THE EFFECTS OF LY293558, AN AMPA RECEPTOR ANTAGONIST, ON ACUTE AND CHRONIC MORPHINE-DEPENDENCE

In rodents, noncompetitive and competitive NMDA receptor antagonists h ave been shown to attenuate and, in some cases, reverse tolerance to t he analgesic effects of morphine. However, the ability of these same e xcitatory amino acid (EAA) receptor antagonists to modulate morphine d ependence is controversial, and very little is known about the role of AMPA receptors in morphine dependence. LY293558, a novel, systemicall y active, competitive AMPA receptor antagonist and the NMDA receptor a ntagonists, MK-801 and/or LY235959, were evaluated in tolerant or depe ndent CD-1 mice. In mice rendered tolerant by morphine injection or pe llet implantation, continuous s.c. infusion of LY293558 (60 mg/kg per 24 h) or MK-801 (1 mg/kg per 24 h) attenuated the development of toler ance. Neither LY293558 nor MK-801 produced analgesia or altered the ED 50 value of morphine. Continuous s.c. infusion of LY293558 (60 mg/kg p er 24 h), MK-801 (1 mg/kg per 24 h) or LY235959 (12 mg/kg per 24 h) at tenuated the development of acute (3 h) morphine dependence (i.e., dec reased naloxone-precipitated withdrawal jumping). In contrast, continu ous s.c. infusion of LY293558 (60 mg/kg per 24 h) or LY235959 (12 mg/k g per 24 h) did not significantly attenuate the development of chronic dependence produced by morphine pellet implantation. These data indic ate that the development of morphine tolerance is more sensitive to mo dulation by EAA receptor antagonists than is the development of morphi ne dependence as assessed by naloxone-precipitated withdrawal jumping. (C) 1997 Elsevier Science B.V.