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)

Recent studies have led to a greater understanding of the behavioral, cellular, and molecular mechanisms underlying opiate tolerance and physical dependence. Behavioral studies have demonstrated that both direct pharmacological effects and the learning of interactions between drug effects and environmental cues are important in these phenomena. Behavioral studies have also revealed that N-methyl-D-aspartate receptors may play a role in their development (or acquisition). Although in early cellular studies no consistent role was found for opioid receptors or endogenous opioid peptides in opiate tolerance and dependence, recent experiments suggest that beta-endorphin, enkephalin, and dynorphin neurons may indeed have a role. Finally, studies at the molecular level suggest that a functional decoupling of opioid receptors from GTP-binding proteins (G proteins) may be important. In this review, we discuss these disparate findings and present a synthesis that shows how they might together contribute to the phenomena of opiate tolerance and physical dependence.
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PMID:Opiate tolerance and dependence: recent findings and synthesis. 166 85

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.
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PMID:Effect of pretreatment with pertussis toxin on the development of physical dependence on morphine. 837 45

The nucleus locus coeruleus is involved in the expression of opiate physical dependence and withdrawal, and has been characterized extensively with regard to chronic morphine-induced alterations in biochemical and electrophysiological responses. In the present study the effects of chronic morphine treatment on opioid receptor-coupled G-protein activity was investigated in membranes from rat locus coeruleus. Opioid agonists stimulated low Km GTPase activity with pharmacology consistent with mu receptors. Chronic morphine treatment resulted in decreases in both basal and opioid-stimulated low Km GTPase activity, with no change in the percent stimulation by agonist. The decrease in low Km GTPase activity appeared to be due to a decrease in the Vmax of the enzyme, with no change in the Km for GTP hydrolysis. These results were confirmed by assays of basal and opioid receptor-stimulated [35S]GTP gamma S binding in the presence of excess GDP. Thus, chronic morphine treatment apparently decreased inhibitory G-protein activity in the locus coeruleus without producing any detectable desensitization. These results suggest a potential adaptation at the receptor/transducer level which may contribute to other biochemical changes produced in the locus coeruleus by chronic morphine treatment.
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PMID:Opioid receptor-coupled G-proteins in rat locus coeruleus membranes: decrease in activity after chronic morphine treatment. 903 78