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

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 (IC 50 ≤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.