Naloxone precipitates nicotine abstinence syndrome in the rat

Recently, a rodent model of nicotine abstinence syndrome has been developed based on continuous subcutaneous infusion of nicotine tartrate and observing the frequency of spontaneous behavioral signs following termination of infusion. The observed signs closely resemble those commonly seen in rat opiate abstinence syndrome, raising the possibility that there is an endogenous opioid component in nicotine dependence. The present study demonstrates that the opiate antagonist naloxone can precipitate an abstinence syndrome in nicotine-dependent rats. Fourteen rats were infused for 7 days with 9 mg/kg/day nicotine tartrate in saline via an Alzet osmotic minipump. Fourteen rats were sham-operated and remained nicotine-naive. Half of each group received 4.5 mg/kg naloxone SC immediately before a blind 15-min observation, while the other half received saline alone. ANOVA revealed significant nicotine infusion, naloxone injection and interaction effects. Post-hoc analysis showed that the nicotine-infused rats injected with naloxone had significantly more signs than all other groups (P<0.01). In a second experiment, 2 mg/kg morphine sulfate SC produced a significant (P<0.01) 91.2% reduction of spontaneous abstinence signs observed 21 h after termination of nicotine infusion. These results are consistent with the hypothesized endogenous opioid component in nicotine dependence and abstinence syndrome.     

Nociceptin/orphanin FQ blocks the antinociception induced by mu, kappa and delta opioid agonists on the cold water tail-flick test

Nociceptin/orphanin FQ (N/OFQ), a 17-amino-acid peptide, is an endogenous agonist whose receptor is similar in sequence to mu, delta and kappa opioid receptors. It has been reported that N/OFQ can block antinociceptive effects induced by opioid receptor agonists in the radiant heat tail-flick test and warm water tail-withdrawal test. The present study was designed to see the effect of N/OFQ on antinociception induced by opioid receptor agonists in the cold water tail-flick (CWT) test, which measures a different type of pain. In adult male Sprague-Dawley (S-D) rats given subcutaneous (s.c.) injections of saline or morphine (8 mg/kg), intracerebroventricular (i.c.v.) injection of N/OFQ (18 microg) 15 min later produced a significant reversal of morphine antinociception (P<0.01, ANOVA followed by Duncan's test), compared to the corresponding saline control group. Saline (t=+15 min, i.c.v.) had no effect on s.c. morphine antinociception (P>0.01), compared to the corresponding saline control group. When the kappa opioid receptor agonist spiradoline (80 mg/kg, s.c.) was used instead of morphine, similar results were observed. In another series of experiments, it was found that i.c.v. injection of N/OFQ (18 microg) reversed the antinociception induced by i.c.v. injection of the selective mu opioid agonist PL017 (2 microg), delta opioid agonist DPDPE (50 ng) and kappa opioid agonist dynorphin (21.5 microg), respectively. These results indicate that N/OFQ may be an endogenous anti-opioid peptide in the brain of rats in the CWT test.     

Opiate physical dependence and N-methyl-d-aspartate receptors

The present review focused the involvement of N-methyl-d-aspartate (NMDA) receptors in morphine physical dependence. The increased levels of extracellular glutamate, NMDA receptor ζ subunit (NR1) mRNA, NMDA receptor 1 subunit (NR2A) protein, phosphorylated Ca²⁺/calmodulin kinase II (p-CaMKII) protein, c-fos mRNA, c-Fos protein, are observed in the specific brain areas of mice and/or rats showing signs of naloxone-precipitated withdrawal. In preclinical and clinical studies, a variety of NMDA receptor antagonists and pretreatment with an antisense oligonucleotide of the NR1 have been reported to inhibit the development, expression and/or maintenance of opiate physical dependence. In contrast to data obtained in adult animals, NMDA receptor antagonists are neither effective in blocking the development of opiate dependence nor the expression of opiate withdrawal in neonatal rats. In the NMDA receptor-deficient mice, the NR2A knockout mice show the marked loss of typical withdrawal abstinence behaviors precipitated by naloxone. The rescue of NR2A protein by electroporation into the nucleus accumbens of NR2A knockout mice reverses the loss of abstinence behaviors. The activation of CaMKII and increased expression of c-Fos protein in the brain of animals with naloxone-precipitated withdrawal syndrome are prevented by NMDA receptor antagonists, whereas the increased levels of extracellular glutamate are not prevented by them. These findings indicate that glutamatergic neurotransmission at the NMDA receptor site contributes to the development, expression and maintenance of opiate dependence, and suggest that NMDA receptor antagonists may be a useful adjunct in the treatment of opiate dependence.     

Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats

1. Recent evidence from studies in mice lacking the opioid receptor-like (ORL-1) receptor and from experiments using antibodies raised against orphanin FQ/nociceptin (OFQ/N) suggest that this peptide may be involved in morphine tolerance. In the present study we sought to investigate if administration of exogenous OFQ/N would modulate the development of tolerance to the antinociceptive effect of morphine. 2. Rats were treated for 3 days with either saline or morphine (10 mg kg(-1), s.c.) followed, 15 and 75 min later, by two intracerebroventricular injections of either artificial cerebrospinal fluid (aCSF) or OFQ/N. The dose of OFQ/N was doubled each day (7.5, 15, 30 nmol). On day 4, rats were tested on a hot plate apparatus before and 30, 60 and 90 min after morphine administration. 3. Repeated OFQ/N treatment did not affect basal nociceptive responses or morphine-induced antinociception. However, the same treatment significantly attenuated the development of morphine tolerance. 4. Since learning and memory could contribute to the development of morphine tolerance, in subsequent studies, we examined the effect of OFQ/N administered in the CA3 region of the hippocampus, where OFQ/N has been shown to block LTP and impair spatial memory. A greater attenuation of morphine tolerance with no alteration of baseline hot plate latency or morphine-induced antinociception was observed when OFQ/N was administered in this area of the rat brain. 5. Taken together, our results demonstrate that OFQ/N may act in the hippocampus to attenuate morphine tolerance.     

Buprenorphrine: demonstration of physical dependence liability

This study was designed to assess the dependence-producing capacity of the opiate partial agonist, buprenorphine. Rats chronically treated with buprenorphine for 4 days showed only very weak signs of withdrawal upon cessation of buprenorphine treatment or upon challenge with naloxone, although complete tolerance had developed to the drug at this time. However, more intense withdrawal could be induced when buprenorphine treatment was followed by substitution treatment with morphine. Even one injection of morphine given 12 h after the last buprenorphine treatment enabled the precipitation of withdrawal with naloxone. Naloxone could not precipitate signs of withdrawal in naive rats treated with this dose of morphine. Thus, contrary to some claims in the literature, buprenorphine, like other opiate agonists and partial agonists, induces dependence. The fact that only few signs of withdrawal are seen in direct dependence tests, probably reflects the slow dissociation of the drug from the receptor - which probably limits the intensity of withdrawal by preventing the rapid uncovery of the receptor upon discontinuance of treatment with the drug or upon injection of an antagonist. In addition, the maximum degree of dependence induced by buprenorphine - in comparison to pure agonists is limited, like that of other partial agonists.     

侧脑室注射东莨菪碱对吗啡依赖大鼠戒断反应的抑制作用

目的 观察非选择性毒蕈碱（M）受体拮抗剂东莨菪碱、选择性M1受体拮抗剂哌拉唑嗪以及选择性M2受体拮抗剂美索四氨对吗啡戒断反应的影响。方法 采用吗啡依赖大鼠模型侧脑室注射上述药物,并用腹腔注射纳洛酮诱发戒断反应,记录60min内戒断症状。结果 侧脑室注射东莨菪碱（25,50μg)、派拉唑嗪（20μg)和美索四氨（25μg)可明显抑制由纳洛酮诱发戒断反应,东莨菪碱减轻吗啡戒断症状呈明显量效关系。结论 侧脑室注射东莨菪碱能减轻吗啡戒断反应,提示中枢胆碱能神经毒碱（M）受体在吗啡依赖和耐受过程中起重要作用。     

Continuous infusion of naloxone: effects on behavior and oxygen consumption

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.     

Sex differences in the Nociceptin/Orphanin FQ system in rat spinal cord following chronic morphine treatment

Nociceptin/Orphanin FQ (N/OFQ) appears to contribute to the development of morphine tolerance, as blockade of its actions will block or reverse the process. To better understand the contribution of N/OFQ to the development of morphine tolerance, this study examined the effect of chronic morphine treatment on levels of N/OFQ and levels and activity of the N/OFQ peptide (NOP) receptor in spinal cord (SC) from male and female rats. Both male and female Wistar rats showed less responsiveness to morphine after subcutaneous injection of escalating doses of morphine (10, 20, 40, 60 and 80 mg/kg, respectively) twice daily for five consecutive days. Male rats were more tolerant to the antinociceptive actions of morphine than females. The N/OFQ content of SC extracts was higher in females than in males, regardless of treatment; following chronic morphine treatment the difference in N/OFQ levels between males and females was more pronounced. N/OFQ content in cerebrospinal fluid (CSF) was reduced 40% in male and 16% in female rats with chronic morphine exposure, but increased in periaqueductal grey of both sexes. Chronic morphine treatment increased NOP receptor levels 173% in males and 137% in females, while decreasing affinity in both. Chronic morphine increased the efficacy of N/OFQ-stimulated [³⁵S]GTPγS binding to SC membranes from male rats, consistent with increased receptor levels. Taken together, these findings demonstrate sex differences in N/OFQ–NOP receptor expression and NOP receptor activity following chronic morphine treatment. They also suggest interplay between endogenous N/OFQ and chronic morphine treatment that results in nociceptive modulation.     

Ethanol attenuation of morphine dependence: comparison to dizocilpine

Recent studies indicate that morphine dependence, assessed as the severity of naloxone-precipitated opiate withdrawal in rats, is attenuated by dizocilpine, a non-competitive, excitatory amino acid antagonist. Because ethanol is a putative excitatory amino acid antagonist, the present study compared the effects of co-administration of ethanol to that of dizocilpine on morphine dependence. Rats were administered morphine (10 mg/kg) twice daily for 9 days. One group received ethanol (1 g/kg) co-administration, another received dizocilpine (0.05 mg/kg) co-administration, and a third served as vehicle controls. On day 10, all rats received naloxone (4 mg/kg) injections and ratings of several classic signs of opiate withdrawal were made. Both ethanol-and dizocilpine-treated rats showed significantly less severe precipitated opiate withdrawal overall, with the ethanol group showing reduced ratings of some specific signs. These results demonstrate that ethanol, like dizocilpine, attenuates the development of morphine dependence. The results are consistent with the action of ethanol at glutamate receptors. Received: 4 February 1997/Final version: 8 May 1997     

Behavioral alterations produced by chronic naloxone injections

Repeated blockade of the endorphin receptors eventually induces symptoms resembling an opiate abstinence syndrome, despite the complete absence of opiate narcotics. Rats were injected with 0.6 mg/kg naloxone or with injection vehicle alone twice a day for six days. They were observed twice a day for four subsequent days. Body shakes, head shakes, scratches and total symptoms were significantly elevated in the naloxone treated group over controls. Symptoms were completely reversed by a small dose of morphine but not by naloxone. In a second experiment, rats were injected for ten days with the same dosage of naloxone. The abstinence-like syndrome began after six days of naloxone and continued for several days after cessation of injections. Total symptoms, body shakes, scratches and aggression were significantly elevated over controls and were reversed by morphine but not by naloxone.     

Matricaria chamomilla extract inhibits both development of morphine dependence and expression of abstinence syndrome in rats

The effect of Matricaria chamomilla (M. chamomilla) on the development of morphine dependence and expression of abstinence was investigated in rats. The frequencies of withdrawal behavioral signs (paw tremor, rearing, teeth chattering, body shakes, ptosis, diarrhea, and urination) and weight loss induced by naloxone challenge were demonstrated in morphine-dependent rats receiving M. chamomilla extract or saline. The withdrawal behavioral manifestations and weight loss were inhibited significantly by chronic co-administration of M. chamomilla extract with morphine. Administration of a single dose of M. chamomilla before the naloxone challenge in morphine-dependent animals abolished the withdrawal behavioral manifestations. The dramatic increase of plasma cAMP induced by naloxone-precipitated abstinence was prevented by chronic co-administration of M. chamomilla extract with morphine. These results suggest that M. chamomilla extract inhibits the development of morphine dependence and expression of abstinence syndrome.     

Comparaisons des effets de l'apomorphine et de la naloxone chez des rats et des souris en état de dépendance aiguë a la morphine

The actions of acute morphinization on the behavioural signs induced by apomorphine have been studied in rats and in two strains of mice with various doses of morphine and time-intervals also used for naloxone-precipitated abstinence.In naive rats, some of the effects of apomorphine but not all of them resembled signs of abstinence; some of these latter were not observed after apomorphine alone. Acute morphinization decreased or increased the frequencies of various effects of apomorphine, depending on the particular sign and time-schedule; these modifications were antagonized by naloxone. Depressions were observed for most of the signs, shortly after the administration of morphine. Increases appeared for only some signs either early or late but the increased effects were not abstinence-like signs.In naive mice, apomorphine produced infrequent jumping, an abstinence-like sign; acute morphinization enhanced it considerably. This phenomenon was antagonized by naloxone; its time-course was not quite identical to that of abstinence. In morphinized mice, the jumping produced by apomorphine was antagonized by low doses of various neuroleptics (haloperidol, chlorpromazine, pimozide and benperidol) whereas in the same conditions the jumping precipited by naloxone was not antagonized even by high doses of haloperidol or chlorpromazine, pimozide being effective in only one of the two strains. Benperidol was the less discriminating neuroleptic; its efficacy on naloxone-precipitated jumping might be related to its affinity for opiate receptor, as described in the literature. Naloxone-precipitated jumping was also not antagonized by -MT. These results, especially those obtained in the mice, do not favor the conception that the studied abstinence-signs have a dopaminergic mechanism, even when apomorphine produced apparently similar effects.

Attachée de recherche à l'INSERM: A qui doivent être adressées les demandes de tirés-à-part     

孤啡肽与八肽胆囊收缩素在大鼠脑内拮抗吗啡镇痛的协同作用

目的观察孤啡肽（ＯＦＱ）和八肽胆囊收缩素（ＣＣＫ ８）在大鼠脑内拮抗吗啡镇痛是否具有协同作用。方法应用等高线法设计实验,用辐射热甩尾法测定痛阈。皮下注射吗啡（５ｍｇ·ｋｇ－１）２０ｍｉｎ之后,选择有明显镇痛效应的大鼠,侧脑室（ｉｃｖ）分别注射不同剂量的ＯＦＱ和ＣＣＫ ８以及由两者不同比例（５∶１,２５∶１）不同剂量组成的混合物,观察对吗啡镇痛效应的影响。结果联合应用ＯＦＱ和ＣＣＫ ８所产生的抗吗啡镇痛作用明显大于单独使用ＯＦＱ或ＣＣＫ ８。结论ＯＦＱ和ＣＣＫ ８在一定比例、一定剂量组合范围内,对抗吗啡镇痛具有协同效应。     

Anatomical and pharmacological specificity of the rewarding effect elicited by microinjections of morphine into the nucleus accumbens of mice

RATIONALE: The involvement of nucleus accumbens (NAc) in initiating opiate-induced reward has been difficult to demonstrate in rats, and has not been studied in mice. OBJECTIVES: To determine whether a reward-sensitive strain of mice (BALB/c) would self-administer morphine directly into the NAc or sub-regions of the dorsal striatum. METHODS: BALB/c mice were unilaterally implanted with a guide-cannula above either the NAc, the anterior caudate putamen, or the posterior caudate putamen. On each experimental day, a stainless-steel injection cannula was inserted into the guide cannula to test the capacity for morphine self-administration (6.5 pmol or 65 pmol/50 nl) using a spatial discrimination task in a Y maze. RESULTS: Only the ventro-medial NAc group discriminated between the arm enabling a microinjection of morphine and the neutral arm. Once self-administration had been acquired, the effects of a pretreatment with two doses of the opiate antagonist naloxone (0.4 mg/kg or 4 mg/kg) were tested. Both doses slightly disrupted self-administration on the first 2 days. Only subjects receiving the 4-mg/kg dose exhibited an extinction of self-administration, related to an increasing number of jump attempts; none of the other opiate withdrawal-associated signs were observed. Self-administration was reinstated when naloxone was replaced with saline. CONCLUSIONS: (1) Medio-ventral NAc is involved in acute rewarding effects of opiates in mice. (2) Neither anterior nor posterior dorsal striatum seem to participate in these effects. (3) NAc is involved in jumping caused by naloxone-induced extinction, a behavior presumably revealing an aversive state associated with the unexpected suppression of reward.     

Alterations in the level of OFQ/N-IR in rat brain regions by cocaine

We have previously shown that administration of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, into the lateral ventricles or VTA blocked cocaine sensitization. In the present study, we determined the effect of acute and chronic cocaine treatment on the level of endogenous OFQ/N in rat brain regions. Male Sprague Dawley rats were tested for motor activity in response to saline or cocaine (20 mg/kg) injection once daily for three consecutive days. To determine the effect of single or repeated cocaine administration on the level of OFQ/N, rats were sacrificed 1 h following saline or cocaine injection either on day 1 or 3, respectively. Additional groups of rats were treated similarly with saline or cocaine on days 1-3 and sacrificed or tested for locomotor sensitization on day 8. Consistent with previous studies, repeated cocaine administration induced locomotor sensitization to a challenge dose of cocaine (7.5 mg/kg) given on day 8. Measurements of tissue content of OFQ/N-IR using radioimmunoassay indicated that the rat hypothalamus and striatum, respectively, contained the highest and lowest levels of the peptide among the brain regions tested. Acute cocaine decreased the level of OFQ-IR in the rat midbrain and to a lesser extent in the striatum. On the other hand, the level of OFQ/N was higher in rats treated with cocaine on days 1-3 and sacrificed on day 8. These findings suggest that endogenous OFQ/N may be involved in the actions of cocaine and possibly in cocaine-induced motor stimulation and locomotor sensitization.     

Role of noradrenergic hyperactivity in neonatal opiate abstinence

Despite the existence of a well-defined abstinence syndrome in offspring of opiate-dependent mothers, the mechanisms involved in neonatal abstinence remain unclear. The goal of the present study was to determine the contribution of noradrenergic neurons in the opiate abstinence syndrome in neonatal rats (10 days old). First, the ability of the α2-adrenergic agonist, clonidine to attenuate the symptoms of neonatal opiate abstinence precipitated by naloxone was determined. Secondly, the activity of noradrenergic neurons was determined by measuring postmortem levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the hypothalamus, hippocampus and cortex in opiate-abstinent pups. Neonatal opiate abstinence was characterized by an increased incidence of wall climbing, tremors and mouthing. Acute treatment with morphine and naloxone in chronic saline-treated pups also produced the tremor, albeit less severe than in pups treated chronically with morphine. Clonidine (0.2 mg/kg) attenuated the expression of tremor and mouthing in neonates, but increased wall climbing. Clonidine elicited wall climbing in opiate-naive neonates. Treatment with morphine followed by naltrexone increased MHPG levels in all of the brain areas examined, irrespective of the chronic treatment, but naltrexone treatment elicited a larger increase in MHPG levels in pups treated chronically with morphine. Acute morphine treatment increased MHPG levels only in the hypothalamus. The results of the present study provide behavioral and neurochemical data supporting the hypothesis that noradrenergic hyperactivity plays a role in neonatal opiate abstinence.     

吗啡依赖及戒断大鼠下丘脑前阿黑皮素原mRNA的变化

目的··:观察大鼠吗啡依赖和戒断状态下脑内前阿黑皮素原 (POMC )mRNA的变化。方法·· :采用腹腔注射法 ,按剂量递增原则建立大鼠吗啡依赖动物模型 ,同时建立生理盐水对照组。吗啡依赖大鼠随机分为依赖组和戒断组。对照组和依赖组动物于末次注射后3h ,戒断组大鼠于末次注射后72h迅速断头处死取脑 ,收集各个脑区组织总RNA标本。以POMC反义RNA探针对得到的RNA标本进行NorthernBlot印迹杂交 ,用电子计算机图像处理系统对所得结果进行分析。结果·· :吗啡依赖大鼠下丘脑POMCmRNA的表达仅为生理盐水对照组的69.56%±s4.7 % ,戒断72h状态下的吗啡依赖大鼠下丘脑POMCmRNA的表达恢复至生理盐水对照组的78.26 %±s5.3 % ;海马、纹状体和垂体POMCmRNA表达均为阴性。结论··:吗啡依赖大鼠下丘脑POMCmRNA的表达较生理盐水对照组有显著下降 ,戒断72h状态下的吗啡依赖大鼠其下丘脑POMCmRNA的表达较依赖组大鼠有显著回升 ,但仍显著低于正常组水平。此结果从分子生物学水平证实阿片类药物依赖机制与其引起内源性阿片肽系统功能变化有关     

Assessment of precipitated abstinence in morphine- dependent rats

An experimental model is described for quantifying the precipitated abstinence syndrome in morphine-dependent rats. Male rats were made dependent on morphine by subcutaneous implantation of a morphine pellet and the abstinence syndrome precipitated by intraperitoneal injection of naloxone hydrochloride. A ranking system, based on the median effective dose of naloxone for abstinence signs, quantitatively related the incidence of certain precipitated signs to the dose of naloxone. The time course for the development of dependence was shown to be maximal 70–74 h after pellet implantation. Food or water deprivation for 48 h dissociated the body weight loss during abstinence from the behavioral signs of precipitated withdrawal. Ganglionic blockade did not significantly modify abstinence behavior. An evaluative procedure which ranks abstinence signs is proposed for quantifying physical dependence on morphine.     

Differential expression of response-disruptive and somatic indices of opiate withdrawal during the initiation and development of opiate dependence

The current study examined the conditions that are necessary and sufficient for the initiation and progression of acute morphine dependence using two indices of opiate withdrawal: suppression of operant response rates and a somatic withdrawal rating scale. Separate groups of rats were pretreated with morphine (5 mg/kg, s.c.) a total of three times at intervals of 24 h, 1, 3, or 6 weeks. Rats received a single dose of naloxone 4 h after each morphine pretreatment. Naloxone-induced suppression of operant responding (0.33 mg/kg, s.c.) was significantly potentiated with repeated exposure to morphine even at the 6-week inter-treatment interval (ITI). At 24-h, 1-week and 3-week ITIs, rats treated with naloxone only after the third and final morphine pretreatment showed similar suppression of operant responding following naloxone to rats treated with naloxone after all three morphine pretreatments. However, at the 6-week ITI, the response-disruptive effects of naloxone administered for the first time after the third morphine pretreatment were no greater than the effects of naloxone administered after a single morphine pretreatment. In contrast to results seen with suppression of operant responding as the withdrawal index, potentiation of somatic signs of withdrawal was observed only at the 24-h ITI. These results indicate that a neuroadaptive state resembling opiate dependence can be initiated after just one injection of morphine, and that the response-disruptive effects of naloxone appear to be a particularly sensitive index of the initiation and progression of acute opiate dependence.     

Aspects of abstinence after morphine ingestion

Sprague-Dawley male rats were intoxicated with morphine, using an ingestion method where exposed and control rats received equivalent amounts of calories and nutrients. The degree of physical dependence on morphine was demonstrated by studying and quantifying abstinence symptoms after withdrawal or after administration of opiate antagonists. The aims of the study were (1) to further enlighten the specificity and validity of the intoxication method concerning physical dependence, and (2) to determine whether some of the abstinence signs might be of value to facilitate quantitation of the degree of physical dependence on morphine, with diet and fluid intake being maintained under control. Withdrawn rats showed a decreased fluid diet intake and a body weight loss, the latter partly due to anorexia. Other mild abstinence signs were irritation, tremor and some motor excitation. The body weight loss during the first day of morphine withdrawal was proportional to the accumulated drug dose (between 25 and 300 mg morphine PO/kg b.wt.). However, prolonged morphine treatment on one dose (340 mg/kg b.wt.) did not reinforce the body weight changes caused by morphine withdrawal. The succeeding weight gain some days after morphine withdrawal was not entirely dependent on the amount of fluid diet intake. Methadone was shown to partially block the decrease in diet intake and the weight loss seen during morphine withdrawal. The naloxone-precipitated withdrawal symptoms were motor excitation, cholinergic signs, body weight loss, diarrhoea and decreased diet intake. The weight loss 2 hr after naloxone administration to long-term intoxicated rats was proportional to the naloxone dose.(ABSTRACT TRUNCATED AT 250 WORDS)