3-Isobutyl-1-methylxanthine inhibits basal μ-opioid receptor phosphorylation and reverses acute morphine tolerance and dependence in mice

Zaijie Wang, Edward J. Bilsky, Danxin Wang, Frank Porreca, Wolfgang Sadée

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Phosphorylation of the μ-opioid receptor may play a role in opioid tolerance and dependence. 3-Isobutyl-1-methylxanthine (IBMX) was found to inhibit basal μ-opioid receptor phosphorylation (IC50≤10 μM) either upon acute treatment or after 8 h pre-treatment in HEK293 cells transfected with the μ-opioid receptor. In mice made acutely tolerant to and dependent on morphine, IBMX (30-100 nmol, i.c.v.) significantly attenuated the naloxone-induced withdrawal jumping and partially reversed morphine antinociceptive tolerance. IBMX also blocked changes to μ-opioid receptor signaling associated with chronic morphine treatment, specifically, the inverse agonist effect elicited by naloxone, in which naloxone paradoxically elevated the cAMP levels in cells previously exposed to morphine for ≥12 h. These results suggest a new effect of IBMX in inhibiting basal μ-opioid receptor phosphorylation, and provide additional evidence for the involvement of receptor phosphorylation in the development of opioid tolerance and dependence. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalEuropean Journal of Pharmacology
Volume371
Issue number1
DOIs
StatePublished - Apr 23 1999

Keywords

  • Dependence
  • Inverse agonist
  • Opioid receptor
  • Phosphorylation
  • Tolerance

ASJC Scopus subject areas

  • Pharmacology

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