In vivo regulation of mu-opioid receptor density and gene expression in CXBK and outbred Swiss Webster mice.
Chronic in vivo treatment with the opioid agonist etorphine downregulates mu-opioid receptor density, produces tolerance, and regulates gene expression in the mouse. After cessation of treatment, there is an increase in mu-opioid receptor mRNA level associated with the recovery of mu-opioid receptors. However, the effect of etorphine on the regulation of mRNA during treatment is currently not known. In this study, etorphine-induced changes in mu-opioid receptor density, mRNA, and opioid analgesic potency were determined in two mouse strains that differ in basal mu-opioid receptor density in brain. CXBK mice (mu-opioid receptor deficient) and outbred Swiss Webster mice were implanted s.c. with placebo pellets (controls) or etorphine minipumps (250 microg/kg/day) for 1-7 days and mu-opioid receptor density or mRNA levels in whole brain were assessed or mice were tested for etorphine analgesia following 7 days of treatment. In control CXBK mice, mu-receptor density was approximately 40% less than that for the Swiss Webster, although mRNA abundance was similar in both strains. Etorphine's potency was 4-fold greater in control Swiss Webster compared to CXBK mice. Etorphine treatment decreased ( approximately 25-40%) mu-receptor density similarly in both strains throughout treatment. The magnitude of analgesic tolerance to etorphine was 8-fold in both mouse strains. Etorphine produced a biphasic effect on receptor mRNA in both strains with levels decreased (25%) by 3 days and increased (30-40%) at 7 days. mRNA levels remained elevated (55%) 16 h following the end of the 7 day etorphine treatment. Taken together, these data suggest that in vivo etorphine treatment that produces mu-opioid receptor downregulation and tolerance, can regulate mu-opioid receptor mRNA abundance. Receptor downregulation may initially induce decreases in mRNA levels since downregulation preceded a decrease in gene expression. Prolonged (>3 days) receptor downregulation may be responsible for increasing message levels and may be important in recovery of receptors following treatment. In addition, the magnitude of changes in receptor density, mRNA, and tolerance were similar in both CXBK and Swiss Webster mice, indicating that the mechanisms required for receptor regulation and its functional consequences are independent of basal mu-opioid receptor density.
Duttaroy
A
A
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, New York, USA.
Yoburn
B C
BC
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005048:Etorphine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D051379:Mice / Q000378:metabolism*; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D013045:Species Specificity; D013997:Time Factors
D000701:Analgesics, Opioid; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D005048:Etorphine