Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of morphine-like and nalorphine-like drugs were studied in the nondependent, morphine-dependent and cyclazocine-dependent chronic spinal dog. In the nondependent dog, three profiles of activity were found which could be utilized to distinguish between morphine, WIN 35, 197-2 and cyclazocine. Propiram, a prototypic partial agonist of the morphine type, produced morphine-like effects in nondependent dogs and both precipitated and suppressed abstinence in cyclazocine-dependent dogs as was needed to precipitate abstinence in morphine-dependent dogs. WIN 35, 197-2, a strong agonist in the guinea-pig ileum which has been shown to be resistant to antagonism by naloxone, neither precipitated nor suppressed morphine abstinence but suppressed cyclazocine abstinence. In the nondependent dog, it depressed the flexor reflex but not skin twitch reflex. Cyclazocine altered reflex activity much like WIN 35, 197-2 but produced tachycardia, tachypnea, mydriasis and canine delirum. The morphine and cyclazocine precipitated and withdrawal abstinence syndromes were qualitatively different. Twenty times as much naltrexone was needed to precipitate abstinence in morphine-dependent dogs. Nalorphine both precipitated and suppressed cyclazocine abstinence and appeared to be a partial agonist of the nalorphine-type. Morphine suppressed the cyclazocine abstinence syndrome. Cross-tolerance was not observed in ketocyclazocine-dependent dogs. These data are consistent with the hypothesis that there are strong and partial agonists of the mu and kappa types, and further, that physical dependence on morphine and cyclazocine is mediated through different receptors. WIN 35, 197-2 appears to be a pure strong agonist of the kappa type. Cyclazocine is a mu antagonist and mixed kappa and sigma agonist.
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PMID:The effects of morphine and nalorphine-like drugs in the nondependent, morphine-dependent and cyclazocine-dependent chronic spinal dog. 94 50

The cross-tolerance and convergent dependence between morphine and the cannabimimetic agent R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-+ ++benzoxazin-yl]-(1-naphthalenyl) methanone mesylate (WIN 55,212-2) were assessed in vitro on guinea-pig ileum. To induce tolerance and dependence the myenteric plexus-longitudinal muscle was incubated at 37 degrees C for 5 h with a fixed concentration representing the IC50 for each compound. Myenteric plexus-longitudinal muscle exposed to WIN 55,212-2 (5 x 10(-8) M) was less sensitive to its inhibitory effect on electrically evoked contractions than naive myenteric plexus-longitudinal muscle. The exposure to cannabinoid induced a parallel rightward shift in the lower part of the concentration-response curve of WIN 55,212-2 and a marked reduction in the maximal inhibitory effect of the drug. Myenteric plexus-longitudinal muscle tolerant to WIN 55,212-2 was subsensitive to the inhibitory effect of morphine on the twitch response. The cross-tolerance between WIN 55,212-2 and morphine was bidirectional. In fact, after 5 h the morphine (10(-7) M)-incubated myenteric plexus-longitudinal muscle was less sensitive to the inhibitory effect of WIN 55,212-2. The tissue tolerant to morphine or WIN 55,212-2 was tested for the presence of physical dependence. Naloxone (10(-5) M) produced a typical withdrawal contracture in morphine-tolerant myenteric plexus-longitudinal muscle which could be reduced by a 15-min pretreatment with WIN 55,212-2 (5 X 10(-8) M). In contrast, SR141716 (10(-6) M) [N-(piperidino)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyr azole-carboxamide], a concentration which fully antagonized the inhibitory effect of WIN 55,212-2 (10(-7) M) in control preparations, did not produce significant contracture in WIN 55,212-2-tolerant myenteric plexus-longitudinal muscle. The mechanisms underlying the cross-tolerance and convergent dependence remain to be ascertained.
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PMID:Cross-tolerance and convergent dependence between morphine and cannabimimetic agent WIN 55,212-2 in the guinea-pig ileum myenteric plexus. 1044 86

Physical dependence on the synthetic cannabinoid-receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN 55212-2) was demonstrated in rats by the use of a chronic continuous infusion. Spontaneous withdrawal, of moderate intensity, was shown for the first time with this class of drugs of abuse. Behavioral withdrawal signs were also elicited after challenge with (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide.HCl (SR141716A), a specific CB(1) cannabinoid-receptor antagonist. In both instances, the high-dose regimen (4, 8, 16 and 16 mg/kg/day, i.p. on days 1-4, respectively) was sufficient to evoke a typical withdrawal syndrome quantified by the signs wet-dog shakes and facial rubs. These results are discussed relative to those obtained with Delta(9)-tetrahydrocannabinol and anandamide. With Delta(9)-tetrahydrocannabinol, precipitated but not spontaneous or abrupt withdrawal was observed, and this was ascribed to pharmacokinetic properties. Anandamide, which showed little, if any, physical dependence potential, behaved atypically. Possible implications regarding pharmacotherapeutic and human abuse issues are discussed.
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PMID:Spontaneous and precipitated withdrawal with a synthetic cannabinoid, WIN 55212-2. 1128 15

Different animal models have been used to clarify the consequences of chronic exposure to cannabinoid agonists and their abuse liability. Following the chronic administration of cannabinoids, tolerance develops to most of their pharmacological effects. The development of cannabinoid tolerance is particularly rapid, and seems to be due to pharmacodynamic events. A cross-tolerance among different exogenous cannabinoid agonists has been reported. Somatic signs of spontaneous withdrawal have not been reported after chronic Delta(9)-tetrahydrocannabinol (THC) treatment, but were observed after chronic treatment with the cannabinoid agonist WIN-55,212-2. The administration of the CB(1) cannabinoid antagonist SR141716A in animals chronically treated with THC and other cannabinoid agonists precipitated somatic manifestations of withdrawal. The potential ability of anandamide to induce physical dependence has not been clarified. Subjective drug effects of cannabinoids have been reported by drug discrimination studies, which show cross discrimination among different natural and synthetic agonists. The rewarding effects of cannabinoids have been revealed by using several paradigms: place conditioning, intracranial self-stimulation, and self-administration. Cannabinoids have been reported to lower intracranial self-stimulation thresholds in rats. However, particular experimental conditions are required to induce conditioned place preference with cannabinoids. Numerous studies have shown that THC is unable to induce a self-administration behaviour in animals. However, WIN-55,212-2 was intravenously self-administered in mice, and monkeys that had a previous history of cocaine self-administration also self-administered THC. The mesolimbic dopaminergic system seems to be the substrate for the rewarding properties of cannabinoids.
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PMID:Study of cannabinoid dependence in animals. 1218 62

It has been suggested recently that the endocannabinoid system might be a component of the brain reward circuitry and thus play a role not only in cannabinoid tolerance/dependence, but also in dependence/withdrawal to other drugs of abuse. Here we have examined the changes in endocannabinoid ligands and their receptors in different brain regions, with particular attention to those areas related to reinforcement processes, during dependence on the powerful addictive drug, morphine. Thus, we analysed the brain contents of N-arachidonoylethanolamine (anandamide, AEA), the first discovered endocannabinoid, in rats subjected to daily injections of increasing doses of morphine, according to a schedule designed to render the animals opiate-dependent. Although evidence of physical dependence was assured by the appearance of somatic and neurovegetative responses in these animals after an acute challenge with naloxone, there were no changes in the contents of this endocannabinoid in any of the brain regions analysed. By contrast, we observed a significant decrease in the specific binding for CB(1) receptors in the midbrain and the cerebral cortex of morphine-dependent rats, with no changes in the other regions. The decrease in the cerebral cortex was, however, accompanied by a rise in the activation of signalling mechanisms by CB(1) receptor agonists, as revealed by WIN-55,212-2-stimulated [(35)S]GTPgammaS binding, whereas a reduction in this parameter was measured in the brainstem of morphine-dependent rats. In summary, the present data are indicative of the existence of an alteration of the endocannabinoid transmission during morphine dependence in rats, although the changes observed were region-dependent and affected exclusively CB(1) receptors with no changes in endocannabinoid levels. Because the changes occurred in regions of the midbrain, the cerebral cortex and the brainstem, which have been implicated in drug dependence, our data suggest that pharmacological manipulation of the endocannabinoid system might be a novel tool to reduce morphine addiction.
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PMID:Region-dependent changes in endocannabinoid transmission in the brain of morphine-dependent rats. 1285 Jul 74

We have evaluated several responses induced by the cannabinoid agonist WIN 55,212-2 related to its addictive properties, including rewarding effects and the development of physical dependence in mice. Moreover, we have studied the specific involvement of several brain regions with high density of CB1 cannabinoid receptors, such as striatum, hippocampus, amygdala and cerebellum, in the behavioural expression of SR 141716A-precipitated WIN 55,212-2 withdrawal. The systemic administration of the CB1 receptor antagonist SR 141716A (10 mg kg(-1), s.c.) precipitated behavioural signs of withdrawal in mice chronically treated with WIN 55,212-2 (1 and 2 mg kg(-1), intraperitoneal (i.p.)), revealing the development of physical dependence. The microinjection of SR 141716A (1.5 and 3 micrograms) into the cerebellum induced severe manifestations of abstinence in mice dependent on WIN 55,212-2 (1 mg kg(-1), i.p.). Out of 10 signs evaluated, seven were statistically significant: wet dog shakes, body tremor, paw tremor, piloerection, mastication, genital licks and sniffing. When the cannabinoid antagonist was administered into the hippocampus and the amygdala, a moderate but significant withdrawal syndrome was also observed. However, no signs of abstinence were induced when SR 141716A was microinjected into the striatum. WIN 55,212-2 produced rewarding effects in the place-conditioning paradigm in mice pre-exposed to a priming injection of the drug. These results show a reliable behavioural model to reveal rewarding effects and physical dependence induced by the repeated administration of WIN 55,212-2 in mice. The cerebellum and to a lesser extent the hippocampus and the amygdala participate in the behavioural expression of cannabinoid withdrawal.
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PMID:Role of different brain structures in the behavioural expression of WIN 55,212-2 withdrawal in mice. 1526 4

The mechanisms that facilitate the development and expression of cannabinoid physical dependence in humans and other mammals are poorly understood. The present experiments used a planarian model to provide evidence that pharmacological antagonism of NMDA receptors significantly attenuates the development of cannabinoid physical dependence. Abstinence-induced withdrawal from the cannabinoid agonist WIN 55212-2 (10 microM) was manifested as a significant (P<0.05) decrease in the rate of planarian spontaneous locomotor velocity (pLMV) when WIN 55212-2 (10 microM)-exposed planarians were placed into drug-free water. No change in pLMV occurred when WIN 55212-2 (10 microM)-exposed planarians were placed into water containing WIN 55212-2 (10 microM). WIN 55212-2 (10 microM)-exposed planarians placed into water containing LY 235959 (1 or 10 microM) did not display withdrawal (no significant difference, P>0.05, in pLMV). In addition, withdrawal was not observed (no significant difference, P>0.05, in pLMV) in planarians that were co-exposed to a solution containing WIN 55212-2 (10 microM) and LY 235959 (10 microM). The present results reveal that NMDA receptor activation mediates the development of cannabinoid physical dependence and the expression of cannabinoid withdrawal in planarians.
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PMID:An NMDA antagonist (LY 235959) attenuates abstinence-induced withdrawal of planarians following acute exposure to a cannabinoid agonist (WIN 55212-2). 1730 70

The broad applicability of receptor theory to diverse species, from invertebrates to mammals, provides evidence for the evolution in complexity of pharmacologic receptor diversification and of receptor-effector signal transduction mechanisms. However, pre-mammalian species have less receptor subtype differentiation, and thus, might share signal transduction pathways to a greater extent than do mammals, a phenomenon that we term 'pharmacologic congruence'. We have demonstrated previously that the lowest species considered to have a centralized nervous system, planarians, display both abstinence-induced and antagonist-precipitated withdrawal signs, indicative of the development of physical dependence. We report here: (1) amphetamine abstinence-induced withdrawal, and (2) the attenuation of cocaine and amphetamine, but not cannabinoid agonist (WIN 52212-2), abstinence-induced withdrawal by the opioid receptor antagonist naloxone and by the selective kappa-opioid receptor subtype antagonist nor-BNI (nor-Binaltorphimine), but not by the selective mu-opioid or the delta-opioid receptor subtype antagonists CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) and naltrindole. These results provide evidence that the withdrawal from cocaine and amphetamine, but not cannabinoids, in planarians is mediated through a common nor-BNI-sensitive (kappa-opioid receptor-like) pathway.
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PMID:The kappa-opioid receptor antagonist nor-BNI inhibits cocaine and amphetamine, but not cannabinoid (WIN 52212-2), abstinence-induced withdrawal in planarians: an instance of 'pharmacologic congruence'. 1817 75

Agmatine blocks morphine physical dependence in mammals, but its effects on withdrawal signs caused by other abused drugs have been less studied. One of the reasons is that withdrawal to some of these drugs is difficult to quantify in mammals. An alternative to mammals is planarians, a type of flatworm. Planarians possess mammalian-like neurotransmitters and display withdrawal from amphetamines, benzodiazepines, cannabinoids, cocaine, and opioids. The withdrawal is manifested as a reduction in locomotor behavior following discontinuation of drug exposure. In the present study, our goal was to identify agmatine in planarians and to determine if planarians exposed to agmatine display withdrawal to methamphetamine, a cannabinoid receptor agonist (WIN 55,212-2), or a kappa-opioid receptor agonist (U-50,488H). Neurochemical experiments revealed that the concentration of agmatine in planarians was 185 +/- 33.7 pmol per mg of planarian weight (dry weight). In behavioral experiments, withdrawal (i.e., reduced locomotor activity) was observed when planarians exposed to each drug (10 microM) for 60 min were placed into water. The withdrawal was attenuated when methamphetamine- or U-50,488H-exposed planarians were tested in agmatine (100 microM). Withdrawal was inhibited similarly when planarians coexposed to agmatine (100 microM) plus methamphetamine (10 microM), WIN 55,212-2 (10 microM), or U-50,488H (10 microM) were tested in water. Arginine, the metabolic precursor to agmatine, was ineffective. Our results identify endogenous agmatine in planarians and demonstrate that agmatine exposure blocks withdrawal to three different drugs in planarians. This suggests that a change in agmatine signaling is a common mechanism in the withdrawal caused by these drugs, at least in planarians.
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PMID:Agmatine: identification and inhibition of methamphetamine, kappa opioid, and cannabinoid withdrawal in planarians. 1879 93