title: The molecular mechanisms of cellular tolerance to delta-opioid agonists. A minireview.
abstract: Chronic treatment with deltaopioid agonists, similar to other agonist drugs, causes tolerance. Tolerance is a complex adaptation process that consists of multiple, cellular and neural-system adaptations. Cellular tolerance to delta-opioid agonists involves feedback-regulation of the function, concentration, and localization of the delta-opioid receptors (receptor desensitization) as well as of intracellular effectors (functional desensitization). We are using a recombinant Chinese hamster ovary cell line expressing the human delta-opioid receptors (hDOR/CHO) to investigate the molecular mechanisms of cellular tolerance. We found that the structurally distinct delta-opioid agonists mediate receptor down-regulation by different mechanisms. Thus, truncation of the last 35 C-terminal amino acids of the hDOR completely abolished DPDPE, but not SNC 80-mediated receptor down-regulation. In addition, down-regulation of the wild type-, and the truncated hDORs exhibited different inhibitor sensitivity-profile. Chronic delta-opioid agonist treatment also causes functional desensitization of forskolin-stimulated cAMP formation and cAMP overshoot in the hDOR/CHO cells. We have demonstrated that chronic SNC 80 treatment also causes concurrent phosphorylation of the adenylyl cyclase (AC) VI isoenzyme hDOR/CHO cells. Both AC superactivation and AC VI phosphorylation were SNC 80 dose-dependent, naltrindole-sensitive, and exhibited similar time course-, and protein kinase inhibitor-sensitivity profile. We hypothesize that phosphorylation of AC VI plays an important role in delta-opioid agonist-mediated AC superactivation in hDOR/CHO cells.
authors.affiliation: Department of Pharmacology, Sarver Heart Center, The University of Arizona, Tucson, Arizona, USA. evarga@email.arizona.edu
authors.forename: Eva V
authors.initials: EV
authors.lastname: Varga
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation; D004361:Drug Tolerance; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases