Effect of nitric oxide synthase inhibition on tolerance to the analgesic action of D-Pen 2, D-Pen 5 enkephalin and morphine in the mouse

Abstract

The effects of N G-nitro-L-arginine (NNA), an inhibitor of nitric oxide synthase (NOS) on the development of tolerance to the analgesic action of D-Pen 2, D-Pen 5 enkephalin (DPDPE), a δ 1 opioid receptor agonist, and morphine were determined in the mouse. Tolerance to DPDPE was induced in male Swiss-Webster mice by twice daily intracerebroventricular (i.c.v.) injections of the drug (20 μg/mouse) for 4 days. NNA was injected intraperitoneally (i.p.) 10 min before each injection of DPDPE. Chronic injections of DPDPE resulted in development of tolerance to its analgesic action. Multiple injections of NNA by itself did not modify the analgesic response to DPDPE. Concurrent injections of NNA did not affect the development of tolerance to the analgesic action of DPDPE. Twice daily injections of morphine (15 mg/kg s.c.) for 4 days resulted in the tolerance to its analgesic action. Concurrent administration of NNA with morphine attenuated the development of tolerance to morphine. It is concluded that NOS inhibition attenuates morphine, but not δ 1 opioid agonist-induced tolerance in the mouse.