duration of opiate receptor blockade and provide compelling evidence that endogenous opioid systems play a crucial role in growth.

Topics: Aging; Animals; Body Weight; Brain; Female; Male; Naloxone; Naltrexone; Organ Size; Rats; Rats, Inbred Strains; Receptors, Opioid

Increased pituitary and plasma concentrations of opioid peptides in genetically obese rodents may be a cause or consequence of obesity. It has been shown that food intake is decreased more in adult genetically obese rats and mice than lean rats and mice by administration of naloxone, an opiate antagonist. Evidence for an opiate-mediated component in the development of rather than the consequence of obesity would be provided if young, not yet obese, genetically obese rats were more sensitive than lean rats to naloxone. In the present experiment two groups of male and female obese and lean Zucker rats, fasted for 2 hr before the onset of the dark portion of the 12-hr light-dark cycle, were administered 0.125 to 0.5 mg/kg naloxone or 0.5 to 2.0 mg/kg naloxone subcutaneously and 30- and 60-min food intakes were measured. In the group administered the lower doses of naloxone, obese rats of the three ages tested responded more than the lean rats after 30 min (70 vs. 79% of control, p less than 0.02). However, increased sensitivity occurred during the 0-60 min period in rats 4-5 weeks old and 0-30 min period in rats 8-9 and 12-13 weeks old. In the second group tested with the higher doses, the obese responded less than the lean rats (73 vs. 66% of control, p less than 0.05) and there was no difference in response after 0-60 min (66 vs. 61% of control, NS). Thus, increased sensitivity to threshold doses of naloxone occurs before the development of substantial obesity and therefore opiate peptides may play a causal role in obesity.

Topics: Aging; Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Female; Male; Naloxone; Rats; Rats, Zucker; Receptors, Opioid; Sex Factors; Weaning

Topics: Animals; Body Weight; Estrus; Female; Luteinizing Hormone; Naloxone; Naltrexone; Pregnancy; Rats; Rats, Inbred Strains; Receptors, Opioid; Reproduction

Prolyl-leucyl-glycinamide (PLG) at a low dose (10 ng/mouse) administered by an intracerebroventricular (i.c.v.) injection did not affect levorphanol analgesia, but PLG at higher doses (10 and 100 micrograms/mouse) and alpha-melanocyte-stimulating hormone (alpha-MSH) (10 ng/mouse) antagonized levorphanol analgesia. Development of levorphanol tolerance was facilitated by 10 ng/mouse of PLG, unaffected by 10 micrograms/mouse of PLG, but antagonized by 100 micrograms/mouse of PLG and 10 ng/mouse of alpha-MSH. The effect of PLG on levorphanol dependence was assessed by changes in body weight and temperature during naloxone-induced withdrawal. PLG (10 ng/mouse) facilitated the development of levorphanol dependence, but 10 micrograms/mouse of PLG had no effect. PLG (100 micrograms/mouse) antagonized development of levorphanol dependence. PLG at doses of 10 and 100 micrograms/mouse precipitated withdrawal in levorphanol-dependent mice. alpha-MSH (10 ng/mouse) antagonized development of levorphanol dependence as evidenced by an increase in the ED50 of naloxone required to induce withdrawal jumping. These results indicate that PLG and alpha-MSH affected levorphanol-induced analgesia, tolerance and dependence in a qualitatively similar manner to their effect on morphine-induced analgesia, tolerance and dependence.

Topics: Analgesia; Animals; Body Temperature; Body Weight; Dose-Response Relationship, Drug; Drug Tolerance; Humans; Levorphanol; Male; Melanocyte-Stimulating Hormones; Mice; MSH Release-Inhibiting Hormone; Naloxone; Substance Withdrawal Syndrome; Substance-Related Disorders

Prolyl-leucyl-glycinamide (PLG) at a low dose (10 ng/mouse) administered intracerebroventricularly (i.c.v.) did not affect morphine analgesia, but produced a greater increase in the ED50 of morphine-pretreated (100 mg/kg of morphine sulfate) mice as compared to control mice. PLG at doses of 10 and 100 micrograms/mouse antagonized morphine analgesia. Development of morphine tolerance was unaffected by 10 micrograms/mouse but antagonized by 100 micrograms/mouse of PLG. Development of morphine dependence was assessed by changes in body weight and temperature during naloxone-induced withdrawal. PLG (10 ng/mouse) potentiated, 10 micrograms/mouse had no effect and 100 micrograms/mouse antagonized development of morphine dependence. PLG at doses of 10 and 100 micrograms/mouse precipitated withdrawal in morphine-dependent mice. When mice were pretreated with 1.0 mg/kg naloxone i.p. 15 min before PLG, all doses of PLG had no effect on morphine analgesia, but potentiated the development of morphine tolerance and dependence. None of the doses of PLG altered whole brain levels of morphine. PLG did not alter the affinity of opioid receptors for etorphine or the maximal number of binding sites but PLG did exhibit a very weak affinity for opioid receptors. These results indicate that PLG potentiated development of morphine tolerance and dependence through a mechanism not involving opioid receptors. However, at very high doses it was a weak opioid receptor antagonist.

Topics: Analgesia; Animals; Body Temperature; Body Weight; Brain Chemistry; Drug Tolerance; Etorphine; Humans; Kinetics; Male; Mice; Morphine; Morphine Dependence; MSH Release-Inhibiting Hormone; Naloxone; Reaction Time; Receptors, Opioid

Although chronic administration of naloxone has been reported to reduce food intake and body weight in rats, there have been no comparable investigations using a nonhuman primate. We examined the effects of repeated injections of two long acting opiate antagonists - naltrexone and diprenorphine - on the ad libitum intake of a nutritional complete liquid diet and on body weight in squirrel monkeys. Naltrexone binds with highest affinity to the mu opioid receptor whereas diprenorphine binds with equally high affinity to several subtypes of opioid receptor. Diprenorphine (ED50 = 0.01 mg/kg) was 22 times more potent than naltrexone (ED50 = 0.22 mg/kg) in decreasing 2 h food intake, suggesting that more than one opioid receptor subtype may be involved in the anorectic effects of opiate antagonists. A 1.0 mg/kg dose of drug reduced 24 h food intake by 50% and was associated with a weekly reduction in body weight of 4 and 5% for naltrexone and diprenorphine, respectively. Thus, in contrast with shorter time intervals, 24 h food intakes were similar for the two drugs, and this was associated with comparable body weight profiles. The decreases in food intake and body weight remained constant over the period of drug administration. Some monkeys showed profuse salivation and "wet dog shakes" after 4 days of treatment with the 1.0 mg/kg dose but not after 1 day. Therefore, opiate antagonists given chronically to monkeys reduced food intake and body weight in a dose-dependent manner with no evidence of tolerance to these effects.

Topics: Animals; Body Weight; Diprenorphine; Dose-Response Relationship, Drug; Drinking; Eating; Female; Humans; Male; Morphinans; Naloxone; Naltrexone; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Saimiri; Salivation

The effects of chronic naltrexone infusions on food intake and energy balance were examined in male rats. Animals were fed either Purina Chow, or chow plus a 32% sucrose solution. After one week of being maintained on these diets, animals were implanted (intrascapularly) with osmotic minipumps infusing either 200 micrograms/kg/hr naltrexone hydrochloride or saline. Sucrose + chow-fed animals exhibited increased O2 consumption, increased CO2 production and an elevation in the respiratory quotient (RQ) relative to chow-fed controls. When infused with naltrexone, sucrose + chow-fed animals decreased food intake and body weight gain. While chow-fed animals also suppressed food intake and body weight gain, these decreases were not as great as those observed in sucrose + chow-fed animals. As a function of naltrexone administration, both chow-fed and sucrose + chow-fed animals altered their metabolism as reflected by decreased RQ and adiposity as determined by skinfold measurements. In addition, sucrose feeding led to a hyperthermia which was reversed by naltrexone infusions. Thus, chronic naltrexone administration depressed appetite, reduced energy production and induced hypothermia in rats. As naltrexone is thought to block the endogenous opioid system, this suggests that the endorphins are involved in the regulation of food intake and thermogenesis.

Topics: Adipose Tissue; Animals; Body Temperature; Body Weight; Carbon Dioxide; Drinking Behavior; Energy Metabolism; Feeding Behavior; Infusions, Parenteral; Male; Naloxone; Naltrexone; Oxygen Consumption; Rats; Rats, Inbred Strains

Topics: Animals; Body Weight; Drug Tolerance; Humans; Methadone; Methadyl Acetate; Morphine; Naloxone; Rats; Reaction Time; Species Specificity; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

Although a possible role for endogenous opioids in the regulation of feeding behavior has been proposed, little direct information is available concerning the impact of long term opiate antagonist treatment on body weight. Therefore, the effect of chronic exposure to naloxone on body weight was examined in WKY and SHR rats. Since the affinity of opiate antagonists for the receptor is increased by the presence of sodium ions, body weight was also determined in animals receiving a diet containing either 0.48% or 4% sodium chloride. Naloxone does not affect body weight in either strain of animals fed a normal (0.48% NaCl, Purina) diet. However, WKY rats fed the diet elevated in sodium chloride showed an increase in body weight which is blocked by treatment with naloxone. In contrast, SHR rats fed this diet weighed less than control animals receiving the normal diet, and naloxone did not decrease their weights further. These results suggest that naloxone may impact on mechanisms which regulate body weight, but is not capable of decreasing weight below a set point in either WKY or SHR rats.

Topics: Animals; Body Weight; Diet; Drug Interactions; Female; Hypertension; Male; Naloxone; Rats; Rats, Inbred Strains; Sodium Chloride

Reproductive toxicology and teratology studies of naltrexone are reviewed. Naltrexone produced behavioral changes in rats at doses below those which affected body weight. Excitatory signs and increased production of seminal plugs occurred in male rats. Prolonged administration to female rats resulted in excitatory signs and impaired maternal activity. Estrus cycling and fertility were decreased in female rats at doses that depressed body weight gain. Higher doses given to pregnant rats for shorter periods of time did not impair fertility or produce embryo or fetal toxicity. In rabbits, there was no evidence of behavioral changes. The highest dosage administered produced transient weight depression and possibly increased resorption. These data are consistent with a report of transient changes in some normal men given single doses of naltrexone. These effects may be mediated via hypothalamic and pituitary mechanisms involved in the control of luteinizing hormone levels.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Estrus; Female; Fertility; Fetus; Humans; Male; Maternal-Fetal Exchange; Naloxone; Naltrexone; Pregnancy; Rabbits; Rats; Reproduction; Sex Factors; Sexual Behavior, Animal; Teratogens

A dose-response study of the effect of naloxone on schedule-induced drinking confirmed that this type of drinking is resistant to the opiate antagonist at doses which depressed drinking induced by water-deprivation, hypertonic saline and salbutamol. Naloxone also failed to reduce intake of saline solution in the presence of scheduled food presentation. The findings support the suggestion that schedule-induced drinking is regulated by a system of neural control which differs from that involved in deprivation and other forms of drinking. It would appear that opiate receptors do not play a part in the regulation of schedule-induced drinking.

Topics: Albuterol; Animals; Body Weight; Drinking Behavior; Drug Administration Schedule; Male; Naloxone; Rats; Rats, Inbred Strains; Saline Solution, Hypertonic; Water Deprivation

Although the morphine withdrawal syndrome has been well described in the rat, a syndrome having similar characteristics has not been demonstrated following chronic methadone treatment. In this study we describe the behavioral effects produced by naloxone (4 mg/kg sc) following 72 hours of continuous iv infusion of methadone, (12.2 micrograms/kg/min), morphine (12.2 to 97.9 micrograms/kg/min) or saline. The cessation of methadone or morphine but not saline treatment followed by naloxone resulted in graded signs including wet dog shakes, escape attempts, self-stimulation and body weight loss and quantal signs including diarrhea, ear blanching, exophthalmos, ptosis, tachypnea and teeth chattering. These results indicate that this mode of methadone administration produces physical dependence characterized by a morphine-like withdrawal syndrome in the rat.

Topics: Animals; Behavior, Animal; Body Weight; Escape Reaction; Humans; Male; Methadone; Morphine; Motor Activity; Naloxone; Rats; Rats, Inbred Strains; Self Stimulation; Substance-Related Disorders; Tremor

The drug-admixed food method was applied to ICR strain mice for studying development of physical dependence on morphine. Mice were treated with morphine-admixed food of increasing concentration (1, 2 and 3 mg/g food) every third day for 9 days. During the treatment, the mice did not show any signs of toxicity. Plasma and brain morphine levels were quantitatively related to the morphine concentration in drug-admixed food. The plasma morphine level showed a circadian rhythm, and the level was higher than 0.15 microgram/ml throughout the day. The morphine-treated mice manifested body weight loss, diarrhea and ptosis from 4 hr after morphine withdrawal and showed maximum body weight loss at 12 hr. In the naloxone-precipitated test, jumping and body shakes were observed in mice treated with morphine-admixed food (2 mg/g food) at least for 1 day. Moreover, in mice treated with morphine (2 mg/g food) for 3 days, marked jumping and body shakes and some writhing were observed after naloxone administration. These results suggest that the drug-admixed food method has advantages of easily and rapidly inducing the physical dependence on morphine in mice without causing toxicity and death.

Topics: Animal Feed; Animals; Body Weight; Brain; Feeding Behavior; Humans; Male; Mice; Mice, Inbred ICR; Morphine; Morphine Dependence; Naloxone; Substance Withdrawal Syndrome; Time Factors

The developmental process of physical dependence on codeine has been explored in rats treated with codeine-admixed food (0.5 mg/g food) during 1 to 7 days. In rats treated with codeine for more than 2 days, body weight loss was markedly observed after the abrupt codeine withdrawal. The intensity and time course of body weight loss increased according to the duration of codeine treatment. After the codeine withdrawal, behavioral signs such as diarrhea, ptosis and vocalization were observed. In the naloxone-precipitated withdrawal test, rats treated with codeine for 1 day manifested a loss of body weight after naloxone challenge, and the intensity of body weight loss increased according to the duration of codeine treatment. After naloxone injection, the codeine-treated rats showed abnormal behaviors such as diarrhea, ptosis, teeth chattering , salivation, body shakes, vocalization, nose bleed, irritability, lacrimation and writhing. The total score, evaluated by the ranking system for precipitated withdrawal behaviors, was correlated with the duration of codeine treatment. These results suggest that naloxone-precipitated withdrawal signs are powerful in comparison with that after codeine withdrawal, and the weight loss is a common index for quantitative assessment of physical dependence on narcotics in the natural and naloxone-precipitated withdrawal tests. It is concluded that the drug-admixed food ingestion method has the advantage of rapidly inducing a high degree of physical dependence on codeine.

Topics: Animals; Behavior, Animal; Body Weight; Codeine; Food; Humans; Male; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Substance-Related Disorders

Tripelennamine, pentazocine and various pentazocine-tripelennamine combinations were tested for their ability to substitute for morphine in morphine-dependent rodents. Rats and mice were rendered physically dependent on morphine by the Drug-Admixed Food Method. Pentazocine produced a dose-related partial suppression of morphine withdrawal signs in mice, as well as in both mildly and severely dependent rats. Tripelennamine did not suppress morphine withdrawal signs, but rather aggravated them. Furthermore, tripelennamine did not potentiate the ability of pentazocine to suppress morphine withdrawal signs. It is concluded that the primary reason for the reported "street" abuse of the tripelennamine-pentazocine combinations is not related to any remarkable ability of the combination to effectively suppress the discomfort of heroin withdrawal.

Topics: Animals; Body Weight; Drug Combinations; Humans; Male; Mice; Mice, Inbred ICR; Morphine Dependence; Naloxone; Pentazocine; Rats; Substance Withdrawal Syndrome; Tripelennamine

Male Sprague-Dawley rats were raised from weaning in one of the three housing conditions: one, two or four per housing unit. At 60 days of age, animals were moved to individual cages and tested in the open field. Following a baseline period in which animals were allowed to adapt to their new housing condition, animals had their water replaced with a 0.8 mg/ml morphine sulfate solution. Following 12 days of access to the drug, animals were injected with naloxone and abstinence precipitated. While no differences were found in body weight among the three groups of animals at 60 days of age, significant differences in open field behavior were noted. Animals that were raised in groups were found to be more active in the open field than animals raised in isolation. Early housing experience was also found to modify later morphine consumption and physical dependence. Animals raised in isolation exhibited a trend to start drinking morphine sooner and experienced less severe withdrawal symptoms following naloxone administration than group-raised animals.

Topics: Animals; Body Weight; Drinking; Housing; Humans; Male; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Self Administration; Social Isolation

Exposure to short photoperiods induces gonadal regression in the golden hamster. This is accompanied by a fall in serum gonadotropins and changes in hypothalamic neurotransmitter turnover. We have attempted to correlate these changes with alterations in neurotransmitter receptor binding parameters. Compared to hamsters held in long photoperiods, opiate ([3H] naloxone) binding in hamsters exposed to short photoperiods is elevated in whole brain and in cerebral cortex but not in hypothalamus. However, beta-adrenergic ([3H] dihydroalprenolol) and benzodiazepine ([3H] flunitrazepam) binding are unaffected in whole brain, cerebral cortex or hypothalamus. Thus, changes in hypothalamic noradrenaline turnover rate previously reported may not be correlated with changes in beta-adrenergic binding.

Topics: Alprenolol; Animals; Anti-Anxiety Agents; Binding Sites; Body Weight; Brain; Cricetinae; Dihydroalprenolol; Flunitrazepam; Male; Naloxone; Organ Size; Periodicity; Photic Stimulation; Testis

The effects of several schedules of multiple morphine pellet implantation on body weight and dependence development in rats were studied. One schedule designated 6/7 (total number of pellets implanted per total number of treatment days), consisting of 1 pellet on day 0, 2 pellets on day 2 and 3 pellets on day 4 and a total treatment period of 7 days, produced high levels of dependence without affecting either body weight or rates of protein synthesis in whole brain or liver. The components of this schedule, 1/2 (one pellet on day 0 and a total treatment period of 2 days), 3/4 (one pellet on day 0 and two pellets on day 2 and a total treatment period of 4 days) and 6/7 (see above), produced a linear increase in the degree of dependence as measured by loss of body weight following naloxone-precipitated withdrawal. Hence, they were used to investigate the relationship between the degree of dependence and the rate of translation in vivo on free and membrane-bound polysomes in seven brain regions (cerebrum, cerebellum, mesencephalon, pons-medulla, striatum-septum, hippocampus-amygdala and thalamus-hypothalamus) following a 6 min pulse with a pool expansion dose of [3H]leucine. The rate of translation on free and membrane-bound polysomes was unaffected except on the bound polysomes of the pons-medulla and striatum-septum, where increased rates of translation were found to be closely correlated with degrees of dependence, measured as loss of body weight. Concomitant administration of naltrexone prevented both the stimulation of protein synthesis and the development of dependence, whereas administration of naltrexone alone did not affect translation rates in either polysome compartment of any region. Thus, it is concluded that the mechanisms underlying opiate dependence involve the stimulation of secretory protein synthesis in the pons-medulla and striatum-septum, presumably by the interaction between morphine and opiate receptors.

Topics: Animals; Body Temperature; Body Weight; Brain; Corpus Striatum; Humans; Male; Medulla Oblongata; Morphine Dependence; Naloxone; Naltrexone; Nerve Tissue Proteins; Pons; Rats; Rats, Inbred Strains; Receptors, Opioid

Rats were (1) sham operated and ad lib fed, (2) given bilateral subdiaphragmatic vagotomies or (3) sham operated and pair fed to the vagotomized group. At the start of the dark period, following a 24 hr fast, the animals were tested for the ability of naloxone (0.5, 1.5, 3.0 and 5.0 mg/kg body weight) to suppress food and water consumption. In comparison to saline control injections the data indicated that naloxone was equally effective in suppressing food intake, over a two hour period, in all groups. Similarly naloxone effectively decreased water consumption of all groups in comparison to their saline trials. When the post naloxone data were calculated as a percentage of saline baseline this suppression was, at times, slightly greater in the vagotomized group than in the other groups. However, this may be an artifact of the low baseline intake of the vagotomized group. The results are discussed with relevance to the recent findings of others concerning this subject.

Topics: Animals; Body Weight; Drinking; Eating; Male; Naloxone; Rats; Rats, Inbred Strains; Receptors, Opioid; Social Environment; Stomach; Vagotomy, Proximal Gastric; Vagus Nerve

Naltrexone, a potent opiate antagonist, had both stimulatory and inhibitory effects on somatic growth in preweaning rats depending on dose. Daily injections of 50 mg/kg naltrexone, which blocked morphine-induced analgesia for 24 hr/day, resulted in increased body and organ weights, and acceleration in the appearance of physical characteristics and maturation of spontaneous motor activity. Naltrexone in a dosage of 1 mg/kg, which blocked morphine-induced analgesia for 4 hr/day, had the opposite effects. These results show that naltrexone can modulate growth, and suggest a role for the endorphins and opiate receptors in developmental events.

Topics: Animals; Animals, Newborn; Body Weight; Ear, External; Eye; Female; Growth; Hair; Male; Motor Activity; Naloxone; Naltrexone; Organ Size; Rats; Receptors, Opioid

In Experiment 1, sham operated (SCON) and dorsomedial hypothalamic nuclei (DMN) lesioned (L) rats were given saline or naloxone (0.1, 1.0 or 2.0 mg/kg) just prior to the onset of the dark cycle, lights out. Compared to saline injections, naloxone at all doses suppressed the cumulative food intake of the SCON during the second and third hr of measurement. Naloxone was without significant effect on the food intake of DMNL rats. Similar results were obtained in Experiment 2, except that naloxone at 2.0 mg/kg significantly suppressed the DMNL rats' food intake by the fourth hr of measurement. Cumulative water intake of both groups was significantly suppressed by naloxone in both experiments but its effects appeared to be attenuated in the DMNL group. In a preliminary trial cholecystokinin octapeptide (3.0 and 6.0 micrograms/kg) given at the onset of the dark cycle significantly suppressed the food intake of the SCON group but had no significant effect on the DMNL rats. The possibility exists that the reduced food intake and lower body weight of DMNL rats may partially result from damage to an opioid system. The data also tentatively suggest that DMN may play a role in cholecystokinin-induced satiety.

Topics: Animals; Body Weight; Dorsomedial Hypothalamic Nucleus; Dose-Response Relationship, Drug; Drinking Behavior; Feeding Behavior; Hypothalamus, Middle; Male; Naloxone; Rats; Rats, Inbred Strains; Satiation; Sincalide

Food intake studies with genetically obese rodents show that these hyperphagic animals, which have increased central and peripheral levels of endogenous opioid peptides (E.O.P.), have an increased sensitivity to the suppressive feeding effects of narcotic antagonists compared to lean controls. Feeding experiments were conducted to determine if genetically obese rats, with enhanced E.O.P., have a reduced sensitivity toward the narcotic agonist property of stimulated feeding seen in non-obese rats. Food intake was monitored continuously over each experimental day in groups of female Sprague-Dawley (S.D.,), fatty Zucker (fa/fa) and their lean heterozygote littermates (Fa/fa) following subcutaneous a.m. injections of sterile saline, morphine sulphate (5 or 10 mg/kg) or naloxone HCl (10 mg/kg) and during recovery. Acute 4-h post-injection feeding was reduced in all groups with the first 10 mg/kg injection of morphine sulphate. With repeated morphine administration, a phase of stimulated feeding occurred in both obese and non-obese groups. Due to the post-injection phase of vigorous feeding with repeated morphine injections, the circadian pattern of day/night food intake of all groups was altered such that daytime feeding increased from saline control levels. Naloxone HCl abolished the post-injection phase of stimulated feeding seen with chronic morphine injections and reduced 4-h post-injection food intakes. Plasma glucose and serum insulin levels were decreased in non-obese rats from saline controls of blood samples taken 2-h following the 7th daily M.S. injection. These levels increased again by the end of the recovery period. No blood glucose or insulin changes were seen in the obese Zucker rats with morphine administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Glucose; Body Weight; Circadian Rhythm; Eating; Female; Insulin; Morphine; Naloxone; Rats; Rats, Inbred Strains; Rats, Zucker

From birth to day 21, rat offspring received daily injections of naltrexone at a dosage that blocked morphine-induced analgesia 24 hours a day. At 21 days, body, brain, and cerebellar weights of naltrexone-injected animals were 18, 11, and 5 percent greater than corresponding control weights. In addition, morphometric analysis of the cerebrum revealed a somatosensory cortex that was 18 percent thicker than that of the controls. The cerebellum of naltrexone-treated rats was 41 percent larger in total area and contained at least 70 percent more glial cells and 30 percent more granule neurons. Neurons derived prenatally were unaffected by drug treatment. These results show that naltrexone can stimulate body and brain growth in rats and suggest a role for the endorphin and opiate receptor system in development.

Topics: Animals; Animals, Newborn; Body Weight; Brain; Cerebellum; Morphine; Naloxone; Naltrexone; Neuroglia; Organ Size; Rats; Rats, Inbred Strains; Somatosensory Cortex

Opioids are proposed to play a role in the control of food intake since administration of opioids increase food intake while administration of opioid antagonists decrease food intake. In these experiments responses to a new opioid antagonist, nalmefene, were measured in Zucker obese and lean rats. In obese male rats 1 mg/kg nalmefene decreased the size of the first meal after a 10-hr fast and decreased 14-hr food intake, indicating nalmefene is relatively long-acting. Administration of 1 mg/kg nalmefene daily for 7 days decreased average meal size and daily food intake and increased meal frequency; feeding responses on day 7 were similar to those on day 1, suggesting a lack of development of tolerance. Food and water intake and weight gain during a 3-week treatment period were decreased more in lean rats by low doses of nalmefene (up to 0.25 mg/kg) and more in obese rats by higher doses of nalmefene (0.50 mg/kg). These responses to a new opioid antagonist further support a possible role for opioids in the control of food intake.

Topics: Animals; Appetite; Appetite Depressants; Body Weight; Drinking; Energy Intake; Female; Male; Naloxone; Naltrexone; Obesity; Rats; Rats, Zucker; Time Factors

Topics: Animals; Body Weight; Gas Chromatography-Mass Spectrometry; Humans; Male; Morphine; Naloxone; Naltrexone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

Topics: Animals; Body Weight; Enkephalins; Humans; Male; Morphine; Naloxone; Pentazocine; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

In rats of either the Sprague-Dawley or Long-Evans strain, either tetrahydroisoquinoline (THP) was infused chronically ICV, or one of three protoberberine (PBN) compounds was administered subcutaneously at birth. When the animals were 120-180 days of age, a constant concentration of alcohol was offered simultaneously with water to those rats which demonstrated a clear-cut preference for alcohol. This concentration was selected on the basis of an alcohol preference screen. After alcohol intakes had stabilized, naltrexone was injected subcutaneously in a dose of either 1.0 or 5.0 mg/kg twice a day for three consecutive days. The higher dose (10.0 mg/kg total) of naltrexone suppressed the voluntary intake of alcohol by 26%, whereas the lower dose (2.0 mg/kg total) attenuated alcohol drinking by 14%. Both doses of naltrexone reduced food intake but did not appreciably affect water intake or body weight. When morphine was injected according to the same regimen in a dose of 10.0 or 2.5 mg/kg twice per day, a 49% reduction in alcohol intake was produced by the higher dose and a 32% decline followed the lower dose. Although morphine attenuated food intake, neither water intake nor body weight was affected. Saline control injections administered twice daily in the same way failed to alter any of the intake measures or body weight. These findings indicate that the long-lasting opiate antagonist naltrexone attenuates the voluntary consumption of alcohol in a manner similar to that produced by naloxone. The present results are discussed in terms of the evidence that an opiate agonist and antagonist may exert their actions by different mechanisms in the brain, possibly through separate subpopulations of opiate receptors.

Topics: Alcohol Drinking; Animals; Body Weight; Drinking Behavior; Feeding Behavior; Isoquinolines; Male; Morphine; Naloxone; Naltrexone; Rats; Rats, Inbred Strains; Tetrahydroisoquinolines

Discrete, bilateral, radiofrequency destruction of the ventral noradrenergic bundle (VB) resulted in a pronounced fall in levels of noradrenaline in the hypothalamus but not in the cortex. On days 4 and 12, but not 28, post-surgery, VB-lesioned rats were hyperactive (rearing and ambulation) upon exposure to a novel open-field space. This hyperactivity was greatly attenuated by naloxone, which did not significantly modify sham activity. These data suggest that the VB may be involved in the control of locomotor-exploratory activity via an interaction with an endorphinergic system. On day 4, but not 12 or 25, VB-lesioned rats displayed a significant elevation in core temperature (Tc). No difference in the hyperthermia elicited by introduction into the open-field was, however, seen between VB-lesioned and sham rats on day 4. In both groups, this rise in Tc was strongly attenuated by naloxone. These data indicate that the VB may be involved in the control of Tc but that it does not mediate novelty-stress evoked hyperthermia, for which endorphins are primarily responsible. Within 7 days post-surgery, VB-lesioned rats developed an enhancement of daily food intake which led to a slight obesity. From day 15 onward, a hyperdipsia was also seen in VB-lesioned rats. Naltrexone reduced the food and water intake of both sham and VB-lesioned animals but failed to totally block this hyperphagia. It is suggested that the VB is involved in the regulation of daily ingestive behaviour and that endorphins do not exclusively mediate the VB-lesion induced hyperphagia.

Topics: Afferent Pathways; Animals; Behavior, Animal; Body Temperature Regulation; Body Weight; Drinking; Eating; Endorphins; Feeding Behavior; Fever; Male; Medulla Oblongata; Naloxone; Norepinephrine; Pons; Rats; Rats, Inbred Strains; Time Factors

Previous studies have reported age-related changes in opiate receptors and in their response to narcotics during the process of normal growth of the brain. By inducing alterations in this developmental sequence, the present study attempted to provide correlates of the opiate receptor system with naloxone-induced anorexia. Offspring of mothers treated with morphine (7.5 mg/kg twice daily, s.c.) or saline during pregnancy, and infants from untreated mothers given morphine (5 mg/kg), naltrexone (10 mg/kg) or saline subcutaneously on postnatal days 1-5, were tested at days 10, 12 and 14 for deprivation-induced milk consumption following an acute dose of naloxone (1 or 5 mg/kg, i.p.). Naloxone reduced the food intake of 10- and 12-day old infants chronically treated with morphine postnatally. At age 14, naloxone reduced the food consumed by all the pretreatment groups, and pretreatment with morphine altered the dose-response curves for feeding modulation induced by naloxone. Naloxone had no effect on the food consumed by 10- or 12-day old offspring of mothers treated with morphine or saline, or on those age-groups that received naltrexone chronically or saline pretreatments postnatally. The observed changes occurred in the absence of gross malformations, drug-withdrawal symptoms and differences in activity. These results demonstrate that opiate receptors may participate in feeding.

Topics: Aging; Animals; Animals, Suckling; Body Weight; Drug Interactions; Feeding Behavior; Female; Motor Activity; Naloxone; Naltrexone; Narcotics; Pregnancy; Prenatal Exposure Delayed Effects; Rats

The incidence of neonatal morbidity and mortality in rats exposed to opiates in utero is generally high. To determine the extent to which neonatal opioid intoxication and/or withdrawal contribute to this effect, addicted pups from dams treated chronically with the long-acting opioid levo-alpha-acetylmethadol (LAAM) and appropriate controls were injected within 12 h of birth with saline, an opioid agonist (LAAM and metabolites) or an antagonist (naloxone). The incidence of neonatal mortality for pups born to dams maintained on a high dose of LAAM was 52%. A single injection of agonist on the first day of life reduced mortality in this group to 29% while a single injection of the antagonist increased mortality to 88%. In contrast, administration of the agonist to control pups and pups born to dams maintained on lower doses of LAAM resulted in increased mortality. Naloxone was apparently innocuous in non-dependent neonates. These data show that, despite LAAM's long duration of action in the mature rat, newborn rats experience withdrawal soon after drug exposure is terminated. These data also indicate that continued opioid exposure is a highly effective means of treating/preventing severe spontaneous withdrawal in the newborn.

Topics: Animals; Animals, Newborn; Body Weight; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Male; Methadone; Methadyl Acetate; Naloxone; Pregnancy; Rats; Rats, Inbred Strains

Topics: Adolescent; Adult; Anorexia; Body Weight; Feeding and Eating Disorders; Female; Humans; Male; Naloxone; Naltrexone

Three experiments were done with the lizard, Anolis carolinensis, as a follow-up on our previous work which showed that MIF-I reduced tonic immobility (TI) during the breeding season and that females had longer TI durations than males in the non-breeding season. In June, during the breeding season, 60 male and 60 female lizards were injected with 0.1 mg/kg of MIF-I or naloxone or the diluent vehicle and placed in small aquaria for ten minutes. TI was then induced in the small aquaria. Similar experiments were conducted in September and October (non-breeding season). There was a reduction in TI durations in MIF-I and naloxone-treated lizards of both sexes in June, but the differences between drug treatment groups and controls were not significant. In September and October, MIF-I treatment resulted in TI durations similar to controls but naloxone treatment resulted in slightly shorter durations. Increased TI duration in females as compared to males was seen during both seasons, but diminished during the breeding season. Weight was found to be a factor in male lizards, with males greater than or equal to 4.0 g showing significantly longer TI durations. The lack of a significant effect of MIF-I on TI durations during the breeding season is possibly due to changes in the experimental design from the earlier report.

Topics: Animals; Body Weight; Female; Lizards; Male; Motor Activity; MSH Release-Inhibiting Hormone; Naloxone; Narcotic Antagonists; Seasons; Sex Factors

The present studies tested the effect of acute and chronic administration of naloxone on food intake of lean and genetically obese (ob/ob) mice. Acute administration of naloxone, a drug which blocks opiate receptors, produced a greater reduction of food intake in obese (ob/ob) mice than in the lean littermates. For chronic experiments with naloxone, the daily feeding period was shortened to eight hours and two injections of naloxone were given four hours apart. With this procedure of scheduled-feeding the food intake of both lean and obese mice was depressed during the first hour after injecting naloxone. However, beginning on the second day of treatment, the lean mice began to eat more food than the untreated controls during the eight hour feeding period. Food consumption by lean mice reached values 140 to 200% above the control levels between the fourth and sixth day. In the obese mice the rise in food intake was more gradual and did not reach 200% of the control value until the sixth day. Body weight changes reflected the changes in food intake. In contrast to naloxone, chronic treatment with morphine lowered food intake and blocked the stimulatory effect of naloxone. Our findings suggest that endogenous opioids may play a role in signalling satiety and in regulating long-term energy balance.

Topics: Animals; Body Weight; Diet; Eating; Energy Intake; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Morphine; Naloxone; Obesity; Receptors, Opioid; Time Factors

The action of chronic morphine administration on catecholamine levels in the cervical (SCG) and iris of the rat pup was studied by radioenzymatic assay. Catecholamine levels in the SCG and iris were unaltered after chronic morphine administration and withdrawal. Norepinephrine (NE) uptake was unchanged throughout drug treatment. beta-adrenergic receptors were increased 30.8% in the iris of morphine-dependent animals. This increase in beta receptors closely parallels the increase in beta receptors found in the brainstem of adult morphine-dependent animals.

Topics: Animals; Body Weight; Dihydroalprenolol; Dopamine; Epinephrine; Ganglia, Sympathetic; Iris; Morphine; Naloxone; Norepinephrine; Rats; Rats, Inbred Strains; Receptors, Adrenergic; Receptors, Adrenergic, beta

Topics: Animals; Body Weight; Endorphins; Energy Intake; Energy Metabolism; Feeding Behavior; Naloxone; Oxygen Consumption; Rats

The observation that acute administration of opiate agonists to rodent adults increased food intake while the reverse was true with a single injection of an opiate antagonist has led to the suggestion that endogenous opioids may in part mediate feeding behaviour in adult rodents. Studies were performed in infant rats to explore further the generality and ontogeny of this function. In three models of food availability, the effects of naloxone and naltrexone were assessed in deprivation-induced feeding tests in 3-, 10-, 12, 14- and 19-day-old preweanling rats. Naloxone or naltrexone attenuated food intake only after 14 days. Functional immaturity of the opioid systems vis-a-vis ingestive behaviour may account for this developmental sequence.

Topics: Aging; Animals; Animals, Suckling; Behavior, Animal; Body Weight; Feeding Behavior; Female; Male; Naloxone; Narcotic Antagonists; Rats

Food intake over 90 min post-injection was studied in groups of food deprived (20 hr) female Sprague-Dawley (S.D.) rats, fatty Zucker (fa/fa) rats and their heterozygous lean litter mates (Fa/fa) of various ages, that bar-pressed for food pellets on a FR-1 schedule following a subcutaneous (SC) or an intracerebroventricular (IVT) injection of sterile saline or naloxone HCl. Subcutaneous injections of naloxone HCl (10 mg/kg) reduced feeding in all three groups of rats compared to SC saline; in addition, a greater percentage reduction in food intake over the whole 90 min test period occurred in the fa/fa rats given SC naloxone compared to the Fa/fa group. Intracerebroventricular naloxone (50 micrograms) decreased feeding over the initial 30 min period in the S.D. and Fa/fa rats but a 100 micrograms IVT dose was needed to reduce feeding in the fa/fa group. The results demonstrate that central naloxone administration can suppress feeding in both non-obese and obese strains of rats as it is known to do when given peripherally. These findings add yet further evidence to the premise that endogenous opioid peptides may play an intricate and important physiological role in the regulation of feeding behavior.

Topics: Animals; Body Weight; Eating; Female; Food Deprivation; Injections, Intraventricular; Injections, Subcutaneous; Naloxone; Rats; Rats, Inbred Strains; Rats, Zucker

1 Rats are capable of consuming solutions of morphine sulphate in drinking water ad libitum in the absence of taste-masking chemicals and without the need for scheduled provision or prior parenteral administration of the drug. 2 The success of this method depends on the initial provision of a 0.1 mg/ml solution of morphine sulphate. 3 When the drug concentration is increased to 0.4 mg/ml, the rats achieve an average daily intake of 50 mg/kg body wt. each. 4 Daily intake of morphine may be increased by at least about three fold by increasing the drug concentration to 1.2 mg/ml. 5 Oral morphine administration causes only a moderate loss in body weight. 6 Rats whose daily intake of the drug is 50 mg/kg exhibit tolerance to the analgesic action of morphine and show a drastic loss in body weight at 24 h after withdrawal and most of the behavioural symptoms of the naloxone-precipitated withdrawal syndrome. 7 It is suggested that this simple method of morphine administration is suitable for further biochemical and behavioural studies of the actions of the drug.

Topics: Animals; Body Weight; Drinking; Drug Tolerance; Humans; Male; Morphine; Morphine Dependence; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Time Factors

The pretreatment of mice with 30 mg/kg morphine s.c. did not alter the analgesic effect of morphine in mice pretreated with saline but decreased the analgesic effect of morphine in mice pretreated with prolyl-leucyl-glycinamide (PLG). Tolerance was evaluated by the effect of PLG on morphine-induced enhancement of naloxone potency which is a measure of the capacity of naloxone to antagonize morphine-induced analgesia and is postulated to be an indicator of tolerance development. The naloxone potency of PLG-treated mice was 2-fold greater than that of control mice. PLG did not alter the whole brain levels of morphine, nor did it alter the naloxone potency in mice which were not pretreated with 30 mg/kg morphine. In mice treated with 100 mg/kg morphine or implanted with 50 mg morphine pellets for 24 or 72 h, the amount of naloxone required to induce jumping was not altered by PLG. However, PLG treatment did increase the hypothermia and body weight loss seen after naloxone-induced withdrawal. Administration of PLG to morphine-dependent mice 1 h prior to naloxone did not modify the resultant hypothermia or body weight loss. These results indicate that PLG facilitated the development of morphine tolerance and dependence.

Topics: Analgesia; Animals; Body Temperature; Body Weight; Brain Chemistry; Drug Tolerance; Glycine; Humans; Leucine; Male; Mice; Morphine; Morphine Dependence; MSH Release-Inhibiting Hormone; Naloxone; Proline

The morphine withdrawal syndrome was studied in rats which had been made dependent on morphine administered by the intermittent infusion technique. Rats made rapidly dependent on morphine by an hourly infusion of 0.12-4 mg/kg/h showed a withdrawal syndrome when they were abruptly withdrawn, after infusion for 7 days, or when they were challenged by naloxone after infusion for 4 days. Abruptly withdrawn rats showed a marked weight loss and other mild symptoms. The weight loss seems to mainly due to anorexia, partly because it was attenuated by IV feeding throughout the withdrawal and partly because the fasted rats showed a weight loss comparable to the withdrawn rats. The naloxone-precipitated withdrawal syndrome showed characteristics, which, from their time course of incidence and their three groups; motor excitation, cholinergic signs, and others. These groups and their interrelationships were discussed. All characteristics were suppressed by deep anesthesia with ether or pentobarbital. A sudden fall in blood pressure was indicated in the anesthetized morphine-dependent rats immediately after the naloxone challenge. This suggests that the intrinsic withdrawal syndrome was progressing even under anesthesia.

Topics: Animals; Body Weight; Humans; Infusions, Parenteral; Male; Morphine; Morphine Dependence; Motor Activity; Naloxone; Pilocarpine; Rats; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Body Temperature; Body Weight; Dose-Response Relationship, Drug; Humans; Lethal Dose 50; Male; Mice; Morphine Dependence; Motor Activity; Naloxone; Pentazocine; Substance Withdrawal Syndrome; Tripelennamine

The injection of high dose of naloxone 15 minutes after a single injection of morphine in mice was found to produce a jumping response which was behaviorly similar to the jumping response observed during the withdrawal from chronic morphine administration. In addition the jumping response following the acute administration of morphine-naloxone was increased by the injection of atropine and attenuated by oxotremorine. These data are consistent with the reports of effect of these cholinergic drugs on the jumping response which occurred during withdrawal after chronic morphine administration. However, other symptoms associated with opiate withdrawal (hypothermia, weight loss and diarrhea) were not produced by the acute injection of morphine-naloxone. It is therefore suggested that this single injection paradigm is particular to the jumping response rather than a demonstration of the rapid development of opiate dependence.

Topics: Animals; Body Temperature; Body Weight; Diarrhea; Humans; Male; Mice; Morphine; Motor Activity; Naloxone; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Body Temperature; Body Weight; Catalepsy; Drug Implants; Drug Tolerance; Electroshock; Humans; Morphine; Naloxone; Rats; Respiration

Rats of 30, 45, 60 and 120 days of age, maternally exposed to methadone (5 mg/kg daily) during gestation and/or lactation, were evaluated on a variety of behavioral and physiological parameters related to drug withdrawal. Animals were tested before and after an acute injection of naloxone (10 mg/kg). Prior to naloxone injection, methadone-exposed rats were subnormal in body temperature at 30 days of age, hypoalgesic at 45 days, and weighed less than controls at 60 days. Additionally, and in contrast to control rats, methadone-exposed animals at most ages displayed head shake and wet-dog shake behaviors. After naloxone administration, methadone-exposed rats exhibited an increase in the mean number of head and wet-dog shakes over pre-injection levels. Although control rats injected with naloxone also demonstrated head shakes (at all ages) and wet-dog shakes (at 45 days), these behavior were usually not of the magnitude as noted for methadone-exposed offspring receiving naloxone. Perturbations in body weight and hypothermia during development, along with head shake and wet-dog shake behaviors which were exacerbated following naloxone administration, suggest a protracted state of physical dependence/withdrawal and/or permanent damage as a result of perinatal exposure to methadone.

Topics: Age Factors; Animals; Animals, Newborn; Behavior, Animal; Body Temperature Regulation; Body Weight; Female; Humans; Lactation; Male; Maternal-Fetal Exchange; Methadone; Naloxone; Nociceptors; Pregnancy; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

The effects of a constant intravenous infusion of naloxone in doses ranging from 3.2 to 6.4 mg/day were studied in a group of patients with anorexia nervosa. Patients showed a significantly greater weight gain during the infusion compared with the periods before and after naloxone. Plasma β-hydroxybutyrate and non-esterified fatty acid levels fell during the infusion. It is suggested that, in man, naloxone has an antilipolytic effect in vivo.

Topics: Adolescent; Adult; Anorexia Nervosa; Body Weight; Fatty Acids, Nonesterified; Female; Humans; Hydroxybutyrates; Infusions, Parenteral; Lipolysis; Naloxone

Opioid antagonists have been reported to reduce water and food intake. In the experiments, ingestive behavior was sometimes induced using stressful stimuli. These experiments were conducted to determine the effects of chronic administration of an opioid antagonist on appetitive behaviors of minimally stressed rats. Twelve 4-week old rats were randomly separated into two equal-sized groups, anesthetized with ether, and implanted subcutaneously with poly(epsilon-caprolactone) capsules. One group received naltrexone in the capsules, the other group received vehicle. These capsules released the drug at a rate of approximately 250 microgram/day for over 8 weeks. Gross metabolic behavior (food intake, water intake, urine output, fecal output, and body weight) was monitored for 8 weeks. At three times during the 8 weeks, food deprivation (24 hr)-induced feeding was tested over a period of 60 min. At the end of the eighth week, the animals were subjected to an analgesic test in order to confirm the efficacy of the naltrexone dose. No differences in food intake, body weight, fecal output, or deprivation-induced feeding were observed between the control and naltrexone groups. Water intake and fluid output of the naltrexone group were significantly reduced compared to the control group. These results suggest that endogenous opioids may mediate mechanisms of tonic drinking behavior and cannot be explained as representing effects on stress-induced ingestion.

Topics: Analgesia; Animals; Appetitive Behavior; Body Weight; Drinking Behavior; Food Deprivation; Kinetics; Naloxone; Naltrexone; Rats; Rats, Inbred Strains

To study the effects of chronic morphine treatment on cerebral 5-hydroxytryptamine (5HT) metabolism morphine was administered twice daily for 5 or 8 weeks to male Wistar rats. Control rats were treated with 0.9% NaCl solution for the same period. In rats treated chronically with morphine for 8 weeks the cerebral concentrations of 5HT and 5HIAA were reduced by 12--15% (P less than 0.05) at 26--28 h after the last morphine injection (50 mg/kg s.c.). No such decrease was found in the brain of rats treated with morphine for 5 weeks. A test dose of morphine (30 mg/kg s.c. 2h) increased the cerebral concentration and probenecid-induced accumulation of 5HIAA in the rats treated with morphine for 8 weeks almost as much as in the brain of the control rats. Naloxone (10 mg/kg s.c. 2h) did not cause clear changes in the cerebral 5HT or 5HIAA concentration. These experiments suggest that endogenous opioid mechanisms are concerned in the regulation of 5HT neurons and that prolonged morphine treatment weakens these mechanisms. This weakening of endogenous regulation of 5HT neurons, which, however, still respond to acute morphine administration, might be part of the mechanism of compulsive drug use in narcotic addiction. It is possible that these neurons in dependent individuals do not function optimally without exogenous morphine. A similar phenomenon--weakening of endogenous regulation combined with clear responsivity to exogenous opiates--occurs in the cerebral dopamine neurons of rats treated chronically with narcotic analgesics.

Topics: Animals; Body Weight; Brain; Hydroxyindoleacetic Acid; Male; Morphine; Naloxone; Rats; Serotonin

One week old mice were injected subcutaneously once daily with d,1-methadone (5 mg/kg), pentazocine, naltrexone, naloxone, nalorphine or nalbuphine, each at 10 mg/kg. The remaining half of each litter was used as control. Only methadone and pentazocine groups showed reduced weight gain after 3 weeks of treatment (P < 0.01). Injection of pentazocine in dosages of 5-20 mg/kg inhibited weight gain and protein synthesis in a dose-related manner. The incorporation of labeled leucine was followed in brain, liver and muscles. Methadone and pentazocine groups showed a significant decrease in protein synthesis in all tissues studied. The nalbuphine, nalorphine, naloxone, and naltrexone-treated groups incorporated leucine normally, correlating with normal weight gain. These data suggest that pentazocine, unlike the other mixed agonist-antagonists and antagonists, adversely affects the growth of very young animals when administered chronically. A specific opioid effect is suggested by the fact that naltrexone given concomitantly with the pentazocine prevents development of the biochemical lesion.

Topics: Animals; Body Weight; Brain; Dose-Response Relationship, Drug; Growth; Liver; Mice; Muscle Proteins; Naloxone; Naltrexone; Pentazocine; Protein Biosynthesis; Receptors, Opioid

Topics: Adrenocorticotropic Hormone; Analgesics; Animals; Behavior, Animal; Body Weight; Female; Growth; Mice; Motor Activity; Naloxone

Naltrexone, an opiate antagonist, was administered to young obese (ob/ob) and lean mice for five weeks. Animals had continuous access to food and received 10 mg/kg SC twice daily with equivalent volumes of saline given to controls. The effects on body weight, and pituitary and plasma levels of beta-endorphin-like material were measured. Naltrexone-injected obese animals gained weight more slowly over the first three weeks while the weight gain of lean animals was not affected by naltrexone. Plasma levels of beta-endorphin were shown to be significantly higher in untreated ob/ob mice and this difference increased with age (4-20 weeks). With naltrexone treatment, plasma levels in +/? mice rose and exceeded those in ob/ob. Saline treatment appeared to be a stress, and pituitary beta-endorphins rose 4-6 fold in ob/ob compared with +/?. While naltrexone reduced the levels of ob/ob pituitary towards normal, no effect on beta-endorphin levels in pituitary of lean mice was obtained. In vitro studies of effects of the opiate antagonists, naloxone, on insulin secretion by isolated islets provided additional evidence of resistance of lean mice to naloxone relative to ob/ob. (IRI secretion fell only in naloxone treated ob/ob islets). These observations support the contention that this form of genetic obesity is characterized by elevated endogenous opiate levels and an increased sensitivity to opiate antagonists such as naltrexone or naloxone.

Topics: Animals; beta-Endorphin; Body Weight; Endorphins; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Obese; Naloxone; Naltrexone; Obesity; Pituitary Gland; Receptors, Opioid

In order to examine the effects of blockade of the opiate-receptor during gestation and parturition, pregnant rats were implanted with subcutaneous minipumps, loaded with either naloxone (100 or 30 mg/ml) or saline, released at a constant rate for 7 days. It was found that neonatal mortality was significantly increased in the group that received naloxone 0.1 mg/h from day 17 of pregnancy, compared to saline controls. Body weight increase was slightly retarded by administration of naloxone 0.03 mg/h, starting day 17. At the age of 40 days, the groups exposed to naloxone 0.03 mg/h during late gestation showed a significant analgetic response to morphine 5 mg/kg, in contrast to saline controls, when tested with the hot-plate technique. The results suggest a role for endorphins during parturition and development.

Topics: Animals; Animals, Newborn; Body Weight; Female; Labor, Obstetric; Litter Size; Male; Morphine; Naloxone; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Receptors, Opioid

The effects of chronic treatment with morphine and cholinergic compounds on the development of morphine tolerance, physical dependence and increased naloxone potency were studied. Using the abdominal constriction method, it was shown that morphine tolerance was apparent after s.c. administration of morphine 20.0 mg/kg three times a day for four days. It was found that, in animals which showed a low degree of morphine tolerance, the naloxone potency was similar to that determined in mice which had been pretreated with only a single dose of morphine which causes no measurable tolerance. Thus, the development of increased naloxone potency and tolerance to morphine do not parallel each other. In addition, while atropine inhibited, and anti-cholinesterase drugs enhanced, the development of increased naloxone potency caused by morphine treatment they had no or little effect on the development of morphine tolerance. Furthermore, chronic treatment with cholinergic agonists reduced, while muscarinic antagonist enhanced, the development of physical dependence on morphine as assessed by withdrawal jumping and body weight loss. It is concluded that the increased potency of naloxone in antagonising the antinociceptive effect of morphine can be dissociated from the development of tolerance to, and physical dependence on, morphine in mice.

Topics: Animals; Atropine; Body Weight; Dose-Response Relationship, Drug; Drug Synergism; Drug Tolerance; Humans; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Nociceptors; Parasympathomimetics; Time Factors

Topics: Animals; Barbiturates; Behavior, Animal; Body Weight; Central Nervous System Depressants; Dose-Response Relationship, Drug; Humans; Levallorphan; Morphine; Naloxone; Piperazines; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

Food and fluid deprived and nondeprived male rats showed 36% and 46% decreases, respectively, in sucrose consumption 15-min after injection with 2 mg/kg of naloxone in one hr tests. The magnitude of this decrease was not correlated with an index of naloxone's ability to produce a sickness, as measured by the conditioned taste aversion test. Tests with animals scheduled to drink water in a 15-min daily session showed naloxone had similar effects in reducing water intake in 23-hr and 47-hr water deprived rats. Morphine, when self-administered, produced an increase in water intake during 6-hr sessions. The data support the idea that naloxone disrupts a component of normal regulation of ingestion.

Topics: Animals; Body Weight; Drinking Behavior; Food Deprivation; Male; Naloxone; Rats; Water Deprivation

The effect of an opiate antagonist, naloxone, on hypertonic NaCl-induced drinking was studied in rats in a within-subject design. Naloxone reduced drinking at all dosage levels used (0.3-10.0 mg/kg) when compared to a control condition. These results extend previous findings of naloxone mediated reduction in fluid intake in water deprived and osmotically challenged animals. Naloxone's effects on fluid intake seems to be independent of procedure employed, and thus quite general. Possible mechanisms were considered.

Topics: Animals; Body Weight; Depression, Chemical; Drinking; Hypertonic Solutions; Injections, Intraperitoneal; Male; Naloxone; Rats; Sodium Chloride; Water-Electrolyte Balance

Experimental evidence has shown that an intermittent food delivery schedule interacts with the pharmacological properties of a variety of drugs to produce significant increases in self-injection rates. This self-infusion drug seeking behaviour is further strengthened when body weight reduction is introduced. This experiment studies the effect of the opiate antagonist naloxone upon a strongly established response pattern for heroin self-administration, using naive rats at 80% body weight which were made dependent upon the drug by the schedule-induced self-injection procedure. Results show a clear reversal in responding following naloxone treatment, suggesting that once an interaction between schedule-induced behaviour and a drug is established, blockage of the reinforcing effects of the drug extinguishes the behaviour altogether.

Topics: Animals; Body Weight; Heroin; Male; Naloxone; Rats; Reinforcement Schedule; Self Administration

Topics: Animals; Behavior, Animal; Body Weight; Drug Tolerance; Humans; Male; Melanocyte-Stimulating Hormones; Morphine; MSH Release-Inhibiting Hormone; Naloxone; Rats; Substance-Related Disorders

Complex zinc tannate salts of heroin, hydromorphone and l-alpha-acetylmethadol were synthesized and injected in a slow-release vehicle, into rats. One, 3, 7, 10 and 14 days after the drug was administered rats were injected with naloxone hydrochloride (10 mg/kg) and during the following 4 hours body weights, core temperature and behavioral signs such as diarrhea, writhing, teeth chattering and wet dog shakes were recorded. On every naloxone testing day the narcotic-treated groups presented behavioral signs of abstinence, but weight loss and temperature changes were much less consistent. Reduction of core temperature following naloxone administration seems to be an earlier indicator of physical dependence than weight loss. According to the parameters tested a level of physical dependence can persist for at least two weeks after a single injection of these narcotic salts.

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Heroin; Heroin Dependence; Humans; Hydromorphone; Methadone; Methadyl Acetate; Naloxone; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

The effects of morphine pellet implantation and naloxone administration were examined in rats lever pressing under inter-response time schedules of food presentation. Subcutaneous implantation of a morphine pellet initially decreased lever-pressing rates. Tolerance to this effect developed within 3--4 days. Naloxone (0.25--1.0 mg/kg) decreased response rates in morphine-pelleted rats in a dose-dependent and time-dependent manner. All doses of naloxone severely decreased rates of lever pressing on days four to nine post-pellet. This rate-decreasing effect persisted 7--17 days for 0.25 mg/kg naloxone, 9--22 days for 0.50 mg/kg, and 13--28 days for 1.0 mg/kg. Decreases in response rate were due to an increased frequency of long pauses and not to marked shifts in the temporal patterning of those lever presses that did occur. Changes in response rate after naloxone were accompanied by body weight loss. Area values summarizing the naloxone-induced changes in response rate or body weight over time after pellet implantation increased as a function of naloxone dose. Naloxone (0.25--1.0 mg/kg) did not alter performance by placebo-pelleted rats.

Topics: Animals; Body Weight; Conditioning, Operant; Drug Implants; Humans; Male; Morphine; Morphine Dependence; Naloxone; Rats; Reinforcement Schedule; Time Factors

Pregnant mice were treated with naloxone via subcutaneous implants, from about 5 days prior to parturition. At birth entire litters were cross-fostered so that groups of offspring were exposed to naloxone treated mothers; before birth, after birth to weaning, from about 5 days prior to birth to weaning, or not exposed to naloxone. When tested on a hot-plate at 50 days of age, females either prenatally treated or treated pre- and postnatally showed hyperalgesia to heat. For males, this effect was not evident. This sex difference may have been induced by the cross-fostering procedure.

Topics: Aging; Animals; Body Weight; Female; Hyperalgesia; Hyperesthesia; Male; Mice; Naloxone; Reaction Time; Sex Factors; Time Factors

Parenteral administration of naltrexone to water-deprived female rats suppressed water intake when injected 4, but not 12 hours prior to the drinking session. Intraperitoneal injection 5 mg/kg naltrexone twice daily or oral self-administration of naltrexone in doses sufficient to block morphine-induced analgesia failed to reduce water intake or to alter body weight in non-deprived animals. These findings suggest that the suppressant effects of naltrexone on appetitive behavior are mediated by a different population of opiate receptors than those mediating morphine-induced analgesia.

Topics: Animals; Body Weight; Depression, Chemical; Drinking Behavior; Female; Naloxone; Naltrexone; Pain; Quinine; Rats; Self Administration; Sensory Thresholds; Time Factors; Water Deprivation

Topics: Animals; Body Weight; Crowding; Male; Naloxone; Naltrexone; Rats; Time Factors

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Drug Tolerance; Humans; Male; Morphine; Morphine Dependence; Naloxone; Physical Exertion; Rats; Reaction Time; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Body Weight; Energy Intake; Feeding Behavior; Humans; Kinetics; Male; Naloxone; Rats; Substance Withdrawal Syndrome

The pharmacological and toxicological responses of three phenothiazine neuroleptics, acetophenazine, chlorpromazine and thioridazine were determined in morphine-dependent mice. The mice were rendered dependent on morphine by implantation of a morphine pellet for 3 days. The control animals received placebo pellets. The pellets were removed and at 6, 24, 48 and 72 hr after the pellet removal, naloxone ED50's for the stereotyped jumping response were determined. The effect of phenothiazine derivatives administered intraperitoneally, at 6, 24 and 72 hr after pellet removal were determined on the 24 hr LD50, locomotor activity and body temperature. The LD50 of all phenothiazines was decreased significantly in mice from which morphine pellets were removed for 6 hr in comparison to placebo pelleted mice. This was the time when maximum degree of dependence on morphine was observed. At 24 and 72 hr after pellet removal, the LD50's in morphine and placebo treated mice were not different. The relative decrease in locomotor activity by all the phenothiazines was less in morphine withdrawn mice as compared to placebo withdrawn mice. The hypothermic response of phenothiazines was enhanced in morphine withdrawn mice. It is concluded that the effects of phenothiazine neuroleptic drugs can be modified in narcotic-dependent subjects. Possible mechanisms of such altered effects are discussed.

Topics: Animals; Body Temperature; Body Weight; Chlorpromazine; Humans; Lethal Dose 50; Male; Mice; Morphine Dependence; Motor Activity; Naloxone; Phenothiazines; Thioridazine

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; Body Weight; Estrus; Female; Luteinizing Hormone; Mice; Naloxone; Organ Size; Ovary; Pregnancy; Reproduction; Sexual Maturation; Spleen; Thymus Gland; Uterus

Administration of the opiate antagonist naloxone to rats after acute or chronic heat exposure precipitates an increase in colonic temperature, an increase in escape attempts, and a decrease in body weight. These changes are accompanied by signs associated with hyperthermia such as salivation, diarrhea, and an abnormal extended posture. Although brain endorphin involvement is possible, hypophysectomy diminishes the intensity and magnitude of these naloxone effects, indicating that the naloxone effect in intact animals may be due to a functional antagonism of pituitary endorphins. These observations suggest that endorphins attenuate physiological responses to thermal and noxious stimuli triggered in common neuroanatomical pathways by heat.

Topics: Adaptation, Physiological; Animals; Body Temperature Regulation; Body Weight; Endorphins; Escape Reaction; Hot Temperature; Hypophysectomy; Male; Naloxone; Posture; Rats; Salivation; Time Factors

The peptide-Z-Pro-D-Leu, injected daily in mice receiving morphine chronically, was found to prevent development of physical dependence as measured by changes in body temperature and body weight due either to abrupt or to naloxone-induced withdrawal. On the other hand, administration of Z-Pro-D-Leu only on the last day of morphine treatment did not alter the overt signs of withdrawal. Daily administration of Z-Pro-D-Leu was also effective in blocking the development of tolerance to the analgesic and the hypothermic effects of subsequent challenge doses of morphine. However, the peptide treatment did not alter the acute effects of a challenge dose of morphine on either analgesia or body temperature. No effects on memory were noted, as evaluated in a one-trial passive avoidance task. Clinical implications of the use of Z-Pro-D-Leu are discussed.

Topics: Animals; Body Temperature Regulation; Body Weight; Dipeptides; Drug Tolerance; Humans; Male; Mice; Morphine; Morphine Dependence; Naloxone; Pain; Retention, Psychology

Clonidine's action on naloxone (Nx)-induced suppression of fixed-ratio (FR15) responding and body weight loss was studied in morphine (M)-dependent rats. Clonidine (10--70 microgram/kg IP) injected 30 min prior to the behavioral session resulted in a dose-related suppression of operant behavior in M-naive animals. A small, but significant decrease (3--5%) in body weight was also observed at the higher doses of clonidine. More than twice as much weight loss, associated with diarrhea, was obtained when Nx (5.0 mg/kg IP) was administered to M-dependent animals. When clonidine (10--50 microgram/kg IP) was administered prior to Nx, in M-dependent animals, the withdrawal-induced disruption of operant responding was significantly attenuated. Concurrent weight loss, which was significantly antagonized by 1 microgram clonidine/kg, was decreased by as much as 40 percent. The degree of amelioration of withdrawal that was observed appeared to be inversely related to the dose of clonidine. The optimal dose was 10 microgram/kg, which by itself was only partially behaviorally active. At higher doses, clonidine's blocking properties were less apparent as a result of its own potent behavioral suppressant and diuretic effects which masked its capacity to attenuate withdrawal. The data are discussed in relation to the application of operant technics for assessing drug treatment(s) designed to alter the severity of narcotic withdrawal.

Topics: Animals; Body Weight; Clonidine; Conditioning, Operant; Dose-Response Relationship, Drug; Humans; Male; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome

A new drug delivery system to induce physical dependence to morphine in rats is described. The device consists of a silicone polymer containing a water soluble "carrier" material, sodium alginate, which swells on contact with moisture to release the drug. The silicone or silastic pellets formulated to contain morphine sulfate are very easily prepared and the advantages over existing methods to induce physical dependence to morphine are discussed. In addition, a comparison of the percent of drug released and withdrawal intensities in rats was made with a silastic-morphine sulfate pellet, silastic-morphine base pellet and a microcrystalline cellulose-morphine base pellet.

Topics: Animals; Body Weight; Delayed-Action Preparations; Drug Implants; Humans; Male; Morphine; Naloxone; Rats; Substance Withdrawal Syndrome; Time Factors

Rats rendered tolerant to and dependent on heroin by administering escalating dosages of heroin from 5 mg/kg-1 to 30 mg/kg-1 s,c, twice daily for 10 days exhibited disrupted diurnal feeding patterns. Daylight food intake was significantly increased, whereas night-time feeding was significantly decreased, as compared with the saline-control group. Growth rate evaluated on the basis of changes in daily body weights was considerably attenuated. The heroin-treated rats showed typical abstinence signs upon naloxone challenge 8 hr after the last heroin challenge. No significant changes were observed in the brain levels of tryptophan, serotonin and 5-hydroxyindoleacetic acid. The formation of newly synthesised 3H-serotonin from 3H-tryptophan was significantly reduced, as evidenced from the decreased specific activity of serotonin. The results obtained in this study indicate that whereas the perturbed diurnal feeding activity cannot be ascribed exclusively to altered central serotonergic mechanism, chronic heroin treatment appears to decrease the rate of serotonin via a negative feedback loop.

Topics: Animals; Biogenic Amines; Body Weight; Brain; Circadian Rhythm; Feeding Behavior; Heroin Dependence; Humans; Male; Naloxone; Rats; Serotonin; Time Factors

Four schedules of subcutaneous morphine pellet implantation were developed to render rats rapidly physically dependent on morphine. The schedules included implantation of four morphine pellets over a 3-day period (schedule 1), six morphine pellets over a 3-day period (schedule 2), six pellets over a 7-day period (schedule 3), and ten pellets over a 10-day period (schedule 4). Each morphine pellet contained 75 mg of morphine base. The degree of morphine dependence was quantitated by determining the median effective dose (ED50) of naloxone required to induce the stereotyped jumping response. Hypothermia and weight loss, during abrupt and naloxone-induced withdrawal, were also measured. Rats on schedule 4 exhibited a high degree of dependence on morphine as evidenced by an extremely low naloxone ED50 for the precipitated withdrawal jumping response, whereas schedules 1 and 2 produced a low degree of dependence as shown by high naloxone ED50's. Further evidence for a high degree of physical dependence on morphine is schedule 4 rats was indicated by their greater loss in body weight and greater hypothermic response after abrupt and after naloxone precipitated withdrawal compared with these responsed in the rats in the other three schedules. A correlation was found to exist between naloxone ED50 for the jumping response, body weight loss, and hypothermia observed during naloxone-induced withdrawal in morphine-dependent rats. These studies suggest that the implantation of four morphine pellets in the rat produces a mild degree of dependence and that caution should be exercised when making generalized conclusions about the biochemical correlations involved when four or less number of pellets, each containing 75 mg of morphine base, are used to induce morphine dependence in the rat.

Topics: Animals; Body Temperature; Body Weight; Dose-Response Relationship, Drug; Drug Implants; Humans; Male; Morphine; Morphine Dependence; Naloxone; Rats; Stereotyped Behavior; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Body Weight; Defecation; Dronabinol; Drug Tolerance; Female; Humans; Motor Activity; Naloxone; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Urination

Rats were trained to press a lever (respond) under a fixed-ratio 20 schedule for food presentation. Administration of 10 or 25 mg of naloxone (NX) per kg i.p. to drug-naive rats supressed responding whereas 1 mg of NX per kg was without effect. However, administration of 0.25 mg of NX per kg to rats which had received 10 or 15 mg of morphine sulfate per kg 48 hours previously induced small, but statistically reliable, decrements in responding. Rats implanted with one pellet containing 75 mg of morphine base displayed tolerance to the depressant effects of the morphine pellet within 2 days after implantation. A systematic study of the effects of naloxone given to morphine tolerant-dependent rats revealed good concordance between the amount of weight lost and the severity of behavioral disruption, within the same subject, after administration of the antagonist. Although 0.03 mg of NX per kg given 3 to 6 days after pellet implantation significantly suppressed responding, 0.1 mg of NX per kg was required to produce a significant reduction in body weight. Semiweekly injections of 1 mg of NX per kg continued to suppress responding up to 4 weeks after implantation of a single morphine pellet. The body weight changes were significant only up to 3 weeks after implantation. The data suggest that disruption of fixed-ratio responding is a sensitive indicator of antagonist-precipitated morphine withdrawal.

Topics: Animals; Body Weight; Conditioning, Operant; Drug Implants; Humans; Injections, Intraperitoneal; Male; Morphine; Morphine Dependence; Naloxone; Rats; Reinforcement Schedule; Substance Withdrawal Syndrome; Time Factors

Tolerance to and physical dependence on morphine in the rat was induced by injecting increasing doses of morphine sulfate (M.S.) administered i.p. twice daily for 14 days. The last dose of M.S. was 200 mg/kg. This procedure produced a 4-fold tolerance to morphine as evidence by the increased dose of morphine required to produce analgesia. The degree of dependence was quantified by determining the naloxone ED50 for the stereotyped withdrawal jumping response. Body weight loss and hypothermic responses during abrupt and naloxone-induced withdrawal were also measured. The degree of tolerance and dependence produced by multiple injection procedure was comparable to that produced by 2 pellets containing 75 mg of morphine base implanted for 3 days. The level and turnover of brain serotonin, determined 6 or 12 h after the last morphine sulfate injection did not differ significantly from that of saline injected control animals. These data indicate that multiple injection technique produces a mild degree of tolerance to, and physical dependence on, morphine which was not related to changes in brain serotonin level or turnover.

Topics: Animals; Body Temperature; Body Weight; Brain; Drug Tolerance; Growth; Humans; Male; Morphine; Morphine Dependence; Naloxone; Rats; Serotonin; Stereotyped Behavior; Substance Withdrawal Syndrome; Time Factors

Neonatal mice were treated with d,1-methadone, 1-alpha-acetylmethadol (LAAM) or the narcotic antagonists, naloxone, nalorphine or levallorphan. Litter mates were injected with normal saline solution and handled in the same way. Treatment began on the second postpartum day and continued daily or on alternate days for up to 6 weeks. Injection of methadone in dosages of 2 mg/kg to mg/kg inhibited weight gain in a log dose-related fashion. LAAM, 1 mg/kg or 2 mg/kg also retarded weight gain. Mice gained weight normally when naloxone, 10 mg/kg was injected with methadone, 2 mg/kg. Furthermore the daily injection of d-methadone, 4 mg/kg, did not inhibit weight gain nor did any of the narcotic antagonists. There findings indicate that growth inhibition induced by methadone is a stereospecific, opioid effect.

Topics: Animals; Animals, Newborn; Appetite Depressants; Body Weight; Depression, Chemical; Drug Tolerance; Female; Growth; Levallorphan; Methadone; Methadyl Acetate; Mice; Nalorphine; Naloxone; Reaction Time; Stereoisomerism; Time Factors

Topics: Animals; Body Weight; Brain; Hypophysectomy; Ligands; Male; Naloxone; Nerve Tissue Proteins; Peptide Biosynthesis; Pituitary Gland; Rats; Receptors, Opioid

Topics: Analgesia; Animals; Body Weight; Drug Interactions; Drug Tolerance; Humans; Male; Morphine; Nalorphine; Naloxone; Rats; Reaction Time; Receptors, Opioid; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors

The effects of centrally acting drugs on body weight changes during 8-h periods in the daytime were studied in the rat in attempts to relate those effects with morphine-type physical liability. Repeated administration of drugs which have morphine-type physical dependence liability altered the prevailing pattern of continuous body weight decrease during the observation period in control animals to an initial increase and subsequent decrease. Withdrawal of these drugs following chronic drug treatment caused a precipitous loss of body weight. Such a body weight loss was further enhanced by the administration of naloxone. In chronically morphine-treated animals, substitution for morphine with a single dose of a test drug caused an increase in body weight or attenuated the loss of body weight due to morphine withdrawal when the test drug has physical dependence liability. Drugs may be classified according to their effects on body weight changes into several groups, each with different physical dependence liability. It is concluded that physical dependence liability of centrally acting drugs can be predicted simply, inexpensively and objectively, by their effects on the pattern of daily body weight changes.

Topics: Animals; Body Weight; Circadian Rhythm; Drug Evaluation, Preclinical; Humans; Male; Morphine Dependence; Naloxone; Rats; Substance-Related Disorders

Rats drank solutions of narcotic analgesics as the only drinking fluid available in their cages. Relative to their daily water intake before the drug solutions were introduced, the rats drank more etonitazene solution, less methadone solution, and about the same volume of morphine, meperidine and levorphanol solution as water, although some rats would not drink the higher concentrations of morphine (1.0 mg/ml), levorphanol (1.0 mg/ml) and methadone (1.0 mg/ml). When naloxone (1.0 mg/kg) was administered after 12 days of drinking the drug solutions, the severity of the abstinence syndromes based on scoring of symptoms and on weight loss was morphine greater than or equal to etonitazine greater than levorphanol greater than meperidine greater than methadone. The animals showing the most severe syndrome after naloxone usually consumed more drug solution than usual during the next 24 hours, so that body weights were normal at the end of the 24-hour period. Nonprecipitated abstinence was also studied in these rats by replacing the drug solutions with water 3 to 5 days after the naloxone injection. Rats that had been drinking morphine, etonitazene and levorphanol lost weight for 2 or 3 days and then began to regain their lost weight. In contrast, rats which had been switched from methadone and meperidine solutions to water gained weight rapidly. Morphine and etonitazene drinkers which had been switched to water drank a lesser volume of water than they had been drinking of drug solution whereas some ex-methadone drinkers drank more water.

Topics: Administration, Oral; Animals; Body Weight; Circadian Rhythm; Drinking; Humans; Male; Morphine; Naloxone; Narcotic Antagonists; Rats; Substance Withdrawal Syndrome; Time Factors; Water

Chronic but not acute treatment with morphine resulted in a significant decrease in the histamine concentration in the rat hypothalamus while a slight decrease was noted in the brain stem and cortex. Naloxone precipitated morphine withdrawal caused a significant decrease in histamine concentration in all three brain regions investigated. Withdrawal of morphine resulted in a further significant decrease in histamine level in the hypothalamus, brain stem and cortex. Substitution of morphine by methadone induced changes similar to these seen in rats chronically treated with morphine alone. The present data suggest that in addition to the other biogenic amines histamine may be involved in the pharmacological effects of morphine.

Topics: Animals; Body Weight; Brain; Brain Stem; Cerebral Cortex; Histamine; Humans; Male; Methadone; Morphine; Naloxone; Rats; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Apomorphine; Behavior, Animal; Body Weight; Clonidine; Drug Interactions; Male; Naloxone; Rats; Reinforcement Schedule; Synapses

Topics: Analgesia; Animals; Arginine Vasopressin; Body Temperature; Body Weight; Drug Synergism; Female; Humans; Morphine Dependence; Naloxone; Oligopeptides; Oxytocin; Rats; Structure-Activity Relationship; Vasopressins

Topics: Animals; Body Weight; Corpus Striatum; Dopamine; Humans; Male; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Norepinephrine; Species Specificity; Substance Withdrawal Syndrome

Time course and duration and physical dependence was investigated in rats implanted subcutaneously with 3 different types of morphine (M) pellets. Each was formulated according to the method of Gibson and Tingstand [8], but differed in surface area and hardness. Animals were maintained for 19 days after implantation and physical dependence was assessed every other day. Severity of naloxone (Nx)-induced withdrawal was quantified by the use of a composite symptom score and weight loss. Withdrawal severity was greatest following implantation of a pellet (Type C) of large surface area and low hardness rating, and least following implantation of a pellet (Type A) of small surface area and high hardness rating. Abstinence severity which resulted from implantation of a pellet (Type B) of moderate surface area and low hardness rating was intermediate. When 2 pellets were implanted the difference between Type C and B was amplified. It was concluded that formulation per se was not sufficient for specifying M pellet characteristics.

Topics: Animals; Body Weight; Drug Implants; Hardness; Humans; Male; Morphine; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome; Surface Properties; Tablets; Time Factors

Rats were trained to bar press for intravenous infusions of morphine sulfate during 1-hr daily test sessions. Small, centrally placed bilateral lesions of the caudate nucleus reduced rats of morphine self-administration to approximately one seventh of preoperative levels; postoperative rates were similar to preoperative rates when the postoperative unit infusion dose of morphine was one tenth of the preoperative dose. Caudate lesions also lowered the threshold dose at which morphine's rewarding property could be detected. Physical dependence was studied in other rats receiving a 3-day continuous infusion of morphine sulfate via implanted subcutaneous silicone reservoirs. Caudate lesions ameliorated withdrawal-induced weight loss and naloxone-induced "wet dog shakes". Both the self-administration and dependence data are consistent with the idea that morphine blocks dopaminergic transmission in the striatum.

Topics: Animals; Body Weight; Caudate Nucleus; Conditioning, Operant; Female; Humans; Morphine; Morphine Dependence; Naloxone; Rats; Reward; Stereotaxic Techniques; Substance Withdrawal Syndrome

Morphine was injected subcutaneously in doses of 2.5 to 10 mg/kg every 6 hours into pregnant rabbits from early pregnancy until delivery by hysterotomy on the 27th, 28th or 29th day. Pregnant control animals received 0.9% NaC1 injections. Abortions occurred in 34% of the morphine-treated does as a doserelated effect and in 6.5% of the controls. In preserved pregnancies the prevalence of intrauterine death was identical in both samples. Fetuses of treated animals weighed significantly less than those of the controls.However, the normally present effect of intrauterine position on fetal growth was not altered in fetuses of treated animals, so that growth-retarded as well as normal fetuses weighed more when located in the ovarium rather than the cervical portion of the uterus. The fetal lungs were inflated to 35 cm H2O and the remaining air at a deflation pressure of 10 cm H2O (V10) was determined as a measure of lung stability. There were no differences in this indicator of fetal lung maturity between fetuses of treated and control animals. It was found that the lecithin/sphingomyelin (L/S) ratio in the amniotic fluid of rabbits does not correlate with lung maturity; there were no differences between fetuses of treated and control animals. Morphine, when administered to pregnant rabbits does not accelerate fetal lung development. Therefore, the observed reduction in the incidence of respiratory distress syndrome in infants of heroin-addicted women has no direct equivalent in this animal model.

Topics: Abortion, Spontaneous; Amniotic Fluid; Animals; Birth Weight; Body Weight; Dose-Response Relationship, Drug; Embryo Implantation; Female; Fetal Death; Fetus; Gestational Age; Humans; Injections, Subcutaneous; Lung; Morphine; Naloxone; Phosphatidylcholines; Pregnancy; Pregnancy, Animal; Rabbits; Residual Volume; Sphingomyelins; Substance Withdrawal Syndrome

Weight loss and shock-elicited aggression have been compared as quantitative indices of morphine abstinence in rats. A range of doses of morphine was administered to rats by i.p. injection twice daily for 12-15 days. After injections were stopped, morphine-abstinent rats lost weight precipitously, and showed an increased frequency of fighting in response to aversive stimulation (foot-shock). Recovery of weight appeared complete after 15-20 days but a significant increase in aggression was found at 18 days post-withdrawal; this virtually disappeared after 52 days. Both the amount of weight lost and the frequency of fighting increased as a function of the previous maintenance dose of morphine; the effective dose range appeared similar for these two indices. Weight loss was much less variable than fighting, had the advantage of rapid, objective measurement, and appeared to be the more reliable index of abstinence.

Topics: Aggression; Animals; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Humans; Male; Morphine; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome

Topics: 5-Hydroxytryptophan; Adrenergic beta-Antagonists; Analgesics; Animals; Body Weight; Brain; Brain Chemistry; Cyclic AMP; Cycloheximide; Drug Tolerance; Fenclonine; Humans; Mice; Morphine; Morphine Dependence; Naloxone; Rats; Serotonin; Serotonin Antagonists; Time Factors; Tryptamines; Tryptophan; Tryptophan Hydroxylase

Topics: Adrenergic beta-Antagonists; Animals; Behavior, Animal; Body Weight; Chlorpromazine; Depression, Chemical; Dose-Response Relationship, Drug; Haloperidol; Humans; Male; Morphine Dependence; Naloxone; Pentobarbital; Phenoxybenzamine; Phentolamine; Promethazine; Propranolol; Rats; Substance Withdrawal Syndrome; Time Factors

Topics: Analgesia; Animals; Behavior, Animal; Body Weight; Cannabis; Catalepsy; Dealkylation; Dronabinol; Drug Interactions; Humans; Mice; Morphine; Morphine Dependence; Naloxone; Rats; Time Factors

Topics: Administration, Oral; Animals; Behavior, Animal; Body Weight; Diarrhea; Dose-Response Relationship, Drug; Humans; Male; Mice; Morphine; Morphine Dependence; Motor Activity; Naloxone; Posture; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Behavior, Animal; Body Weight; Codeine; Dose-Response Relationship, Drug; Humans; Infusions, Parenteral; Injections, Intraperitoneal; Male; Meperidine; Methadone; Morphine; Morphine Dependence; Nalorphine; Naloxone; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders; Time Factors; Vocalization, Animal

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Inbred Strains; Morphine Dependence; Motor Activity; Naloxone; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Dogs; Dose-Response Relationship, Drug; Haloperidol; Hot Temperature; Humans; Morphinans; Morphine; Morphine Dependence; Naloxone; Propranolol; Pulse; Pupil; Reflex; Respiration; Skin; Substance Withdrawal Syndrome; Time Factors

Topics: Acetylcholine; Analgesia; Animals; Behavior, Animal; Body Weight; Brain; Choline; Chromatography, Gas; Copper; Dopamine; Dopamine beta-Hydroxylase; Drug Synergism; Drug Tolerance; Humans; Male; Mice; Morphine; Morphine Dependence; Naloxone; Norepinephrine; Phenylthiourea; Serotonin; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Behavior, Animal; Body Temperature; Body Weight; Catalepsy; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methadone; Naloxone; Norepinephrine; Rats; Reserpine; Serotonin; Stereotyped Behavior; Time Factors

Topics: Analgesia; Animals; Body Weight; Cyclic AMP; Cycloheximide; Drug Tolerance; Humans; Male; Mice; Mice, Inbred ICR; Morphine; Morphine Dependence; Naloxone; Pargyline; Substance Withdrawal Syndrome; Time Factors

Topics: Anesthesia; Body Weight; Doxapram; Female; Humans; Meperidine; Morphine; Naloxone; Nikethamide; Pain; Pressure; Time Factors

Newborn mice injected daily for 6 weeks with dl-methadone in dosages of 2 to 8 milligrams per kilogram grew significantly more slowly than their saline-treated littermates. Litters given d-methadone, 4 milligrams per kilogram, grew normally. Concomitant treatment with naloxone, 10 milligrams per kilogram, prevented growth inhibition. A weight deficit persisted in mice observed 6 weeks after cessation of methadone treatment.

Topics: Animals; Animals, Newborn; Body Weight; Dose-Response Relationship, Drug; Female; Growth; Injections, Subcutaneous; Male; Methadone; Mice; Naloxone

Topics: Animals; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Humans; Male; Morphine Dependence; Naloxone; Placebos; Rats; Semen; Substance Withdrawal Syndrome

Topics: Analgesia; Animals; Body Weight; Female; Humans; Hyperesthesia; Morphine; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Body Weight; Drug Tolerance; Electric Stimulation; Humans; Morphine; Naloxone; Rats; Self Stimulation; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Body Weight; Food Deprivation; Humans; Injections, Intraperitoneal; Morphine; Morphine Dependence; Naloxone; Pentolinium Tartrate; Rats; Substance Withdrawal Syndrome; Water Deprivation

1. Adrenalectomy reduced the median antinociceptive dose (AD50) of morphine in male Sprague-Dawley rats. The antinociceptive effect was assessed by the tail-flick method of D'Amour & Smith (1941).2. Tolerance to the antinociceptive effect of morphine developed in adrenalectomized and sham-operated rats after chronic exposure to morphine. Development of tolerance did not significantly alter the increased sensitivity of adrenalectomized rats to the antinociceptive effect of morphine.3. Adrenal weights were not increased in rats rendered physically dependent on morphine by subcutaneous implantation of a morphine pellet. Withdrawal, induced by intraperitoneal injection of naloxone hydrochloride, 4 mg/kg, or by removal of the implanted pellet, resulted in a rapid increase in adrenal weight.4. In morphine-dependent animals, the incidence of abstinence signs and body weight loss during precipitated withdrawal did not appear to be significantly influenced by adrenalectomy or by corticosterone-pretreatment.

Topics: Adrenal Glands; Adrenalectomy; Analgesia; Animals; Body Weight; Corticosterone; Drug Tolerance; Humans; Male; Morphine; Morphine Dependence; Naloxone; Organ Size; Pituitary Gland; Placebos; Rats; Substance Withdrawal Syndrome; Time Factors

Topics: Analgesics; Animals; Body Weight; Cyclazocine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Injections, Subcutaneous; Male; Mice; Morphine; Motor Activity; Nalorphine; Naloxone; Narcotic Antagonists; Placebos; Reflex; Tail; Time Factors

Topics: Animals; Avoidance Learning; Body Weight; Conditioning, Classical; Dose-Response Relationship, Drug; Drinking; Drug Tolerance; Humans; Male; Mice; Morphine; Morphine Dependence; Naloxone; Rats; Saccharin; Substance Withdrawal Syndrome; Water

Topics: Analgesia; Animals; Body Weight; Brain Chemistry; Brain Stem; Drug Tolerance; Fenclonine; Humans; Hypothalamus; Male; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Pargyline; Phenylalanine; Rats; Rats, Inbred Strains; Serotonin; Substance Withdrawal Syndrome; Time Factors

Topics: Analgesia; Animals; Behavior, Animal; Body Weight; Drug Tolerance; Humans; Infusions, Parenteral; Injections; Male; Meperidine; Methadone; Mice; Morphine; Morphine Dependence; Motor Activity; Naloxone; Pentazocine; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Body Weight; Brain Chemistry; Drug Interactions; Female; Fenclonine; Humans; Kinetics; Mice; Mice, Inbred Strains; Monoamine Oxidase Inhibitors; Morphine; Morphine Dependence; Motor Activity; Naloxone; Serotonin; Substance Withdrawal Syndrome; Tranylcypromine; Tryptophan