Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic opioid receptor (OR) activation by morphine causes distinct cellular adaptations responsible for the development of tolerance. The present study examines the effect of chronic morphine exposure on the ability of high-efficacy agonists to mediate delta-OR (DOR) and mu-OR (MOR) uncoupling and internalization, two regulatory mechanisms contributing to rapid desensitization of OR function. Chronic morphine treatment (1 microm; 72 hr) of DOR carrying neuroblastoma x glioma (NG108-15) hybrid cells, a prototypical model system frequently used to study cellular aspects of opioid tolerance, completely blocked the capacity of [d-Ala2, d-Leu5]enkephalin (DADLE) and etorphine to desensitize opioid-stimulated [35S]GTPgammaS binding and to mediate DOR internalization. Similar findings were obtained on stably DOR- and MOR-transfected human embryonic kidney (HEK) 293 cells. Chronic morphine treatment also heterologously impaired agonist regulation of non-opioid G-protein-coupled receptors, such as the m(4)-muscarinic acetylcholine receptor and the brain-type cannabinoid receptor. As a possible underlying mechanism, we found that chronic morphine treatment completely blocked agonist-induced redistribution of beta-arrestin1 in both NG108-15 and stably MOR-transfected HEK293 cells. Moreover, attenuation of beta-arrestin1 function appears to depend on persistent stimulation of MAP kinase activity during the course of chronic morphine treatment, because coincubation of the cells together with the MAP kinase blocker PD98059 fully restored beta-arrestin1 translocation and receptor internalization. These results demonstrate that chronic morphine treatment produces adaptational changes at the beta-arrestin1 level, which in turn attenuates agonist-mediated desensitization and internalization of G-protein-coupled receptors.
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PMID:Chronic morphine treatment inhibits opioid receptor desensitization and internalization. 1245 Nov 20

The heritability of nociception and antinociception has been well established in the mouse. The pharmacogenetics of morphine analgesia are fairly well characterized, but far less is known about other analgesics. The purpose of this work was to begin the systematic genetic study of non-mu-opioid analgesics. We tested mice of 12 inbred mouse strains for baseline nociceptive sensitivity (49 degrees C tail-withdrawal assay) and subsequent antinociceptive sensitivity to systemic administration of (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate (U50,488; 10-150 mg/kg), a kappa-opioid receptor agonist; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; 0.5-480 mg/kg), a synthetic cannabinoid receptor agonist; epibatidine (7.5-150 microg/kg), a nicotinic receptor agonist; clonidine (0.1-5 mg/kg), an alpha(2)-adrenergic receptor agonist; and, for purposes of comparison, the prototypic mu-opioid receptor agonist, morphine (5-200 mg/kg). Robust interstrain variability was observed in nociceptive sensitivity and in the antinociceptive effects of each of the drugs, with extreme-responding strains exhibiting antinociceptive potencies differing up to 37-fold. Unexpectedly, we observed moderate-to-high genetic correlations of strain sensitivities to the five drugs (r = 0.39-0.77). We also found moderate-to-high correlations between baseline nociceptive sensitivity and subsequent analgesic response to each drug (r = 0.33-0.68). The generalizability of these findings was established in follow-up experiments investigating morphine and clonidine inhibition of formalin test nociception. Despite the fact that each drug activates a unique receptor, our results suggest that the potency of each drug is affected by a common set of genes. However, the genes in question may affect antinociception indirectly, via a primary action on baseline nociceptive sensitivity.
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PMID:The heritability of antinociception: common pharmacogenetic mediation of five neurochemically distinct analgesics. 1253 6

We have studied the possible interaction between three selective opioid-receptor antagonists, nor-binaltorphimine (NB: kappa) (5 mg/kg), cyprodime (CY: mu) (10 mg/kg) and naltrindole (NTI: delta) (1 mg/kg), and the cannabinoid receptor agonist CP 55,940, in the modulation of anxiety (plus-maze) and adrenocortical activity (serum corticosterone levels by radioimmunoassay) in male rats. The holeboard was used to evaluate motor activity and directed exploration. CP 55,940 (75 microg/kg, but not 10 microg/kg) induced an anxiogenic-like effect, which was antagonised by NB. The other effects of CP 55,940 (75 microg/kg), a decreased holeboard activity and stimulation of adrenocortical activity, were not antagonised by any of the three opioid receptor antagonists. CY and NTI, when administered alone, induced marked reductions in motor activity, anxiogenic-like effects and stimulation of adrenocortical activity. The selective kappa-opioid receptor antagonist NB, on its own, did not modify the level of anxiety but stimulated adrenocortical activity. We provide the first pharmacological evidence about the involvement of the kappa-opioid receptor in the anxiogenic-like effect of CP 55,940.
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PMID:Involvement of the kappa-opioid receptor in the anxiogenic-like effect of CP 55,940 in male rats. 1254 31

Several lines of evidence indicate that the opioid and cannabinoid systems produce synergistic interactions. The present study examined the opioid receptors involved in the antitussive effect of WIN 55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-[4-morpholinylmethyl]-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl) methanone mesylate), a high-affinity cannabinoid receptor agonist, in mice. WIN 55212-2, at doses of 0.3-3 mg/kg ip, produced a dose-dependent antitussive effect. This antitussive effect of WIN 55212-2 was antagonized by pretreatment with either methysergide (3 mg/kg ip), a 5-HT receptor antagonist, or naloxone (1 mg/kg ip), an opioid receptor antagonist. Furthermore, pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 3 mg/kg ip), a cannabinoid CB(1) receptor antagonist, also significantly reduced the antitussive effect of WIN 55212-2. Blockade of mu-opioid receptors by pretreatment with beta-funaltrexamine (40 mg/kg sc) significantly reduced the antitussive effect of WIN 55212-2. However, pretreatment with nor-binaltorphimine (20 mg/kg sc), a kappa-opioid receptor antagonist, did not affect the antitussive effect of WIN 55212-2. Pretreatment with naloxonazine (35 mg/kg sc), a mu(1)-opioid receptor antagonist, also did not affect the antitussive effect of WIN 55212-2. These results indicate that the antitussive effect of WIN 55212-2 is mediated by the activation of cannabinoid CB(1) receptors and mu(2) (naloxonazine-insensitive)-opioid receptors, but not mu(1) (naloxonazine-sensitive)- or kappa-opioid receptors.
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PMID:Antitussive effect of WIN 55212-2, a cannabinoid receptor agonist. 1292 73

Numerous studies have shown the existence of functional links between the endogenous cannabinoid and opioid systems. However, extensive research is still needed to elucidate the biochemical mechanisms involved in this cannabinoid-opioid interaction. Mice lacking mu- (MOR), delta- (DOR) and kappa- (KOR) opioid receptors have been generated and some specific pharmacological effects induced by cannabinoids have been reported to be modified in these animals. In order to clarify further the possible mechanisms involved in this modification of cannabinoid responses we have now evaluated the expression and functional activity of cannabinoid receptors in different brain structures in these mutant animals. For this purpose, we have performed quantitative receptor autoradiography of CB1 cannabinoid receptors and activation of GTP-binding proteins by CB1 agonists in the brain of wild-type and homozygous MOR, DOR and KOR knockout mice. There were no significant differences in the levels of CB1 receptors in the brain of MOR mutant mice. In contrast, the efficacy of CB1 receptor activation by the cannabinoid agonist WIN 55 212-2 was dramatically reduced in the caudate-putamen of MOR knockout animals. The density of CB1 receptors as well as the stimulation of GTP-binding proteins by WIN 55 212-2 were significantly increased in the substantia nigra of mice deficient in DOR. Finally, there were no major changes in the levels and functional activity of CB1 cannabinoid receptors in any brain region in KOR knockout mice. Taken together, these results indicate that deletion of MOR and DOR causes alterations in cannabinoid receptor levels and functional activity in specific brain structures, which could explain some of the functional interactions observed between these two neuronal systems.
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PMID:Cannabinoid receptor and WIN 55 212-2-stimulated [35S]-GTPgammaS binding in the brain of mu-, delta- and kappa-opioid receptor knockout mice. 1462 80

1 The primary aim was to study the central respiratory effects of cannabinoids (CB). To this end, the cannabinoid receptor agonist WIN55212-2 was injected into the cisterna magna of urethane-anaesthetised rats and changes in respiratory parameters were observed. The secondary aim was to observe the centrally elicited cardiovascular actions of WIN55212-2. Involvement of opioid mechanisms in the central effects of WIN55212-2 was also studied. 2 Intracisternal (i.c.) application of WIN55212-2 (1, 3, 10 and 30 microg kg(-1)) dose-dependently decreased the respiratory rate and minute volume. Tidal volume was slightly increased, whereas peak inspiratory flow remained unchanged. In addition, WIN55212-2 increased mean arterial pressure and the plasma noradrenaline concentration and decreased heart rate. 3 I.c. injection of WIN55212-3 (1, 3, 10 and 30 microg kg(-1)), an enantiomer of WIN55212-2 lacking affinity for cannabinoid receptors, elicited no effects. All effects of WIN55212-2 were prevented by the CB1 receptor antagonist SR141716 (2 mg kg(-1) i.v.). I.c. administration of the opioid receptor agonist DAMGO (0.1, 0.3, 1 and 3 microg kg(-1)) markedly lowered the respiratory rate, tidal volume, minute volume and peak inspiratory flow. These effects were attenuated by the opioid receptor antagonist naloxone (0.2 mg kg(-1) i.v.). In contrast, naloxone did not affect the respiratory and cardiovascular effects of i.c. administered WIN55212-2. 4 Our results show that activation of CB1 cannabinoid receptors in the brain stem depresses respiration and enhances sympathetic tone and cardiac vagal tone. Opioid mechanisms are not involved in these central cannabinoid effects.
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PMID:Central effects of the cannabinoid receptor agonist WIN55212-2 on respiratory and cardiovascular regulation in anaesthetised rats. 1522 90

Current pharmacotherapies for alcohol dependence in humans (e.g., naltrexone, acamprosate) are meeting with only limited therapeutic success. The development of novel pharmacotherapies is urgently needed but is reliant upon the screening of large numbers of candidate "anticraving" drugs using appropriate animal models. The development of animal models is complex because (1) laboratory animals are often reluctant to consume large quantities of alcohol, (2) inducing a state of alcohol dependence, analogous to the human condition, may require many months of alcohol exposure, (3) concluding that a given drug selectively reduces alcohol craving requires very carefully controlled experiments, and (4) false positives and false negatives may result from the sometimes distinct physiology and psychology of the alcohol-addicted human and rat. To address some of these problems, our laboratory has recently developed the "beer model" of alcohol dependence and craving. Rats, like humans, have a prodigious appetite for beer and will drink much more beer than equivalent ethanol solutions in water. Beer consumption in rats leads to clear signs of intoxication, anxiety reduction, and signs of withdrawal when beer access is suddenly denied. We have found that beer craving in rats is selectively reduced by the cannabinoid receptor antagonist SR 141716 and the opioid receptor antagonist naltrexone. Combining these two drugs appears to have a synergistic anticraving effect. Other promising pharmacotherapies for the future are discussed.
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PMID:Rats on the grog: novel pharmacotherapies for alcohol craving. 1534 69

CB(2) cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB(2) receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB(2) receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB(2) receptor-mediated inhibition of pain responses. Here, we test the hypothesis that CB(2) receptor activation stimulates release from keratinocytes of the endogenous opioid beta-endorphin, which then acts at opioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB(2) receptor-selective agonist AM1241 were prevented in rats when naloxone or antiserum to beta-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that beta-endorphin is necessary for CB(2) receptor-mediated antinociception. Further, AM1241 did not inhibit nociception in mu-opioid receptor-deficient mice. Hindpaw injection of beta-endorphin was sufficient to produce antinociception. AM1241 stimulated beta-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB(2) cannabinoid receptor-selective antagonist and was not observed in skin from CB(2) cannabinoid receptor-deficient mice. These data suggest that CB(2) receptor activation stimulates release from keratinocytes of beta-endorphin, which acts at local neuronal mu-opioid receptors to inhibit nociception. Supporting this possibility, CB(2) immunolabeling was detected on beta-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of beta-endorphin, where CB(2) receptors are present, leading to anatomical specificity of opioid effects.
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PMID:CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. 1570 14

1. Cannabinoid receptor agonists elicit analgesic effects in acute and chronic pain states via spinal and supraspinal pathways. We investigated whether the combination of a cannabinoid agonist with other classes of antinociceptive drugs exerted supra-additive (synergistic) or additive effects in acute pain models in mice. 2. The interactions between the cannabinoid agonist CP55,940, alpha2-adrenoceptor agonist dexmedetomidine and mu-opioid receptor agonist morphine were evaluated by isobolographic analysis of antinociception in hot plate (55 degrees C) and tail flick assays in conscious male Swiss mice. Drug interactions were examined by administering fixed-ratio combinations of agonists (s.c.) in 1:1, 3:1 and 1:3 ratios of their respective ED50 fractions. 3. CP55,940, dexmedetomidine and morphine all caused dose-dependent antinociception. In the hot plate and tail flick assays, ED50 values (mg kg(-1)) were CP55,940 1.13 and 0.51, dexmedetomidine 0.066 and 0.023, and morphine 29.4 and 11.3, respectively. Synergistic interactions existed between CP55,940 and dexmedetomidine in the hot plate assay, and CP55,940 and morphine in both assays. Additive interactions were found for CP55,940 and dexmedetomidine in the tail flick assay, and dexmedetomidine and morphine in both assays. 4. Thus, an alpha2-adrenoceptor agonist or mu opioid receptor agonist when combined with a cannabinoid receptor agonist showed significant synergy in antinociception in the hot plate test. However, for the tail flick nociceptive response to heat, only cannabinoid and mu opioid receptor antinociceptive synergy was demonstrated. If these results translate to humans, then prudent selection of dose and receptor-specific agonists may allow an improved therapeutic separation from unwanted side effects.
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PMID:Synergistic and additive interactions of the cannabinoid agonist CP55,940 with mu opioid receptor and alpha2-adrenoceptor agonists in acute pain models in mice. 1577 4

The purpose of this study was to examine the functional interaction between endogenous opioid and cannabinoid receptor systems in the caudate putamen and nucleus accumbens. We therefore examined by autoradiography the functional activity and density of micro-, kappa- and delta-opioid receptors in both brain regions of cannabinoid CB1 receptor knockout mice. Functional activity was estimated by measuring agonist-stimulated [35S]GTPgammaS binding. Results showed that deletion of the CB1 cannabinoid receptor markedly increased kappa-opioid (50%) and delta-opioid (42%) receptor activities whereas no differences were found in micro-opioid receptor in the caudate putamen. In contrast, binding autoradiography showed a similar density of micro-, kappa- and delta-opioid receptors between mutant and wild-type mice. No differences were found in densities or activities of micro-, kappa- and delta-opioid receptors between mutant and wild-type mice in the nucleus accumbens. Taken together, our results revealed that deletion of CB1 cannabinoid receptors produced a pronounced increase in the activity of kappa- and delta-opioid receptors in the caudate putamen. This endogenous interaction between opioid and cannabinoid receptors may be relevant to further understand a variety of neuroadaptative processes involving the participation of opioid receptors, such as motor behaviour, emotional responses and drug dependence.
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PMID:Kappa- and delta-opioid receptor functional activities are increased in the caudate putamen of cannabinoid CB1 receptor knockout mice. 1626 48


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