THE COMPETITIVE PHA-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONATE RECEPTOR ANTAGONIST LY293558 ATTENUATES AND REVERSES ANALGESIC TOLERANCETO MORPHINE BUT NOT TO DELTA-OPIOID OR KAPPA-OPIOID

Antagonists of the NMDA type of excitatory amino acid (EAA) receptor a ttenuate or reverse the development of tolerance to the analgesic effe cts of the mu opioid agonist morphine, the delta-1 opioid agonist DPDP E but not the kappa-1 agonist U50,488H or the kappa-3 agonist naloxone benzoylhydrazone. The role of the AMPA subtype of EAA receptor in ana lgesic tolerance was examined using LY293558, a selective competitive antagonist that is active after systemic administration. Administratio n of morphine, DPDPE, or U50,488H three times daily for 3 days accordi ng to an escalating dosing schedule resulted in analgesic tolerance as indicated by an increase in analgesic ED50 values using the tail-flic k test in mice. Analgesic tolerance was attenuated when mice received a continuous subcutaneous infusion of LY293558 at doses of 30, 45 or 6 0 mg/kg/24 hr via an osmotic pump concurrent with the morphine treatme nt. Continuous subcutaneous infusion of LY293558 (45 mg/kg/24 hr) also reversed established morphine tolerance. In contrast, continuous subc utaneous infusion of the highest dose of LY293558 (60 mg/kg/24 hr) was ineffective in preventing the development of analgesic tolerance to D PDPE or U50,488H. Continuous subcutaneous infusion of LY293558 (60 mg/ kg/24 hr) for 3 days protected mice from generalized convulsions produ ced by the selective AMPA agonist ATPA, indicating that the dosage of LY293558 that attenuated morphine tolerance was effective as an antago nist at AMPA receptors. These results demonstrate that AMPA receptors may play a role in the development and maintenance of morphine, but no t DPDPE or U50,488H, analgesic tolerance.