Effects of NMDA receptor blockade and nitric oxide synthase inhibition on the acute and chronic actions of delta 9-tetrahydrocannabinol in mice.

The present studies examined the hypothesis that the N-methyl-D-aspartate (NMDA) receptor-nitric oxide (NO) pathway might be involved in the acute and chronic actions of delta 9-tetrahydrocannabinol (THC). The ability of dizocilpine (MK-801), a competitive NMDA receptor antagonist and NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase enzyme to modify the analgesic and hypothermic responses following the acute and chronic treatment of animals with THC was determined in male Swiss-Webster mice. Intraperitoneal administration of THC (5, 10 and 20 mg/kg) produced dose-dependent analgesic and hypothermic effects. MK-801 at 0.1 mg/kg i.p. attenuated the analgesic but not the hypothermic responses to THC (10 and 20 mg/kg, i.p.). The effects of various doses of MK-801 (0.03, 0.1 and 0.3 mg/kg, i.p.) on the analgesic and hypothermic responses to a 10 mg/kg, i.p. dose of THC was also determined. All the doses of MK-801 antagonized the analgesic but not the hypothermic effects of THC. The chronic treatment of animals with THC (10 mg/kg, i.p.) twice daily for 4 days produced tolerance to its analgesic and hypothermic effects. Pretreatment of animals with MK-801 (0.03-0.30 mg/kg, i.p.) did not affect the development of tolerance to the analgesic or the hypothermic action of THC. The pretreatment of animals with L-NMMA (2-8 mg/kg, i.p.), did not alter the analgesic or hypothermic effects of THC. Also, it did not modify the tolerance to its pharmacological actions.(ABSTRACT TRUNCATED AT 250 WORDS)