In vivo regulation of μ‐opioid receptor density and gene expression in CXBK and outbred Swiss Webster mice

In vivo regulation of μ‐opioid receptor density and gene expression in CXBK and outbred Swiss... Chronic in vivo treatment with the opioid agonist etorphine downregulates μ‐opioid receptor density, produces tolerance, and regulates gene expression in the mouse. After cessation of treatment, there is an increase in μ‐opioid receptor mRNA level associated with the recovery of μ‐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 μ‐opioid receptor density, mRNA, and opioid analgesic potency were determined in two mouse strains that differ in basal μ‐opioid receptor density in brain. CXBK mice (μ‐opioid receptor deficient) and outbred Swiss Webster mice were implanted s.c. with placebo pellets (controls) or etorphine minipumps (250 μg/kg/day) for 1–7 days and μ‐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, μ‐receptor density was ≈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 (≈25–40%) μ‐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 μ‐opioid receptor downregulation and tolerance, can regulate μ‐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 μ‐opioid receptor density. Synapse 37:118–124, 2000. © 2000 Wiley‐Liss, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Synapse Wiley

In vivo regulation of μ‐opioid receptor density and gene expression in CXBK and outbred Swiss Webster mice

Synapse, Volume 37 (2) – Aug 1, 2000

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Publisher
Wiley
Copyright
Copyright © 2000 Wiley‐Liss, Inc.
ISSN
0887-4476
eISSN
1098-2396
D.O.I.
10.1002/1098-2396(200008)37:2<118::AID-SYN6>3.0.CO;2-2
Publisher site
See Article on Publisher Site

Abstract

Chronic in vivo treatment with the opioid agonist etorphine downregulates μ‐opioid receptor density, produces tolerance, and regulates gene expression in the mouse. After cessation of treatment, there is an increase in μ‐opioid receptor mRNA level associated with the recovery of μ‐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 μ‐opioid receptor density, mRNA, and opioid analgesic potency were determined in two mouse strains that differ in basal μ‐opioid receptor density in brain. CXBK mice (μ‐opioid receptor deficient) and outbred Swiss Webster mice were implanted s.c. with placebo pellets (controls) or etorphine minipumps (250 μg/kg/day) for 1–7 days and μ‐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, μ‐receptor density was ≈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 (≈25–40%) μ‐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 μ‐opioid receptor downregulation and tolerance, can regulate μ‐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 μ‐opioid receptor density. Synapse 37:118–124, 2000. © 2000 Wiley‐Liss, Inc.

Journal

SynapseWiley

Published: Aug 1, 2000

References

  • Methadone analgesia in morphine‐insensitive CXBK mice
    Chang, Chang; Emmel, Emmel; Rossi, Rossi; Pasternak, Pasternak
  • Assessment of delta opioid antinociception and receptor mRNA levels in mouse after chronic naltrexone treatment
    Jenab, Jenab; Kest, Kest; Inturrisi, Inturrisi
  • Differences in delta opioid receptor antinociception, binding, and mRNA levels between BALB/c and CXBK mice
    Kest, Kest; Beczkowska, Beczkowska; Franklin, Franklin; Lee, Lee; Mogil, Mogil; Inturrisi, Inturrisi
  • The role of receptor kinases and arrestins in G protein‐coupled receptor regulation
    Krupnic, Krupnic; Benovic, Benovic
  • G protein‐coupled receptor (GPCR) trafficking in the central nervous system: relevance for drugs of abuse
    Roth, Roth; Willins, Willins; Kroeze, Kroeze
  • Opioid receptor regulation in mice
    Yoburn, Yoburn; Billings, Billings; Duttaroy, Duttaroy
  • Supersensitivity to opioid analgesics following chronic opioid antagonist treatment: relationship to receptor selectivity
    Yoburn, Yoburn; Shah, Shah; Chan, Chan; Duttaroy, Duttaroy; Davis, Davis

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