title: Opiate tolerance and dependence: recent findings and synthesis.
abstract: 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.
authors.affiliation: Mental Health Research Institute, University of Michigan, Ann Arbor 48109-0720.
authors.forename: K A
authors.initials: KA
authors.lastname: Trujillo
authors.forename: H
authors.initials: H
authors.lastname: Akil
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004361:Drug Tolerance; D004723:Endorphins / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008297:Male; D008954:Models, Biological; D009294:Narcotics / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009473:Neuronal Plasticity; D009293:Opioid-Related Disorders / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D011957:Receptors, Opioid / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism
chemical_list: D004723:Endorphins; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D011333:Pro-Opiomelanocortin; D016291:Dizocilpine Maleate; D019204:GTP-Binding Proteins; D002118:Calcium