naloxone and Weight-Gain

Previously we found significant suppression of polydipsia in a schizophrenic patient with PIP syndrome (psychosis, intermittent hyponatremia, and polydipsia). Suppression was obtained with a small dose of naloxone injected once every 2 weeks in long-term repeated studies. We attempted to confirm the effect of naloxone on PIP syndrome by using a double-blind controlled study. The body weights of eight schizophrenic inpatients with PIP syndrome were checked five times daily, and the maximum weight gain during 1 day was chosen as an index of their polydipsia. Naloxone (0.6 mg in three divided doses) or placebo (saline) injection was given once every 2 weeks three times. Assignment to either the naloxone or placebo series was done randomly in a double-blind, crossover design. Naloxone decreased the maximum weight gain per day significantly in five cases. However, naloxone also increased weight gain significantly in three cases. There was no correlation of the weight-increasing effect of naloxone with the duration and intensity of excessive drinking. Our findings showed that the endogenous opioid system might be related to compulsive drinking behavior in the PIP syndrome and that opioid antagonists such as naloxone or naltrexone could be useful in the therapy of PIP syndrome.

Topics: Adult; Aged; Cross-Over Studies; Double-Blind Method; Drinking Behavior; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid Peptides; Schizophrenia; Water Intoxication; Weight Gain

Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic-pituitary-adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Heart Ventricles; Hypothalamo-Hypophyseal System; Male; MAP Kinase Signaling System; Morphine Dependence; Naloxone; Narcotic Antagonists; Phosphorylation; Pituitary-Adrenal System; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Substance Withdrawal Syndrome; Tyrosine 3-Monooxygenase; Ventricular Dysfunction, Right; Weight Gain

Topics: Buprenorphine; Female; Humans; Infant, Newborn; Naloxone; Narcotic Antagonists; Neonatal Abstinence Syndrome; Opioid-Related Disorders; Pregnancy; Pregnancy Complications; Weight Gain; Young Adult

Low-dose combinations of naloxone and rimonabant produce additive effects on food intake and feeding behaviour, yet abolish the scratching syndrome typically induced by rimonabant per se. To assess the generality of these findings, we have examined the acute effects of low-dose combinations of naloxone (0.1 mg/kg) and the rimonabant derivative AM 251 (0.5 and 1.0 mg/kg) on food intake, feeding behaviour and weight gain in non-deprived male rats. Although ineffective when given alone, combined treatment with naloxone and 0.5 mg/kg AM 251 significantly and selectively suppressed mash intake and time spent feeding. By itself, 1.0 mg/kg AM 251 failed to alter any measure of feeding behaviour but did reduce food consumption and induce scratching behaviour. Co-administration of naloxone with 1.0 mg/kg AM 251 not only significantly suppressed both food intake and feeding behaviour but also simultaneously attenuated AM 251-induced scratching. This profile mirrors earlier findings with naloxone/rimonabant and is consistent with the reported diversity of opioid-cannabinoid system interactions at a more molecular level. Although further studies are required (e.g. 'neutral' CB1 receptor antagonists), current data constitute further proof of concept regarding the anorectic efficacy, selectivity and added value of low-dose polytherapy with opioid and CB1 receptor antagonists.

Topics: Animals; Drug Interactions; Eating; Feeding Behavior; Grooming; Male; Motor Activity; Naloxone; Narcotic Antagonists; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Weight Gain

Our previous studies have shown that morphine withdrawal induced an increase in the expression of protein kinase (PK) A and mitogen-activated extracellular kinase (MAPK) pathways in the heart during morphine withdrawal. The purpose of the present study was to evaluate the interaction between PKA and extracellular signal-regulated kinase (ERK) signaling pathways mediating the cardiac adaptive changes observed after naloxone administration to morphine-dependent rats. Dependence on morphine was induced by a 7-day subcutaneous implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (2 mg/kg). ERK1/2 and tyrosine hydroxylase (TH) phosphorylation was determined by quantitative blot immunolabeling using phosphorylation state-specific antibodies. Naloxone-induced morphine withdrawal activates ERK1/2 and phosphorylates TH at Ser31 in the right and left ventricle, with an increase in the mean arterial blood pressure and heart rate. When N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004), a PKA inhibitor, was infused, concomitantly with morphine, it diminished the expression of ERK1/2. In contrast, the infusion of calphostin C (a PKC inhibitor) did not modify the morphine withdrawal-induced activation of ERK1/2. The ability of morphine withdrawal to activate ERK that phosphorylates TH at Ser31 was reduced by HA-1004. The present findings demonstrate that the enhancement of ERK1/2 expression and the phosphorylation state of TH at Ser31 during morphine withdrawal are dependent on PKA and suggest cross-talk between PKA and ERK1/2 transduction pathway mediating morphine withdrawal-induced activation (phosphorylation) of TH.

Topics: Adaptation, Physiological; Aminoacetonitrile; Analgesics, Opioid; Animals; Blotting, Western; Cyclic AMP-Dependent Protein Kinases; Enzyme Inhibitors; Heart; Hemodynamics; Isoquinolines; Male; Mitogen-Activated Protein Kinases; Morphine; Naloxone; Naphthalenes; Narcotic Antagonists; Phosphorylation; Protein Kinase C; Rats; Rats, Sprague-Dawley; Signal Transduction; Substance Withdrawal Syndrome; Sulfonamides; Tyrosine 3-Monooxygenase; Weight Gain

This study investigated the combined effect of neonatal maternal separation and acute psychological stress on pain responses in adult rats. Long-Evans dams and their male pups were reared under two conditions: 1) 180 min daily maternal separation (MS180) on postnatal days 2-14 or 2) no handling or separation (NH). At 2 mo of age, visceromotor responses to graded intensities of phasic colorectal distension (10-80 mmHg) at baseline as well as following acute 60 min water avoidance stress (WA) were significantly higher in MS180 rats. Both groups showed similar stress-induced visceral hyperalgesia in the presence of naloxone (20 mg/kg ip). MS180 rats had smaller stress-induced cutaneous analgesia in the tail-flick test compared with NH rats, with a residual naloxone-resistant component. MS180 rats showed an enhanced fecal pellet output following WA or exposure to a novel environment. These data suggest that early life events predispose adult Long-Evans rats to develop visceral hyperalgesia, reduced somatic analgesia, and increased colonic motility in response to an acute psychological stressor, mimicking the cardinal features of irritable bowel syndrome.

Topics: Animals; Animals, Newborn; Behavior, Animal; Colonic Diseases, Functional; Defecation; Disease Models, Animal; Eating; Female; Gastrointestinal Motility; Hyperalgesia; Male; Maternal Deprivation; Naloxone; Narcotic Antagonists; Nociceptors; Pain Threshold; Pregnancy; Rats; Rats, Long-Evans; Stress, Psychological; Weight Gain

Stressful stimuli repeatedly applied during the first postnatal weeks can induce body weight gain in the mouse during adulthood. This effect can be prevented by injecting naloxone concomitantly with stress. The peptides belonging to the Tyr-MIF-1 family have a great modulating activity on numerous stress-induced phenomena. The aim of the present work was to compare the effect of repeated neonatal injections of Tyr-MIF-1 or naloxone on the long-term body weight gain induced by a stressing procedure applied daily during the first three weeks of life. The results indicate that although naloxone blocked the development of the stress-induced effects, Tyr-MIF-1 potentiated them.

Topics: Adipose Tissue; Animals; Animals, Newborn; Eating; Male; Mice; MSH Release-Inhibiting Hormone; Naloxone; Narcotic Antagonists; Opioid Peptides; Stress, Physiological; Weight Gain

The effects of prolonged exposure of rats to sweetened caloric (sucrose) and non-caloric (saccharin) solutions on subsequent sensitivity to the anorectic effects of naloxone and d-fenfluramine were investigated in a series of experiments. In Experiment 1, rats given 18 days exposure to 10% sucrose showed greater sensitivity to the anorectic effects of naloxone (0.125-1.0 mg/kg, IP) in a separate feeding test, than did controls or rats exposed to 0.2% saccharin. This effect was replicated in Experiment 2, and here rats exposed to a palatable quinine-sucrose solution that was less preferred than saccharin also showed an enhanced sensitivity to naloxone, similar to that seen in the group exposed to sucrose alone. In Experiment 3, prior exposure to sucrose, quinine-sucrose or saccharin had no effect on the anorectic effects of dexfenfluramine (1.0 and 2.0 mg/kg), while the effect of naloxone (1.0 mg/kg SC) was enhanced by exposure to the two sucrose solutions. All sucrose-exposed rats gained more weight than did control or saccharin-exposed rats. These data suggest that the consumption of palatable calorie-containing solutions selectively alters sensitivity to naloxone, and a number of possible explanations are discussed.

Topics: Analysis of Variance; Animals; Appetite Depressants; Eating; Fenfluramine; Male; Naloxone; Narcotic Antagonists; Quinine; Rats; Saccharin; Sucrose; Sweetening Agents; Taste; Weight Gain

To investigate the role of opioids in the mediation of sucrose intake in the preweanling rat pup, we measured the effect of naloxone on intake of pups licking 10% sucrose from the floor of a beaker (independent ingestion test) and of pups ingesting 10% sucrose that was continuously infused through an anterior, sublingual oral catheter (oral catheter test). Pups were tested only once to eliminate the possible effect of test experience. Pups were tested in the second postnatal week (PN7, 9, 10, 11, and 14 days) with naloxone (1 mg/kg) or vehicle controls. Fourteen-day-old pups were also tested with 0.1 and 0.5 mg/kg. Naloxone began to be efficacious for inhibiting intake on PN10 in the oral catheter test and on PN11 in the independent ingestion test. On PN14, the inhibition of intake was dose related and naloxone was more potent for inhibiting intake in independent ingestion tests than in oral catheter tests. Naloxone not only decreased intake, it also decreased the incidence of licking, increased mouthing and resting, and had no significant effect on locomotion. The site of the inhibitory effect of naloxone on intake was in the central nervous system, presumably in the brain, because naloxonemethiodide, an analogue of naloxone that does not cross the blood-brain barrier, did not inhibit sucrose in either test. These results demonstrate that the intake of 10% sucrose depends on endogenous opioids as early as PN10 and that this opioid mechanism operates when pups have not had prior test experience and in a test (oral catheter test) where intake is not dependent on appetitive behaviors.

Topics: Animals; Animals, Newborn; Consummatory Behavior; Eating; Female; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Sucrose; Weight Gain

The adjuvant arthritic rat model has been utilized for the study of chronic pain, as polyarthritic rats present a variety of symptoms similar to those seen in human chronic pain conditions. In particular, hyperventilatory responses are notable in both and may more accurately reflect basal ongoing pain than do evoked noxious stimuli. To assess whether adrenal medullary transplants in the spinal subarachnoid space can alleviate basal arthritic pain, respiratory parameters were determined using whole body plesthmography in polyarthritic rats. Arthritis was induced by inoculation with an intradermal injection of complete Freund's adjuvant. Steady-state ventilation was monitored at weekly intervals in arthritic animals with adrenal medullary or control striated muscle transplants. Results revealed that adjuvant arthritis produced significant hyperventilation in animals with control transplants, as indicated by increased tidal volumes and minute ventilation, which paralleled the progression of the inflammatory process. In contrast, this hyperventilation was eliminated by adrenal medullary transplants. A role for catecholamines and opioid peptides released from the transplants was suggested by the reversal of these effects with phentolamine and naloxone. In addition, the retardation in weight gain normally observed in polyarthritic animals was markedly attenuated by adrenal medullary, but not control transplants. These findings indicate that adrenal medullary transplants in the spinal subarachnoid space can alleviate basal chronic pain as assessed in adjuvant arthritis.

Topics: Adrenal Medulla; Adrenergic alpha-Antagonists; Animals; Arthritis, Experimental; Catecholamines; Chronic Disease; Hyperventilation; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Management; Phentolamine; Rats; Rats, Sprague-Dawley; Respiratory Mechanics; Subarachnoid Space; Weight Gain

The use and abuse of benzodiazepines is widespread and we have begun to address whether maternal exposure to these drugs influences the development of opioid systems. We have studied the effect of maternal diazepam treatment on stress-induced antinociception in the neonatal offspring. Diazepam (1 or 10 mg/kg) was administered twice daily to mothers from conception. Pre- and postweanling rat pups were assessed for opioid-mediated stress-induced antinociception by 3-min swimming and measuring nociception using the tail immersion test. In preweanling rats there was stress-induced antinociception in both vehicle- and diazepam-treated animals but in diazepam-treated groups (1 and 10 mg/kg) this was insensitive to reversal by the opioid antagonist naloxone, suggesting that nonopioid systems are operating this response. In postweanling rats a similar insensitivity to naloxone was observed in 1 mg/kg diazepam-treated groups; with 10 mg/kg diazepam there was no significant antinociception. The results suggest that maternal diazepam treatment interferes with the development of stress-mediated responses and that part of this toxicity is due to actions on opioid systems in the CNS.

Topics: Animals; Animals, Newborn; Central Nervous System; Diazepam; Drinking; Endorphins; Female; Male; Maternal-Fetal Exchange; Naloxone; Nociceptors; Pregnancy; Rats; Rats, Wistar; Stress, Physiological; Swimming; Weight Gain

1. The present study was performed to examine the effect of naloxone on drinking behavior in three schizophrenic inpatients with psychosis, intermittent hyponatremia, and polydipsia. 2. Their body weight were checked five times daily and the maximum weight gain during a day was chosen as an index of their polydipsia. 3. After control recording for six weeks, a daily naloxone (0.6 mg) injection series was performed once every two weeks for three series (six weeks). Withdrawal of this drug for six weeks resulted in weight gain recovering to control level. 4. The present study showed that naloxone seems to be a potential treatment for psychiatric patients displaying self-induced water intoxication and that endogenous opioid systems are involved in the compulsive drinking behavior of this syndrome.

Topics: Drinking Behavior; Female; Humans; Male; Middle Aged; Naloxone; Schizophrenia; Schizophrenic Psychology; Water Intoxication; Weight Gain

We examined the functional status of the hypothalamic-opioid system involved in LH secretion and the pituitary LH sensitivity and reserve in patients with anorexia nervosa were studied during body weight loss and weight recovery. We measured the temporal relationship between weight recovery, expression of hypothalamic-opioid activity and pituitary GnRH responsiveness, and resumption of ovulatory cycles.. Five patients with anorexia nervosa were prospectively studied during weight loss and amenorrhoea, subsequently when they reached their ideal body weight but still remained amenorrhoeic and thereafter every 6 months until resumption of ovulatory cycles; one patient was studied only during weight loss, two during ideal body weight and amenorrhoea and one during ideal body weight and ovulatory cycles. Blood was sampled every 10 minutes over a 16-hour period on two alternate days. On study day 1 (control day), patients received two sets of saline infusion every 6 hours and one saline bolus at the beginning of the seventh hour; on study day 3 (experimental day), they received a saline infusion during the first 6 hours, an intravenous bolus of naloxone (20 mg) at the beginning of the seventh hour and then a continuous naloxone infusion (1.6 mg per hour) during the ensuing 6 hours. Pituitary LH sensitivity and reserve were assessed on both study days by the subsequent administration of 5 and 95 micrograms of GnRH 4 hours before the completion of each sampling period. Patients in ideal body weight and ovulatory cycles as well as five normal menstruating women included in the study for comparative purposes, were studied during the midluteal phase of a cycle.. LH, oestradiol and progesterone were determined by radioimmunoassay. Areas under the LH curve were calculated by the trapezoid method; LH pulse detection was carried out by the program Cluster.. Naloxone administration to patients with anorexia nervosa in the weight loss phase, did not significantly modify their serum LH levels nor the characteristics of its pulsatile secretion. Administration of the opioid blocker induced a significant increase in serum LH concentrations only in those patients in ideal body weight and amenorrhoea who resumed ovulatory cycles within the 6 months following the last study as well as in patients with an ideal body weight and ovulatory cycles and in normal controls. All patients and subjects who responded to naloxone administration exhibited significant increases in the area under the LH curve, mean LH pulse amplitude and peak area. Patients in ideal body weight and amenorrhoea who did not resume ovulatory cycles within the 6 months following the study days, did not respond to naloxone administration. There were no significant correlations between the magnitude of LH response to naloxone administration and the baseline levels of serum oestradiol and progesterone. All patients exhibited significant pituitary LH responses to both GnRH doses, regardless of the stage of the disease; however, the pituitary responsiveness shown by patients in ideal body weight was significantly higher than that presented by patients in weight loss. There were no significant differences between the responses to GnRH exhibited by patients in ideal body weight and amenorrhoea who responded to naloxone administration and those shown by patients in the same clinical condition but who were insensitive to opioid blockade.. The re-establishment of hypothalamic-opioid inhibitory activity involved in LH secretion in patients with anorexia nervosa during the phase of weight gain predicts imminent restoration of ovulatory cycles. Pituitary LH response to exogenous GnRH during weight recovery does not accurately predict the outcome of the disease regarding reinitiation of menstrual cycles; however, it might be an indicator that the normal function of the hypothalamic-pituitary axis is being restored.

Topics: Adolescent; Adult; Anorexia Nervosa; Female; Gonadotropin-Releasing Hormone; Humans; Hypothalamus; Luteinizing Hormone; Naloxone; Ovulation; Pituitary Gland; Secretory Rate; Weight Gain; Weight Loss

We showed recently that bilateral ibotenic acid lesions of the lateral hypothalamus (LH) produced three main behavioral disturbances in the rat, i.e., an increase in the gustatory preference and aversion thresholds for saccharin, permanent body weight and water intake deficits, and an alteration of morphine-induced modulation of taste. The two first results could suggest that the modification of the gustatory thresholds and the ingestive deficits are closely interrelated. Given this situation, we hypothesized that, conversely, a brain lesion known to induce obesity and hyperdipsia would therefore decrease the gustatory preference and aversion thresholds for saccharin. In order to test this hypothesis we analyzed the effects of the bilateral lesion of the hypothalamic paraventricular nucleus (PVH) by injection of ibotenic acid (2 micrograms in each side) on saccharin preference. The main results are as follows: 1) The neurotoxin selectively destroyed parvicellular neurons while the magnocellular cells were spared. 2) In comparison to the normal daily gain in body weight of the sham-lesioned animals, the lesioned rats showed an enhanced weight gain that became significant from the third day after the surgery up until the day of sacrifice, 37 days later. 3) In contrast to electrolytic lesions of the PVH, the ibotenic acid lesions of this nucleus did not induce hyperdipsia. 4) Preference and aversion thresholds for saccharin were not significantly modified by the lesion. 5) Whereas low doses of morphine suppressed the preference for saccharin in sham-lesioned rats when the concentration of the sweetener solution was at the threshold value, this suppressive effect was not observed in PVH-lesioned rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Avoidance Learning; Brain Mapping; Conditioning, Classical; Dose-Response Relationship, Drug; Drinking; Ibotenic Acid; Male; Morphine; Naloxone; Neurons; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Saccharin; Sensory Thresholds; Taste; Water Deprivation; Weight Gain

A study was conducted to determine whether an opioid tonus inhibitory of LH secretion is present in underfed prepubertal sheep. Ten Suffolk ewe lambs were subjected to food restriction during 60 days. During this period they were allowed to pasture only 2 hours per day while control ewe lambs were allowed for 10 hours. Body weight and plasma blood levels of glucose, urea and total proteins were measured weekly. At the end of this period, an intravenous injection of Naloxone (NAL, 1.5 mg/kg BW) was given to control and underfed animals followed 60 min later by an intravenous injection of LHRH to test the pituitary responsiveness. Underfed animals did not show an increase in plasma LH while control animals presented a rise from 0.28 +/- 0.08 to 2.02 +/- 0.6 ng/ml after the NAL stimulus (P less than 0.05). The response to LHRH was similar in both group of animals. Basal plasma levels of insulin were lower in underfed ewe lambs than in control animals (P less than 0.05). Underfed animals were placed on plain feeding with a schedule similar to control lambs for 30 days and the same experiment was repeated. During this occasion, NAL increased plasma LH concentration in both group of lambs. Levels of plasma insulin were not different in both groups. The lack of effect of NAL on LH secretion in food restricted ewe lambs suggests that the opioid modulation of LH secretion is absent by underfeeding in female prepubertal sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Glucose; Blood Proteins; Endorphins; Female; Food Deprivation; Gonadotropin-Releasing Hormone; Luteinizing Hormone; Naloxone; Sexual Maturation; Sheep; Urea; Weight Gain

The effects of stress on food intake and on neural activity in the lateral hypothalamic area (LHA) were investigated. Significant reduction of daily food intake was observed after 2 hr immobilization. The reduction of body weight was also significant during experimental days. Duplicate injections of methysergide (5 mg/kg, IP) antagonized the immobilization-induced anorexia for 3 hr and injection of naloxone had no effect. Single neuron activity was recorded from a chronically implanted electrode. Activity of 80% of LHA neurons was significantly decreased by immobilization stress. Methysergide significantly attenuated the suppressive effect of immobilization. Further, direct effects of 5-HT on LHA neurons were examined in anesthetized rats. Of 43 LHA neurons tested, the activity of 35 was inhibited by electrophoretic application of 5-HT. These results suggest that immobilization-induced anorexia is mediated at least in part through serotonergic mechanisms in the LHA.

Topics: Animals; Behavior, Animal; Feeding Behavior; Hypothalamic Area, Lateral; Iontophoresis; Male; Methysergide; Naloxone; Rats; Rats, Inbred Strains; Restraint, Physical; Serotonin; Stress, Physiological; Weight Gain