The effects of LY293558, an AMPA receptor antagonist, on acute and chronic morphine dependence

In rodents, noncompetitive and competitive NMDA receptor antagonists have been shown to attenuate and, in some cases, reverse tolerance to the analgesic effects of morphine. However, the ability of these same excitatory amino acid (EAA) receptor antagonists to modulate morphine dependence is controversial, and very little is known about the role of AMPA receptors in morphine dependence. LY293558, A novel, systemically active, competitive AMPA receptor antagonist and the NMDA receptor antagonists, MK-801 and/or LY235959, were evaluated in tolerant or dependent CD-1 mice. In mice rendered tolerant by morphine injection or pellet 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 tolerance. Neither LY293558 nor MK-801 produced analgesia or altered the ED₅₀ value of morphine. Continuous s.c. infusion of LY293558 (60 mg/kg per 24 h), MK-801 (1 mg/kg per 24 h) or LY235959 (12 mg/kg per 24 h) attenuated the development of acute (3 h) morphine dependence (i.e., decreased naloxone-precipitated withdrawal jumping). In contrast, continuous s.c. infusion of LY293558 (60 mg/kg per 24 h) or LY235959 (12 mg/kg per 24 h) did not significantly attenuate the development of chronic dependence produced by morphine pellet implantation. These data indicate that the development of morphine tolerance is more sensitive to modulating by EAA receptor antagonists than is the development of morphine dependence as assessed by naloxone-precipitated withdrawal jumping.