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

Phosphorylation of the mu-opioid receptor may play a role in opioid tolerance and dependence. 3-Isobutyl-1-methylxanthine (IBMX) was found to inhibit basal mu-opioid receptor phosphorylation (IC50 less than or equal to 10 mu M) either upon acute treatment or after 8 h pre-treatment in HEK293 cells transfected with the mu-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 mu-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 greater than or equal to 12 h. These results suggest a new effect of IBMX in inhibiting basal mu-opioid receptor phosphorylation, and provide additional evidence for the involvement of receptor phosphorylation in the development of opioid tolerance and dependence. (C) 1999 Elsevier Science B.V. All rights reserved.