Withdrawal Signs In Morphine-dependent Mice Research Articles

Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms through antioxidative effect and nitric oxide pathway in mice

Oxidative stress and the nitric oxide (NO) pathway are involved in the development of opioid analgesic tolerance and dependence. Simvastatin modulates NO and oxidative stress, so the present study aimed to investigate its effect on the development and expression of morphine analgesic tolerance and withdrawal signs in mice. Morphine tolerance and dependence were induced by twice daily morphine injection (10 mg/kg, s.c.) for 5 consecutive days. Tolerance was assessed by the hot-plate test and dependence by naloxone challenge, on the sixth day. To determine if the NO is involved in the effects of simvastatin, mice were pre-treated with l-arginine (200 mg/kg) or the NO synthesis inhibitors (L-NAME; 30 mg/kg) along with simvastatin (300 mg/kg). The results showed that acute and chronic administration of simvastatin reversed the antinociceptive tolerance of morphine and attenuated withdrawal signs in morphine-dependent mice, and this effect is reversed by l-arginine and augmented by l-NAME. Also, the concentration of NO and oxidative stress factors such as malondialdehyde content, total thiol, and glutathione peroxidase (GPx) activity in brain tissues was evaluated. Chronic administration of simvastatin reduced NO and malondialdehyde, and increased total thiol and GPx levels in the cerebral cortex and hippocampus of morphine-dependent mice which were antagonized by l-arginine, and augmented by l-NAME. In summary, simvastatin attenuates morphine-induced antinociceptive tolerance and withdrawal symptoms, at least partly, through antioxidative properties and nitric oxide pathway.

Geraniin attenuates naloxone-precipitated morphine withdrawal and morphine-induced tolerance in mice.

Potentially life-threatening and unpleasant side effects associated with some analgesics have fueled the drive for the search for more analgesics with better side effect profiles. Geraniin, the most dominant secondary metabolite in the aqueous extract of the aerial parts of Phyllanthus muellerianus, has been shown to possess antinociceptive properties mediated partly by opioidergic mechanisms. The purpose of this study is to determine whether geraniin exhibits tolerance and if it is able to ameliorate withdrawal signs in naloxone-precipitated morphine withdrawal. After chronic treatment of mice with geraniin orally, the formalin test was used to ascertain whether tolerance will develop to its antinociceptive effects and if there is morphine-induced tolerance cross-generalization with geraniin. The effect of geraniin on naloxone-precipitated morphine withdrawal signs in morphine-dependent mice was also investigated. Geraniin (3-30 mg/kg) did not produce any tolerant effects after chronic administration and there was also no cross-generalization with the tolerant effects of morphine. Geraniin did not induce withdrawal signs but significantly reduced the number of jumps in morphine-dependent mice. Geraniin does not produce any tolerant effects like morphine and also reduced the signs associated with naloxone-precipitated morphine withdrawal in mice.

Hyperbaric oxygen treatment suppresses withdrawal signs in morphine-dependent mice

Hyperbaric oxygen (HBO2) therapy reportedly reduces opiate withdrawal in human subjects. The purpose of this research was to determine whether HBO2 treatment could suppress physical signs of withdrawal in opiate-dependent mice. Male NIH Swiss mice were injected s.c. with morphine sulfate twice a day for 4 days, the daily dose gradually increasing from 50mg/kg on day 1 to 125mg/kg on day 4. On day 5, withdrawal was precipitated by i.p. injection of 5.0mg/kg naloxone. Mice were observed for physical withdrawal signs, including jumping, forepaw tremor, wet-dog shakes, rearing and defecation for 30min. Sixty min prior to the naloxone injection, different groups of mice received either a 30-min or 60-min HBO2 treatment at 3.5atm absolute. HBO2 treatment significantly reduced naloxone-precipitated jumping, forepaw tremor, wet-dog shakes, rearing and defecation. Based on these experimental findings, we concluded that treatment with HBO2 can suppress physical signs of withdrawal syndrome in morphine-dependent mice.

SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL PROPERTIES OF NEW CODEINE FE(III) COMPLEX

ABSTRACT The reaction of FeCl 3 hexahydrate with C 18 H 20 NO 3 .PO 4 in acetonitrile produced new complex with general formula [Fe(L)]Cl 2 , (L= codeine). Characterization of the ligand and its complex were made by elemental analysis, FT-IR, 1 H-NMR, Raman and UV–visible spectroscopy. This new complex showed antitumor activity against two kinds of cancer cell lines: AGS (Stomach) and MCF-7 (Breast). Cell cytotoxic effects of the ligand and its complex were assayed by MTT and Natural-red tests. The antibacterial activity of ligand and complex against Pseudomonas aeruginosa , Staphylococcus aureus , Streptococcus pyogenes and Escherichia coli were also examined. Keywords: Codeine; Fe(III) complex; Synthesis; Anti-tumor; AGS and MCF-7; Antibacterial. e-mail: mojdeh.golzani@gmail.com INTRODUCTION Natural products play an important role in diseases control and treatment. The plants extracts are used in the treatment of human diseases all the time. From the last century, a scientific interest for phototherapy increased in several medical fields such as immunology, hematology and oncology [1-5].Currently there are three major ways of treating cancer: radiation therapy, surgery and cytotoxic drugs. Application of plants in medicine has affected the identification of natural compounds such as cocaine, morphine, vinblastine, tax land codeine [5-8].Many different coordination compounds and the mechanism of cytotoxic action have been discussed with regard to the development of new antitumor agents [8-15]. Numerous medicinal plants have been screened extensively for their antimicrobial potential worldwide [1, 11]. Morphine and its derivatives have received considerable attention as narcotic and used in lenitive drudge products. Morphine plays an important role in the therapy of acute and chronic pain. Exogenously delivered morphine acts in the body by activating different subtypes of opioid receptors [14].Over the last decades, proposals have accumulated that morphine present in mammalian tissues and fluids comes not only from an exogenous or dietary origin, but may also be biosynthesized de novo. Latest studies have unequivocally proven the existence of a mammalian morphine biosynthetic pathway [15], which consists of at least 19 steps and is different in its primary steps from that occurring in plants [16]. Meanwhile the endogenous morphine biosynthesis takes place in mammals, their cells and tissues are constantly exposed to certain amounts of morphine and its precursors [17].Investigation of lithium effect in opioid receptors on inhibitory avoidance response in mice has been reported. The results suggest that the opioid receptors in the central nervous system may be involved in the retrieval of lithium state dependent learning [18]. The lithium efficacy in controlling behaviors related with dopamine stimulants and manic states has been proposed [19]. Thus, it may be suggested that lithium‘s action may be mediated through dopamine receptors [20].Furthermore interactions between lithium and opioids have been reported. There is evidence that lithium is able to affect some actions of morphine. In particular, it has been shown that lithium inhibits morphine withdrawal signs in morphine-dependent mice [21], reduces the self-stimulation facilitated by morphine and the expression of tolerance to morphine [22] and alters the morphine induced analgesia in mice [23]. Both drugs produce a conditioned taste avoidance response and suppress schedule-induced polydipsia [24]. Another morphine precursor codeine, which stands in the biosynthetic pathway after salutaridinol, had a higher partial agonist efficacy. Their metal chelates are of interest due to their fascinating chemistry as well as antimicrobial and anti-cancer activities. The other natural ligand from plants such as phenolic compound of mono and sesquiterpenoid, flavonoids also can be used in synthesis of metal complex [25].Codeine is generally named codeine phosphate (Cod.P), morphine-3-methyl ether phosphate, methyl-morphine phosphate, or morphine monomethyl ether phosphate. It takes the general formulae of C

Involvement of 5-HT2 receptors in the expression of withdrawal diarrhea in morphine-dependent mice

The withdrawal syndrome after the cessation of μ-opioid receptor agonists remains an obstacle in the clinical treatment of pain. We recently showed that peripheral opioid receptors play a significant role in the withdrawal signs in morphine-dependent mice. Therefore, the present study was designed to investigate the underlying mechanism of morphine-induced withdrawal symptoms, especially the peripheral oriented body-weight loss that accompanied diarrhea, in mice. Withdrawal signs were precipitated by the injection of naloxone 1 day after the slow-release emulsion administration of morphine. Withdrawal body-weight loss and diarrhea precipitated by naloxone in morphine-dependent mice were significantly suppressed by ritanserin (a 5-HT2 receptor antagonist), olanzapine (5-HT2/D2 receptor antagonist) and fullerene (a free radical scavenger), whereas neither ondansetron (a 5-HT3 receptor antagonist) nor atropine (a muscarine receptor antagonist) significantly suppressed naloxone-precipitated diarrhea. 5-HT3-receptors (but not 5-HT2-receptors) are known to play a significant role in 5-HT-induced diarrhea. Therefore, we also examined the effects of ritanserin and fullerene on 5-HT-induced diarrhea in morphine-dependent mice. Ritaserin significantly suppressed 5-HT-induced diarrhea in morphine-dependent mice, but not saline-treated mice. These results suggest that peripheral 5-HT2-receptor function could be altered in morphine-dependent mice, and the blockade of 5-HT2 receptor or free radical scavengers may be useful for the treatment of opioid-withdrawal diarrhea.

Effects of phosphodieastrase type 5 inhibitions on morphine withdrawal symptoms in mice.

Chronic morphine exposure creates dependence and, upon cessation, withdrawal symptoms. Studies indicate the phosphodiesterase type 5 (PDE5) inhibitor sildenafil may provide centrally mediated benefits against withdrawal, and therefore, this study evaluated morphine withdrawal signs in dependent mice with and without sildenafil treatment. Dependence was induced by repeated treatments with morphine over 5 consecutive days. The morphine-dependent mice received sildenafil (1, 5, 10, or 20 mg/kg, i.p.) 15 min prior to the precipitation of morphine withdrawal. On the last day, naloxone was injected 2 hours after the last morphine injection, and withdrawal signs were evaluated for 30 min after naloxone injection. The administration of sildenafil reduced all of the morphine withdrawal symptoms. The administration of sildenafil diminished morphine withdrawal signs in morphine-dependent mice. We hypothesize that the mechanism involves enhanced cyclic guanosine monophosphate (cGMP) activity, but further studies are recommended for a better understanding.

Dual effect of cAMP agonist on ameliorative function of PKA inhibitor in morphine‐dependent mice

The present study shows interactive effects of bucladesine (db-cAMP) as a cyclic adenosine monophosphate (cAMP) agonist and H-89 as a protein kinase A (PKA) inhibitor on naloxone-induced withdrawal signs in morphine-dependent mice. Animals were treated subcutaneously with morphine thrice daily with doses progressively increased from 50 to 125mg/kg. A last dose of morphine (50mg/kg) was administered on the 4thday. Several withdrawal signs were precipitated by intraperitoneal (i.p.) administration of naloxone (5mg/kg). Different doses of bucladesine (50, 100, 200nm/mouse) and H-89 (0.05, 0.5, 1, 5mg/kg) were administered (i.p.) 60min before naloxone injection. In combination groups, bucladesine was injected 15min before H-89 injection. Single administration of H-89 (0.5, 1, 5mg/kg) and bucladesine (50, 100nm/mouse) significantly attenuated prominent behavioral signs of morphine withdrawal. Lower doses of bucladesine (50, 100nm/mouse) in combination with H-89 (0.05mg/kg) increased the inhibitory effects of H-89 on withdrawal signs while in high dose (200nm/mouse) decreased the ameliorative function of H-89 (0.05mg/kg) in morphine-dependent animals. It is concluded that H-89 and bucladesine could affect morphine withdrawal syndrome via possible interaction with cyclic nucleotide messengering systems, protein kinase A signaling pathways, and modified related neurotransmitters.

Blockade of Endocannabinoid Hydrolytic Enzymes Attenuates Precipitated Opioid Withdrawal Symptoms in Mice

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.

2-MPPA, a selective glutamate carboxypeptidase II inhibitor, attenuates morphine tolerance but not dependence in C57/Bl mice

We have recently reported that conditioned morphine reward and tolerance to its antinociceptive effect, but not expression of morphine dependence, were attenuated by 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a prototypic inhibitor of glutamate carboxipeptidase II (GCP II), which is an enzyme responsible for the supply of glutamate. In the present study, we investigated in more detail the effects of GCP II inhibition on opioid dependence and tolerance to its antinociceptive effect in C57/Bl mice using a novel GCP II inhibitor. The treatment with 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA; 60 but not 10 or 30 mg/kg) prevented the development of morphine tolerance without affecting acute morphine antinociception. 2-MPPA at 30 and 60 mg/kg did not prevent the development of dependence induced by 10 and 30 mg/kg of morphine. The study on opioid withdrawal syndrome, i.e., expression of opioid dependence, demonstrated that 2-MPPA potentiated jumping behavior and teeth chattering but attenuated chewing and ptosis. None of these opioid withdrawal signs were affected by 2-MPPA in morphine nondependent mice. Pretreatment with the mGluR II antagonist LY341495 (1 mg/kg) reversed the 2-MPPA-induced increase or decrease in opioid withdrawal signs in morphine-dependent mice. 2-MPPA (60 mg/kg) administered for 7 days with morphine did not affect brain concentration of this opiate. The present findings suggest complex effects of GCP II inhibition on morphine dependence and tolerance and imply a role of mGluR II in the actions of 2-MPPA.

Barium potentiates the conditioned aversion to, but not the somatic signs of, morphine withdrawal in mice

The effect of barium, a putative blocker of G-protein-activated inwardly rectifying potassium (GIRK) channels, on naltrexone-precipitated withdrawal signs in morphine-dependent mice was investigated. Mice were chronically treated with morphine (8–45 mg/kg) for 6 days. The morphine-dependent mice were then given naltrexone (1 and 3 mg/kg), after which they showed several somatic signs of withdrawal, as well as conditioned aversion, increased cortical noradrenaline turnover, and decreased dopamine turnover in the limbic forebrain. Pretreatment with barium (1.25 and 2.5 nmol) significantly potentiated the naltrexone-precipitated conditioned aversion and augmented the decrease in dopamine turnover in the limbic forebrain. However, barium pretreatment did not affect the naltrexone-precipitated somatic signs of withdrawal and increased cortical noradrenaline turnover. These findings suggest that modification of GIRK channels may be involved in the expression of aversion to morphine withdrawal mediated through the dopaminergic system but it is not involved in the somatic signs of morphine withdrawal mediated through the noradrenergic system.

Endogenous cannabinoid, 2-arachidonoylglycerol, attenuates naloxone-precipitated withdrawal signs in morphine-dependent mice

In the present study, we examined the effects of endogenous ligand 2-arachidonoylglycerol (2-AG) on naloxone-precipitated withdrawal in morphine-dependent mice, in comparison with that of two cannabinoid agonists, an ingredient of Cannabis sativa Δ 8-tetrahydrocannabinol (Δ 8-THC) and the synthetic cannabinoid CB1 receptor agonist HU-210. 2-AG at a dose of 10 μg per mouse (i.c.v.) significantly inhibited both jumping and forepaw tremor as signs of withdrawal following naloxone challenge in morphine-dependent mice. Furthermore, both Δ 8-THC and HU-210 significantly attenuated these symptoms of withdrawal in morphine-dependent mice. Therefore, it is suggested that inactivation of the endogenous cannabinoid system is related to the induction of withdrawal syndrome in morphine-dependent mice. Moreover, hyperlocomotor activity in morphine-dependent mice was markedly increased by Δ 8-THC 10 mg/kg, which had no effect in naive mice. This finding suggested that in morphine dependence, upregulation of cannabinoid CB1 receptors occurred. Non-psychoactive CB1 receptor agonists or accelerators of endocannabinoid synthesis may be potential as therapeutic drugs for opiate withdrawal symptoms.

Modification of naloxone-induced withdrawal signs by dextromethorphan in morphine-dependent mice

In the present study the effect of dextromethorphan on naloxone-induced withdrawal signs in morphine-dependent mice was examined. In addition, the modulatory role of dopaminergic mechanisms upon the effect of dextromethorphan was investigated. Mice were rendered dependent on morphine by subcutaneous (s.c.) injections of morphine sulfate three times a day for 3 days, and withdrawal signs were induced by intraperitoneal (i.p.) administration of naloxone 2 h after the 10th injection of morphine sulfate on day 4. Dextromethorphan (20–50 mg/kg, i.p.) caused a significant decrease in withdrawal jumping, paw-shakes, grooming, burrows, writhing and diarrhea in morphine-dependent mice. The mixed dopamine D 1/D 2 receptor agonist apomorphine (0.5 and 1 mg/kg, s.c.) reduced the response induced by dextromethorphan. The effect of apomorphine was blocked by the dopamine D 1 receptor antagonist SCH 23390 ( R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7-ol maleate) (0.5 and 1 mg/kg, i.p.) but not by the dopamine D 2 receptor antagonist sulpiride (25 and 50 mg/kg, s.c.) nor the peripheral dopamine receptor antagonist domperidone (5 and 10 mg/kg, s.c.). These results suggest that the dopaminergic system(s) may in part mediate the suppressive action of the NMDA receptor antagonist dextromethorphan on naloxone-induced withdrawal signs in morphine-dependent mice.

Modification of the Expression of Naloxone-Precipitated Withdrawal Signs in Morphine-Dependent Mice by Diabetes: Possible Involvement of Protein Kinase C

The involvement of cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) in the modulation of naloxone-precipitated withdrawal jumping in morphine-dependent mice by diabetes was examined. Naloxone-precipitated withdrawal jumps were significantly less in morphine-dependent diabetic mice than in morphine-dependent non-diabetic mice. I.c.v. pretreatment with either calphostin C, a PKC inhibitor, or KT-5720, a PKA inhibitor, attenuated naloxone-precipitated withdrawal jumps in morphine-dependent non-diabetic mice. However, naloxone-precipitated withdrawal jumps in morphine-dependent diabetic mice were not attenuated by i.c.v. pretreatment with either calphostin C or KT5720. Moreover, i.c.v. pretreatment with phorbol-12,13-dibutyrate (PDBu), a PKC activator, attenuated naloxone-precipitated withdrawal jumps in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice. The noradrenaline (NA) turnover in the frontal cortex in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice, was significantly increased 5 min after administration of naloxone. Naloxone-induced enhancement of NA turnover in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice, was blocked by i.c.v. pretreatment with either calphostin C or KT5720 1 hr before naloxone challenge and blocked by PDBu 1 hr before the last injection of morphine. These results suggest that the co-activation of PKC and PKA is needed to elicit naloxone-precipitated withdrawal jumps and enhancement of turnover rate of NA in the frontal cortex in morphine-dependent non-diabetic mice. Furthermore, the attenuation of naloxone-precipitated withdrawal jumps in morphine-dependent diabetic mice may be due, in part, to the desensitization of μ-opioid receptors by the activation of PKC.

Adenosine receptor agonists attenuate and adenosine receptor antagonists exacerbate opiate withdrawal signs

Previous studies have demonstrated a role for adenosine in mediating opiate effects. Adenosine receptors and their functions have been shown to be regulated by chronic opiate treatment. This study examines the role of adenosine receptors in the expression of opiate withdrawal behaviors. The effects of single doses of parenterally administered adenosine receptor subtype-selective agonists and antagonists on opiate withdrawal signs in morphine-dependent mice were measured. Mice received subcutaneous morphine pellet treatment for 72 h and then underwent naloxone-precipitated withdrawal after pretreatment with adenosinergic agents. Adenosine agonists attenuated different opiate withdrawal signs. The A1 agonist R-N6(phenylisopropyl)adenosine (0, 0.01, 0.02 mg/kg, IP) significantly reduced wet dog shakes and withdrawal diarrhea, while the A2a-selective agonist 2-p-(2-carboxethyl)phenylethylamino-5'-N-ethylcarboxamido adenosine or CGS 21680 (0, 0.01, 0.05 mg/kg, IP) significantly inhibited teeth chattering and forepaw treads. Adenosine receptor antagonists enhanced different opiate withdrawal signs. The adenosine A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (0, 1, 10 mg/kg, IP) significantly increased weight loss and the A2 antagonist, 3,7-dimethyl-1-propargylxanthine (0, 1 and 10 mg/kg, IP) enhanced wet dog shakes and withdrawal diarrhea. Treatment effects of adenosinergic agents were not due to nonspecific motor effects, as demonstrated by activity monitoring studies. These results support a role for adenosine receptors in the expression of opiate withdrawal and suggest the potential utility of adenosine agonists in its treatment.

Effect of pretreatment with pertussis toxin on the development of physical dependence on morphine.

The effect of intracerebroventricular (i.c.v.) pretreatment with pertussis toxin (PTX) on the development of physical dependence on morphine was investigated in mice. Twenty four hours after PTX (0.5 microgram, i.c.v.) or vehicle pretreatment, the mice were chronically treated with morphine (8-45 mg/kg, s.c.) for 5 days. Several withdrawal signs were observed following naloxone challenge in morphine-dependent mice which had been pretreated with vehicle. In addition, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and noradrenaline (NA) turnover (MHPG/NA) levels in the cerebral cortex were increased following naloxone challenge in morphine-dependent mice. These findings indicate that activation of the central noradrenergic system may mediate the expression of some withdrawal signs. In contrast, pretreatment with PTX attenuated the naloxone-precipitated withdrawal signs in morphine-dependent mice. The incidence of withdrawal signs such as jumping, "wet dog" shakes, and rearing was significantly reduced by PTX pretreatment. PTX pretreatment also prevented the naloxone-precipitated increases in MHPG concentration and NA ratio (MHPG/NA) in the cerebral cortex, suggesting that central PTX-sensitive GTP-binding proteins (G-proteins) may be involved in the elevation of NA transmission in the cortex which projects from the locus coeruleus (LC) during morphine withdrawal. The blocking effects of PTX on the behavioral and biochemical changes after withdrawal suggest that central PTX-sensitive G-proteins (Gi/Go) may play an important role in the development of physical dependence on morphine.

Modification of morphine-induced analgesia, tolerance and dependence by bromocriptine

The effect of two doses of bromocriptine, a dopamine agonist, on morphine-induced analgesia, tolerance and dependence was investigated in mice. Bromocriptine at doses of 0.04 and 0.08 mg/kg did not affect the baseline tail flick latency of mice but potentiated the morphine analgesia. Pretreatment of mice with 5 mg/kg of sulpiride, a D-2 antagonist, not only blocked the effect of 0.08 mg/kg of bromocriptine but also antagonized the morphine analgesia. Control animals given daily injections of 10 mg/kg of morphine rapidly developed tolerance to the analgesic effect. A combined treatment of bromocriptine with morphine given daily suppressed the development of tolerance to morphine analgesia. However, development of tolerance to morphine analgesia was not significantly modified in the animals treated daily with bromocriptine (0.08 mg/kg) plus sulpiride (5 mg/kg). Acute dependence was induced by the administration of 100 mg/kg of morphine. The administration of bromocriptine 30 min before naloxone significantly decreased the ED 50 value for naloxone for inducing jumping in mice. Coadministration of sulpiride and bromocriptine attenuated the ability of bromocriptine to potentiate the withdrawal syndrome of morphine dependence. The results indicate that bromocriptine potentiates morphine analgesia, suppresses the development of tolerance to morphine analgesia but exacerbates opiate withdrawal signs in morphine-dependent mice. These effects of bromocriptine appear to be mediated via D-2 receptors.