naloxone and Weight-Loss

Previously, we have shown that in the opposite extremes of nutritional status (obesity and anorexia nervosa [AN]), the growth hormone (GH) response to GH-releasing hormone (GHRH) is not inhibited by the ingestion of a normal 800-kcal meal at noon. In obese subjects, GHRH-induced GH release is significantly increased (known as the "paradoxical response"). An opiate antagonist infusion (naloxone [NAL]) inhibited this postprandial meal-induced augmenting effect in obese subjects, suggesting opioid involvement in the paradoxical response. The paradoxical postprandial GH release persisted in obese subjects, who after biliopancreatic diversion (BPD) experienced a reduction in body weight, despite the elevation of fasting GH levels. We therefore tested a group of patients, before and after BPD, composed of 10 females, aged 23 to 54 years, who after surgery had experienced a significant reduction in body weight (mean body mass index [BMI], 25.78 +/- 1.01 kg/mg v 44.68 +/- 1.73 kg/mg). The subjects were studied 16 to 24 months after operation, in a phase of stabilized body weight. They underwent, in randomized order, the following tests: GHRH (1 microg/kg as an intravenous [IV] bolus) at 1:00 PM, in the fasting state; GHRH (1 microg/kg) at 1:00 PM, 45 minutes after a standard 800-kcal meal consumed between noon and 12:15 PM; and fasting state and postprandial GHRH (1 microg/kg) during NAL infusion (1.6 mg/h x 2.5 h, starting at noon). We found that NAL inhibited the paradoxical postprandial GH increase only in pre-BPD subjects (GH area under the concentration time curve [AUC] in microg/L/90 min)-before meal: after GHRH 237.54 +/- 62.28, after NAL + GHRH 699.2 +/- 271.57; after meal: after GHRH 575.46 +/- 109.68, after NAL + GHRH 156.17 +/- 24.96. On the other hand, NAL failed to have significant effects in post-BPD subjects (GH AUC in microg/L/90 min)-before meal: after GHRH 871.11 +/- 256.38, after NAL + GHRH 449.19 +/- 119.13; after meal: after GHRH 1,981.54 +/- 319.92, after NAL + GHRH 1,665.91 +/- 315.4. It could be hypothesized that the opioid system is radically modified by the surgical procedure, and that opioids are not the only mediators in the paradoxical response, which persists after BPD, despite the reversion of the hyposecretory GH state, which is a characteristic of obese subjects.

Topics: Adult; Area Under Curve; Biliopancreatic Diversion; Body Mass Index; Endorphins; Female; Growth Hormone-Releasing Hormone; Humans; Middle Aged; Naloxone; Narcotic Antagonists; Postprandial Period; Weight Loss

To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test.. Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4 mg in bolus IV) patients were divided into two groups: group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underwent two cycles of hormonal replacement therapy with E2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule.. Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3 months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels.. The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.

Topics: Administration, Oral; Amenorrhea; Body Mass Index; Dose-Response Relationship, Drug; Estrogen Replacement Therapy; Estrogens; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Menstrual Cycle; Naloxone; Naltrexone; Narcotic Antagonists; Progestins; Weight Loss

The current study tested the hypothesis that drug withdrawal contributes to the addiction cycle in part because of an action on memory consolidation. Hence, four experiments in male Sprague-Dawley rats compared the effects of precipitated morphine withdrawal and conditioned morphine withdrawal on the consolidation of object memory and on activation of c-Fos in the central nucleus of the amygdala (CeA). It was found that immediate, but not 6 h delayed, post sample administration of 3 mg/kg of naltrexone significantly enhanced object memory in rats maintained, or previously maintained, on 10 mg/kg/day of morphine via osmotic minipumps. To establish whether conditioned withdrawal could also alter object memory, a contextual conditioning procedure was employed whereby morphine-maintained (10 mg/kg/day) animals received naltrexone (3 mg/kg) in a distinctive context (CS+) and vehicle in a separate context (CS-) for 10 days. During conditioning in the CS+, naltrexone suppressed locomotor activity, caused a rapid body weight loss and increased frequency of wet dog shakes. Interestingly, confinement to this CS+ immediately, but not 6 h, after the sample phase, also enhanced object memory. Finally, posttraining naltrexone and exposure to the CS+ both induced significant expression of c-Fos in the CeA. Therefore, this study reports for the first time that both acute precipitated withdrawal and conditioned withdrawal can facilitate memory consolidation, possibly through a common neural pathway that involves the central amygdala.

Topics: Animals; Central Amygdaloid Nucleus; Memory Consolidation; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Weight Loss

Evidence suggests that corticotropin-releasing factor (CRF) system is an important mediator in the negative symptoms of opioid withdrawal.. We used genetically engineered mice lacking functional CRF receptor-1 (CRF1R) levels to study the role for CRF/CRF1R pathways in the negative affective states of opioid withdrawal.. Wild-type and CRF1R(-/-) offspring of CRF1R(+/-) breeders were identified by PCR analysis of tail DNA and were rendered dependent on morphine via intraperitoneal injection of increasing doses of morphine (10-60 mg/kg). Negative state associated with opioid withdrawal was examined by using conditioned place aversion (CPA), TH expression and TH phosphorylation were measured in different brain regions involved in addictive behaviours using immunohistochemistry.. The weight loss in morphine withdrawn CRF1R(-/-) animals was significantly (p < 0.05) lower versus wild-type. The aversion for environmental cues paired with opioid withdrawal was lower (p < 0.001) in the CRF1R-deficient versus wild-type. Using dual immunolabeling for c-Fos, data show that naloxone-induced withdrawal increases the number of TH positive neurons phosphorylated at Ser40 or Ser31 that coexpress c-Fos in the nucleus of tractus solitarius (NTS)-A2 from wild-type and CRF(-/-) deficient mice. By contrast, the number of phospho-Ser40 or phospho-Ser31 positive neurons expressing c-Fos was lower in the ventrolateral medulla (VLM)-A1 in CRF(-/-)-deficient mice.. Our study demonstrates an increased activity of brainstem catecholaminergic neurons after CPA induced by morphine withdrawal suggesting that CRF1R is implicated in the activation of A1 neurons and provides evidence that this receptor is involved in the body weight loss and in the negative aversive effects of morphine withdrawal.

Topics: Adrenergic Neurons; Animals; Avoidance Learning; Brain; Corticotropin-Releasing Hormone; Dopaminergic Neurons; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Molecular Imaging; Morphine; Naloxone; Phosphorylation; Receptors, Corticotropin-Releasing Hormone; Substance Withdrawal Syndrome; Tyrosine 3-Monooxygenase; Weight Loss

Modulation of Na(+), K(+)-ATPase activity by acute and chronic opiates has been established for many years. However, the effects of digoxin, a putative inhibitor of Na(+), K(+)-ATPase, on naloxone-precipitated morphine withdrawal syndrome are unknown. In the present study, a digoxin dose-response curve was conducted to observe the effects on naloxone-precipitated withdrawal and locomotor activity in mice. Higher doses of digoxin (1.0 and 2.5 mg/kg) inhibited locomotor activity and naloxone-precipitated withdrawal jumping and weight loss, while lower doses of digoxin (0.1 and 0.25 mg/kg) inhibited withdrawal weight loss precipitated by naloxone without affecting locomotor activity and naloxone-precipitated withdrawal jumping. To explore the possible mechanisms underlying this behavior, another Na(+), K(+)-ATPase inhibitor ouabain, which does not cross the blood brain barrier, and another cardiotonic drug milrinone, a non-inhibitor of Na(+), K(+)-ATPase, were also included in the present study. Both milrinone and ouabain inhibited, in a dose-dependent manner, naloxone-precipitated weight loss while neither affected naloxone-precipitated withdrawal jumping nor locomotor activity in mice. These results indicate that both the cardiotonic effects and central inhibition of Na(+), K(+)-ATPase contribute to the inhibitory effects of digoxin on morphine withdrawal syndrome in mice.

Topics: Animals; Cardiotonic Agents; Digoxin; Female; Male; Mice; Milrinone; Morphine; Motor Activity; Naloxone; Ouabain; Sodium-Potassium-Exchanging ATPase; Substance Withdrawal Syndrome; Weight Loss

Δ(9)-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB(1) and CB(2) cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB(1) receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB(1) receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.

Topics: Amidohydrolases; Animals; Arachidonic Acid; Behavior, Animal; Benzodioxoles; Brain Chemistry; Cannabinoid Receptor Modulators; Diarrhea; Dronabinol; Electric Stimulation; Endocannabinoids; Hydrolysis; Ileum; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Monoacylglycerol Lipases; Morphine Dependence; Muscle Contraction; Naloxone; Narcotic Antagonists; Piperidines; Prostaglandins; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Substance Withdrawal Syndrome; Weight Loss

In this study we evaluated the effects of sex difference and also sex hormones on the naloxone-precipitated morphine withdrawal in both orchidectomized (ORC) male and ovariectomized (OVX) female mice. Morphine (50, 50 and 75 mg/kg/day for 4 days, s.c.) was administered to animals and at 5th day naloxone (4 mg/kg, i.p.)-precipitated morphine withdrawal signs, jumpings and the percentage of weight loss, were measured. There was no significant alteration in withdrawal jumpings between male and female mice, though weight loss was significantly higher in male ones. Jumpings was significantly lower in both OVX and ORC mice and percentage of weight loss was significantly higher in OVX mice than corresponding non-operated or sham animals. In OVX mice, E(2)V (10 mg/kg, s.c.) increased number of jumpings and decreased percentage of weight loss. Progesterone (25 mg/kg, s.c.) had no effect on jumpings, whereas it decreased weight loss in OVX mice. Testosterone (2.5 mg/kg, s.c.) increased jumpings in ORC mice while it had no effect on percentage of weight loss. Our results demonstrated that sex hormones could play a role in the morphine withdrawal syndrome in both ORC male and OVX female mice.

Topics: Animals; Estrogens; Female; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; Orchiectomy; Ovariectomy; Progesterone; Sex Characteristics; Substance Withdrawal Syndrome; Testosterone; Weight Loss

Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused three-to-five-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, while improving analgesia.

Topics: Analgesia; Analgesics, Opioid; Animals; Anti-Bacterial Agents; Brain; Bronchodilator Agents; Dose-Response Relationship, Drug; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Intraperitoneal; Male; Minocycline; Morphine; Naloxone; Opioid-Related Disorders; Oxycodone; Pain; Pain Measurement; Pyridines; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Weight Loss

Much evidence supports the hypothesis that A2A adenosine receptors play an important role in the expression of morphine withdrawal and that the dopaminergic system might also be involved. We have evaluated morphine withdrawal signs in wild-type and A2A receptor knockout mice and shown a significant enhancement in some withdrawal signs in the knockout mice. In addition, micro -opioid and dopamine D2 receptor autoradiography, as well as micro -opioid receptor-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate ([35S]GTPgammaS) autoradiography was carried out in brain sections of withdrawn wild-type and knockout mice. No significant changes in D2 and micro -opioid receptor binding were observed in any of the brain regions analysed. However, a significant increase in the level of micro receptor-stimulated [35S]GTPgammaS binding was observed in the nucleus accumbens of withdrawn knockout mice. These data indicate that the A2A receptor plays a role in opioid withdrawal related to functional receptor activation.

Topics: Analysis of Variance; Animals; Autoradiography; Behavior, Animal; Binding Sites; Brain; Densitometry; Diarrhea; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Male; Mice; Mice, Knockout; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Raclopride; Receptor, Adenosine A2A; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Sulfur Isotopes; Tremor; Tritium; Urine; Weight Loss

The present study sought to assess whether the blockade of ionotropic glutamate receptors in the ventral tegmental area (VTA) could modulate the morphine withdrawal in male Sprague-Dawley rats. The effects of dizocilpine (MK-801) or 6,7-dinitroquinnoxaline-2,3-dione (DNQX), ionotropic glutamate receptor antagonists, microinjected unilaterally into the VTA 30 min before naloxone [2 mg/kg, intraperitoneally (i.p.)] administration on the morphine withdrawal were assessed. Morphine dependence was developed with increasing morphine injection (i.p.), and morphine withdrawal was induced by injection of naloxone (2 mg/kg, i.p.). Jumping, wet-dog shakes, writhing posture, wall clamber, weight loss and Gellert-Holtzman scale were used as the indices to evaluate the intensity of morphine withdrawal. The results showed that unilateral microinjection of MK-801 or DNQX into the VTA significantly increased the incidence of wall clamber, had no effect on weight loss, and reduced all other symptoms of morphine withdrawal. These data suggest that the ionotropic glutamate receptors in the VTA are involved in mediating naloxone-precipitated opiate withdrawal.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Microinjections; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Substance Withdrawal Syndrome; Synaptic Transmission; Ventral Tegmental Area; Weight Loss

Rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment. We examined the effects of clonidine (alpha(2)-adrenoceptor agonist) and prazosin (alpha(1)-adrenoceptor antagonist) on morphine analgesia, tolerance and withdrawal. Morphine tolerance was induced using a 3-day cumulative twice-daily dosing regimen with s.c. doses up to 120 mg/kg. Tolerance was assessed on day 4, as loss of the antinociceptive effect of a test dose of morphine (5 mg/kg). After 10 h, morphine withdrawal was precipitated with naloxone (1 mg/kg). Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another alpha(1)-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of alpha(2)-adrenoceptors in opioid actions, also alpha(1)-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Analgesics, Opioid; Animals; Behavior, Animal; Clonidine; Dose-Response Relationship, Drug; Drug Synergism; Drug Tolerance; Male; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Pain; Prazosin; Substance Withdrawal Syndrome; Weight Loss

Previous pharmacological studies have implicated serotonergic brain systems in opiate withdrawal. To test the hypothesis that serotonin (5-HT) has a critical role in the development of opiate withdrawal, we have employed a near-total brain 5-HT system lesion technique (90% depletion) using 5,7-dihydroxytryptamine combined with induction of opiate dependence by implantation of morphine pellets or by repeated injections of increasing doses of morphine. The effects of serotonergic neuron lesion were examined on spontaneous opiate withdrawal (changes in circadian locomotor activity) and naloxone-precipitated opiate withdrawal syndrome (the somatic aspect). The antiwithdrawal properties of clonidine, an alpha(2)-adrenoceptor agonist currently used for clinical treatment for the somatic signs of opiate withdrawal, were tested also in the lesioned rats. Our findings show that serotonergic lesions in morphine-dependent rats did not alter either the spontaneous or the naloxone-induced withdrawal syndrome (with exception of jumping behavior). Moreover, clonidine alleviated the naloxone-induced withdrawal syndrome in lesioned as well as in sham-operated morphine-dependent rats. These results demonstrate that 5-HT systems are not directly responsible for the development of the somatic opiate withdrawal syndrome in morphine-dependent rats.

Topics: 5,7-Dihydroxytryptamine; Adrenergic alpha-Agonists; Animals; Behavior, Animal; Biogenic Amines; Clonidine; Male; Morphine; Morphine Dependence; Motor Activity; Naloxone; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Agents; Substance Withdrawal Syndrome; Weight Loss

1. RB 101, a complete inhibitor of enkephalin-catabolizing enzymes, has been previously shown to produce antinociception in normal rats after systemic administration. Moreover, its coadministration with a cholecystokinin-B (CCK-B) receptor antagonist has been shown to strongly enhance its antinociceptive effect in normal rats. In this work, we determined whether RB 101 was able to reduce hyperalgesia and allodynia in diabetic rats, a model of neuropathic pain. The type of opioid receptors (mu or delta) involved was determined using naloxone and naltrindole, respectively, and the interactions between endogenous enkephalins and CCK on nociception control was investigated using coadministration of RB 101 and the CCK-B receptor antagonist CI-988. 2. RB 101 suppressed mechanical hyperalgesia (paw pressure-induced vocalization test), partially alleviated mechanical allodynia (von Frey hair test), and was ineffective in thermal allodynia (tail immersion test). The analgesic effect was completely cancelled by naloxone or naltrindole, suggesting that is requires the availability of mu- and/or delta-opioid receptors. 3. The combination of an inactive dose of CI-988 with the lowest effective dose of RB 101 resulted in a stronger increase in the vocalization threshold comparatively to RB 101 alone. 4. The present study demonstrates that the antinociception generated by RB 101 induced by elevation of extracellular levels of endogenous enkephalins, can be extended to neuropathic pain in diabetic rats and that blockade of CCK-B receptors potentiated antinociceptive effects elicited by RB 101.

Topics: Aminopeptidases; Animals; Diabetes Mellitus, Experimental; Disulfides; Drug Synergism; Indoles; Male; Meglumine; Naloxone; Naltrexone; Neprilysin; Pain; Pain Measurement; Phenylalanine; Pressure; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Time Factors; Vocalization, Animal; Weight Loss

The tolerance to analgesia and dependence liability of dihydroetorphine following topical application were investigated in hairless rats with and without formalin-induced inflammation. The analgesic effect of dihydroetorphine (s.c.) was 4600- to 7200-fold more potent than that of morphine. In non-inflamed rats, the analgesic effect of 24-h topical application of dihydroetorphine tape (35 microg) and 4-day repeated tape applications (20 microg/5 h/day) decreased with time after the start of application, even though the plasma dihydroetorphine concentrations did not decrease. In formalin-inflamed rats, however, the tolerance to analgesia diminished. Naloxone-precipitated weight loss was observed after 24-h infusion of dihydroetorphine but not after the tape application in non-inflamed rats. A significant rewarding effect was found in the non-inflamed rats conditioned by s.c. injection and tape application but not in the formalin-inflamed rats. These results indicate that topical application of dihydroetorphine has a tolerance and dependence liability when there is no pain, and therefore, it should be used only for pain relief.

Topics: Administration, Cutaneous; Analgesics, Opioid; Animals; Conditioning, Psychological; Dose-Response Relationship, Drug; Drug Tolerance; Etorphine; Formaldehyde; Inflammation; Infusions, Intravenous; Injections, Subcutaneous; Male; Morphine; Naloxone; Narcotic Antagonists; Rats; Rats, Nude; Substance-Related Disorders; Time Factors; Weight Loss

We compared the physical dependence liability of biphalin, a dimeric enkephalin analogue that possesses high antinociceptive activity, with that of morphine in equipotent intravenous doses. Naloxone challenge produced severe withdrawal signs after a 5-day infusion of morphine but only minor withdrawal signs after a 5-day biphalin infusion. In a cross-dependence study, biphalin did not suppress body weight loss after morphine withdrawal, but successfully suppressed weight loss after pentazocine withdrawal. These data support consideration of biphalin as a new analgesic with a novel pharmacological profile and minimum dependence liability.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Enkephalins; Infusions, Intravenous; Male; Morphine; Morphine Dependence; Naloxone; Pentazocine; Rats; Rats, Sprague-Dawley; Substance-Related Disorders; Weight Loss

Laser-Doppler flowmetry was used to study cerebral cortical blood flow responses to morphine and naloxone in morphine-naive and -dependent rats. The experiments were performed in spontaneously breathing anesthetized rats. Morphine (10 mg/kg, i.p.) administration reduced regional cerebral blood flow in control, sham-operated and morphine-dependent rats, but the depressant effect of morphine in morphine-dependent animals was less than that in control and sham-operated groups. While naloxone (0.5 mg/kg, s.c.) had no considerable effect on regional cerebral blood flow in control and sham-operated groups, it increased regional blood flow in morphine dependent ones. The depressant effect of morphine in all groups and the enhancing effect of naloxone in morphine-dependent animals were not seen after local application of lidocaine at the recording site. This study may provide a framework to study the cellular and molecular mechanisms responsible for coupling neuronal electrical activity with regional alterations in blood flow during precipitation of morphine withdrawal.

Topics: Anesthesia; Anesthetics, Local; Animals; Brain; Cerebrovascular Circulation; Diarrhea; Lidocaine; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Weight Loss

In this study, we monitored Fos-like immunoreactivity in the sacral spinal cord to identify neurons that are likely to contribute to the autonomic manifestations of opioid antagonist-precipitated withdrawal in morphine-tolerant rats. Injection of systemic antagonist increased the Fos-like immunoreactivity throughout the first sacral segment, particularly in laminae I/II, X, and in the sacral parasympathetic nucleus (SPN). Selective peripheral withdrawal, with a hydrophilic antagonist that does not cross the blood-brain barrier (BBB), induced diarrhea, but no other withdrawal signs were evident. Compared to rats that withdrew systemically, peripherally withdrawal evoked significantly less Fos-like immunoreactivity in laminae V/VI, X and the SPN. By contrast, selective spinal withdrawal, by intrathecal injection of an opioid antagonist that does not cross the BBB, provoked hyperactivity of the hindlimbs and tail, but no diarrhea. These animals demonstrated significantly increased Fos-like immunoreactivity in laminae I/II, V/VI, the SPN, and the ventral horn compared to rats that withdrew systemically. Animals treated neonatally with capsaicin, to eliminate C-fiber input, demonstrated withdrawal behavior similar to intact withdrawing rats, except that the capsaicin-pretreated rats had significantly greater weight loss. However, this group had less Fos-like immunoreactivity in laminae V/VI, X and SPN compared to the intact withdrawing rats. These data suggest that withdrawal from morphine evokes hyperactivity of sacral neurons, particularly those involved in regions that process nociceptive and autonomic information. Peripheral withdrawal is sufficient to induce diarrhea, but it does not fully explain the associated weight loss. Unmyelinated primary afferents may contribute a tonic peripheral inhibition of circuits that regulate gut motility and intestinal fluid transport. Taken together, these data suggest that chronic exposure to opioids induces a latent sensitization in sacral cord neurons that can be manifested as neuronal hyperactivity during withdrawal; this mechanism may underlie withdrawal-induced hyperalgesia and gut hypermotility.

Topics: Animals; Animals, Newborn; Autonomic Nervous System; Capsaicin; Gastrointestinal Motility; Immunohistochemistry; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance Withdrawal Syndrome; Weight Loss

The severity of naloxone-precipitated withdrawal in rats infused intravenously with morphine at the rates of 2.5, 5 and 10 mg/kg/hr over various time periods was investigated. Plasma morphine concentration reached a constant and rate-dependent level at 1 hr after the start of morphine infusion, and this level was maintained until the termination of infusion. Naloxone (2.0 mg/kg, s.c.) was challenged 18 hr after infusion was stopped, and the withdrawal was evaluated by plasma corticosterone (PCS) increase, diarrhea and body weight loss. The incidence of naloxone-precipitated withdrawal signs was related to both the infusion rate and duration of morphine infusion. The duration of morphine infusion (ET50) needed to elicit naloxone-precipitated PCS increase and diarrhea in 50% of the rats was inversely related to the morphine infusion rates, but the total amount of infused morphine (EA50) that elicited naloxone-precipitated withdrawals in 50% of rats was the same at all infusion rates. These results suggest that the total amount of morphine infused may play an important role in the development of acute physical dependence on morphine rendered by continuous intravenous morphine infusion for 1-8 hr.

Topics: Acute Disease; Analysis of Variance; Animals; Corticosterone; Diarrhea; Infusions, Intravenous; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Time Factors; Weight Loss

The effects of histamine antagonists on naloxone-precipitated withdrawal symptoms were studied in morphine-dependent mice. Chlorpheniramine (0.5-10 mg/kg), a H1-blocker, given 1P 30 min before naloxone challenge produced a dose-dependent potentiation of withdrawal body weight loss, burrowing, and hypothermia, but did not influence either jumping or wet-dog shakes. On the other hand, cimetidine (10-100 mg/kg), a H2-blocker, produced dose-dependent potentiation of withdrawal hypothermia and jumping. Cimetidine was without effect on wet-dog shakes, burrowing, and body weight loss. The effect of chlorpheniramine was investigated in mice injected with 6-hydroxydopamine (6-OHDA) intracerebrally to examine whether histamine-mediated effects are some-how linked to noradrenergic pathways. Intracerebral injection of 6-OHDA in 5-day-old mice pups resulted in hyperlocomotion by the end of 30 days before initiation of morphine dependence. Mice pretreated with 6-OHDA developed a higher degree of naloxone-induced withdrawal jumping than nontreated mice. 6-OHDA (50 micrograms) lesions completely blocked the potentiating effect of chlorpheniramine on burrowing, hypothermia, and even reversed the effect on body weight loss. These findings suggest that both histamine H1- and H2-receptors may be involved in the expression of precipitated withdrawal in morphine-dependent mice and histamine receptors function as modulators of noradrenergic neurotransmission.

Topics: Animals; Behavior, Animal; Chlorpheniramine; Cimetidine; Dose-Response Relationship, Drug; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Hypothermia; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; Norepinephrine; Oxidopamine; Substance Withdrawal Syndrome; Sympatholytics; Weight Loss

1. The effects induced in rats on naloxone-precipitated morphine withdrawal syndrome by the new mixed inhibitor of enkephalin catabolism able to cross the blood-brain barrier RB 101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-ox-opropyl-L-phenylalanine benzyl ester) given alone or associated with the selective CCKB antagonist, PD-134,308, were investigated. 2. The systemic administration of RB 101 (5, 10 and 20 mg kg-1, i.v.) elicited a significant decrease in 8 of the 14 withdrawal signs evaluated. PD-134,308 (3 mg kg-1, i.p.) did not modify the expression of morphine abstinence when given alone, but induced a strong facilitation of RB 101 responses (12 of 14 withdrawal signs were decreased). This potentiation was particularly intense in peripherally mediated withdrawal signs. 3. In order to clarify the biochemical mechanisms implicated in these responses, the effects induced by the association of RB 101 and PD-134,308 on the occupation of brain opioid receptors by endogenous enkephalins were also investigated in mice. PD-134,308, as well as RB 101, inhibited [3H]-diprenorphine binding to opioid receptors. These results suggest that an increase in endogenous enkephalin levels induced by PD-134,308 could participate in the facilitation of RB 101 behavioural responses. 4. RB 101 has a promising potential role in the management of the opiate withdrawal syndrome. CCKB antagonists, such as PD-134,308 may be useful in potentiating this anti-withdrawal effect.

Topics: Analgesics; Animals; Behavior, Animal; Binding, Competitive; Body Temperature; Diprenorphine; Disulfides; Drug Combinations; Drug Synergism; Enkephalins; Indoles; Male; Meglumine; Mice; Morphine; Motor Activity; Naloxone; Phenylalanine; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Substance Withdrawal Syndrome; Weight Loss

1. Monoarthritis was induced in Lewis rats by interdermal injection in the left hind paw of a suspension of Mycobacterium tubercolusis in mineral oil (500 micrograms 100 microliters-1). Controls were injected with 100 microliters mineral oil. 2. Withdrawal latencies to thermal stimuli of the inflamed paw, the contralateral and both paws of control rats were measured at daily intervals after injection by the plantar test. 3. After detection of the pain threshold, rat spinal cords were removed and horizontal dorsal slices were mounted in a 3-compartment bath to measure electrically-evoked release of substance P-like immunoreactivity (SP-LI). 4. The inflamed paw of monoarthritic rats exhibited a lower pain threshold to thermal stimuli than the contralateral paw of the same animals and both paws of control rats. Inflamed paw hyperalgesia was maximal two days after injection, and declined gradually between 7 to 21 days with no evidence of excitability of withdrawal reflexes after 28 days. 5. During the 28 days study, monoarthritic rats gained less weight than control rats. 6. Electrical stimulation of the dorsal roots attached to rat isolated spinal cord slices induced a significant increase (174 +/- 18% of basal outflow which was 30.3 fmol 8 ml-1, n = 5) in SP-LI release. 7. One-week after induction of inflammation no differences in the amount of SP-LI released from the spinal cord of incomplete Freund's adjuvant-treated rats (IFA) and Freund's adjuvant-treated rats (CFA) were detected. Two weeks after, CFA spinal cord tended to release more SP-LI than IFA cords and, 21 days after injection, the spinal cord of CFA rats released significantly more peptide than IFA rats (17.8 +/- 2.8 fmol ml-1, n = 12 and 6.9 +/- 3.2 fmol ml-1, n = 9, respectively).8. Twenty-one days after treatment, the evoked release from monoarthritic rat spinal cords was increased by 263 + 42% (n = 3) in the presence of the GABAB receptor antagonist, CGP 36742 (100 micro M)which also significantly potentiated monoarthritis-induced hyperalgesia up to 45 min after injection(100 mgkg-1, i.p.).9. These findings may provide a basis for a novel approach to chronic pain therapy but also an explanation for the lack of analgesia produced by the GABAB agonist, baclofen, in chronic as compared to acute pain.

Topics: Animals; Arthritis, Experimental; Bicuculline; Electric Stimulation; GABA-B Receptor Antagonists; Hyperalgesia; In Vitro Techniques; Male; Naloxone; Pain Measurement; Pain Threshold; Radioimmunoassay; Rats; Rats, Inbred Lew; Receptors, GABA-B; Spinal Cord; Substance P; Weight Loss

Morphine sulfate (1.5 nmoles/h) was chronically infused into various brain regions in rats. After 72 h of continuous infusions, an intraperitoneal injection of naloxone hydrochloride (5 mg/kg) was given to determine if physical dependence had developed. Various withdrawal signs were present following the naloxone challenge in rats chronically infused with morphine into the periventricular gray region. These withdrawal signs included escape behavior, wet-dog shakes, and teeth chattering. Several other brain regions (e.g., amygdala, caudate nucleus, lateral hypothalamus, nucleus accumbens, thalamus) were also tested, but morphine infusions into these areas produced only slight physical dependence. The magnitude of physical dependence produced by morphine infusions into the rostral aspect of the periventricular gray was comparable to that seen following repeated systemic morphine injections, while the physical dependence produced by caudal infusions into the vicinity of the locus coeruleus was considerably less. These data confirm the importance of the periventricular gray region in the development of physical dependence on morphine and reveal that a drug action in the more rostral aspect of this brain region produces the strongest signs of physical dependence.

Topics: Animals; Brain Mapping; Central Nervous System; Injections; Male; Mesencephalon; Morphine; Morphine Dependence; Naloxone; Prosencephalon; Rats; Substance Withdrawal Syndrome; Weight Loss

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

It is known that the CXBK inbred strain of mouse is deficient in mu1 opioid receptors, whereas the strain has a delta opioid receptor population that is less consistently altered. In the present study, we compared physical dependence on morphine between CXBK and C57BL/6 mice. Both strains of mice were treated with morphine-admixed food for 5 days. During the treatment, the two strains of mice showed no signs of toxicity. There was no significant difference in morphine intake during the treatment between CXBK and C57BL/6 mice. After the treatment, the withdrawal was precipitated by injecting naloxone (0.01-30 mg/kg, s.c.). CXBK mice showed weight loss, diarrhea and ptosis, but not jumping and body shakes after low dose of naloxone. Whereas, C57BL/6 mice showed weight loss, diarrhea, ptosis, body shakes and jumping. These results suggest that naloxone-precipitated weight loss, diarrhea and ptosis may be mediated by mu2 and/or delta opioid receptor, while naloxone-precipitated jumping and body shakes may be mediated by mu1 opioid receptors.

Topics: Animals; Blepharoptosis; Diarrhea; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Morphine Dependence; Motor Activity; Naloxone; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Weight Loss

In this study we have examined whether the alpha 2-adrenoceptor agonist clonidine and the calcium channel antagonist nifedipine firstly inhibit the naloxone-precipitated withdrawal syndrome in morphine-dependent rats and secondly reduce central noradrenaline release during withdrawal. We demonstrate that both clonidine (0.1 mg/kg) and nifedipine (10 mg/kg) attenuate the naloxone-precipitated withdrawal syndrome. Using in vivo microdialysis, we demonstrate that following naloxone the release of noradrenaline, as measured by perfusates from hippocampus, increases 300% in morphine-dependent rats. However, whilst pretreatment with clonidine inhibited this increased noradrenaline release, nifedipine did not. These findings suggest that whilst the action of clonidine in attenuating the morphine withdrawal syndrome may be mediated by decreasing central noradrenaline release, this is not the mechanism by which nifedipine acts.

Topics: Animals; Behavior, Animal; Clonidine; Male; Microdialysis; Morphine Dependence; Naloxone; Nifedipine; Norepinephrine; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Weight Loss

Male deer reduce food intake and lose weight during the breeding season (rut) in autumn. Growth hormone (GH) is lipolytic in ruminants; therefore, pulsatile GH secretion was measured in three young reindeer (Rangifer tarandus tarandus) bulls during the natural period of weight loss during rut. Blood samples were withdrawn through a jugular cannula every 20 min for 16 hr on 5 occasions from late summer to early winter in unanaesthetised animals. The deer were group fed a pelleted concentrate ration ad libitum, and food intake, body weight, and testicular diameter were recorded. The hormone profiles were analysed by the pulse detection algorithm PULSAR. The bulls showed the normal pattern of rut-associated weight loss and reduced food intake followed by a period of weight increase in late autumn before weight plateaued in early winter. Mean GH was highest (P less than 0.05) at the time of minimum body weight and food intake compared with all other sampling periods. Neither the amplitude nor the frequency of GH pulses, as detected by PULSAR, differed significantly with sampling period, although the high mean GH values were associated with a different pulse shape; pulses were longer, with a large area under the curve, presumably reflecting a longer duration of secretion or reduced clearance. Thus weight loss and low food intake were associated with long, large area pulses of GH. An opioid antagonist, naloxone, was given to reindeer intravenously at hourly intervals for 4 hr and blood sampling was continued for 7 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Eating; Growth Hormone; Male; Naloxone; Periodicity; Reindeer; Testis; Weight Loss

The purpose of this experiment is to investigate genetic differences in the development of physical dependence on morphine and codeine in inbred strains of mice, C57BL/6, C3H/He and DBA/2. Mice were treated with morphine- or codeine-admixed food (1, 2 and 3 mg/g of food) for 3 to 9 days. After the termination of drug treatment, the mice were given naloxone (5 mg/kg, s.c.). The incidences of jumping and teeth chattering by naloxone challenge in morphine- and codeine-treated C57BL/6 mice were much greater than those in C3H/He and DBA/2 mice. However, the incidences of other naloxone-precipitated withdrawal signs, such as ptosis and diarrhea, were not different among the three inbred strains of mice. These results indicate that genotype is an important determinant of the degree of most naloxone-precipitated withdrawal signs in morphine- and codeine-treated mice.

Topics: Animals; Codeine; Eating; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Morphine Dependence; Motor Activity; Naloxone; Substance Withdrawal Syndrome; Substance-Related Disorders; Weight Loss

1. Four different strains of mice were used to study the influence of psychogenetics in opiate tolerance and abstinence. 2. The CD1 strain seemed to be more sensitive to naloxone administration after four days of morphine implantation, because administration of the antagonist induces a number of jumps in the withdrawal phase higher than in the case of the DBA or C3H strains. 3. DBA and C3H mice elicit analgesia before the CD1 strain, whereas the C3H mice lose body weight at a faster rate than the other strains. 4. C57 bl mice died after morphine implantation (100%). 5. These findings are discussed in relation with neurochemical and receptor variations.

Topics: Animals; Behavior, Animal; Drug Tolerance; Genetics, Behavioral; Male; Mice; Mice, Inbred Strains; Morphine Dependence; Naloxone; Species Specificity; Substance Withdrawal Syndrome; Weight Loss

Topics: Analgesics; Animals; Indoles; Male; Morphinans; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Weight Loss

Topics: Animals; Behavior, Animal; Body Temperature; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Hydroxamic Acids; Naloxone; Narcotics; Oligopeptides; Phenylalanine; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Weight Loss

Previous work in this laboratory has indicated that the transplantation of adrenal medullary tissue into the subarachnoid space of the rat spinal cord can reduce pain sensitivity to acute noxious stimuli, particularly following stimulation by nicotine. This most likely results from the stimulated release of opioid peptides and catecholamines from the transplanted chromaffin cells. However, chronic pain models may more closely resemble human clinical pain, and the arthritic rat model has been used for screening potential therapeutic strategies. The purpose of the present study was to assess the potential for adrenal medullary tissue implanted into the spinal subarachnoid space to alleviate chronic pain. Adrenal medullary tissue was implanted into adjuvant-induced arthritic rats, and changes in body weight and vocalization responses were monitored over the 10 week course of the disease. Results indicate that the severe weight reduction normally associated with this inflammatory arthritis was attenuated by adrenal medullary, but not control, implants. In addition, vocalizations were reduced in animals implanted with adrenal medullary, but not control tissue following nicotine stimulation. This reduction was blocked by the opiate antagonist, naloxone, and partially attenuated by the alpha-adrenergic antagonist, phentolamine. Together, these results suggest that the transplantation of adrenal medullary tissue into the subarachnoid space of the spinal cord may provide a local source of opioid peptides and catecholamines for the reduction of chronic pain.

Topics: Adrenal Medulla; Animals; Arthritis, Experimental; Catecholamines; Chronic Disease; Endorphins; Graft Survival; Male; Naloxone; Pain; Phentolamine; Rats; Rats, Inbred Strains; Spinal Cord; Subarachnoid Space; Transplantation, Heterotopic; Vocalization, Animal; Weight Loss

Regional cerebral glucose utilization (RCGU) and behavior during precipitated morphine withdrawal were studied in rats made dependent by either intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of morphine. [14C]2-deoxy-D-glucose autoradiography revealed that RCGU increased in an anatomically related group of limbic and brainstem structures in rats that were in morphine withdrawal precipitated by naloxone administration compared to morphine-dependent controls that were not in precipitated withdrawal. Correlation of RCGU for 24 brain structures comparing i.c.v. vs s.c. morphine-treated rats was highly significant for groups in withdrawal and for controls (r values, 0.958 and 0.971, respectively). Withdrawal behaviors including autonomic signs of withdrawal, withdrawal jumping, and incidence of diarrhea were not different between the two groups in withdrawal (i.c.v. and s.c.). Weight loss during withdrawal increased (P less than 0.05) in rats made dependent by s.c. morphine administration compared to rats that received morphine by the i.c.v. route. Taken together, these results indicate that RCGU changes during morphine withdrawal result solely from effects of chronic morphine in the central nervous system, not in peripheral sites. The increased weight loss of s.c.-treated, morphine-dependent rats in withdrawal suggests an independent peripheral effect perhaps mediated by visceral opiate receptors.

Topics: Animals; Autonomic Nervous System; Autoradiography; Brain; Carbon Radioisotopes; Cerebral Ventricles; Deoxy Sugars; Deoxyglucose; Diarrhea; Infusions, Parenteral; Male; Morphine; Morphine Dependence; Motor Activity; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Weight Loss

Mice were rendered dependent on morphine by mixing morphine with their food (2 mg/g) for three days. Increasing doses of naloxone precipitated dose-dependent withdrawal reactions such as weight loss and jumping. These withdrawal reactions were antagonized by morphine pretreatment. Effects of morphine, such as increased locomotor activity, inhibition of intestinal transport, and analgesia were antagonized by naloxone in both non-dependent and dependent subjects. The antagonist actions of naloxone were increased in dependent subjects; lower doses of naloxone were sufficient to antagonize effects of morphine. The present results confirm earlier studies indicating that precipitation of withdrawal can be antagonized by morphine pretreatment suggesting that withdrawal reactions are due to actions of naloxone at the same receptor at which opioid agonists act. The increased antagonist potency of naloxone in dependent subjects extends earlier results obtained with analgesic effects to several other agonist effects of morphine and is consistent with the interpretation that exposure to an opioid agonist induces a change in the conformation of opioid receptors.

Topics: Analgesia; Animals; Charcoal; Dose-Response Relationship, Drug; Intestinal Mucosa; Intestines; Male; Mice; Mice, Inbred ICR; Morphine; Morphine Dependence; Motor Activity; Naloxone; Premedication; Substance Withdrawal Syndrome; Weight Loss