NMDA-NO IN THE HYPOXIC EFFECT OF MORPHINE Indian Journal of Pharmacology 2000; 32: 126-128 SHORT COMMUNICATION Correspondence: Ahmet Ulugol e-mail: farmakoloji@trakya.cdu.tr, ulugol@hotmail.com SUMMARY KEY WORDS INVOLVEMENT OF NMDA-NITRIC OXIDE PATHWAY IN THE FACILITATORY EFFECT OF MORPHINE IN HYPOXIA-INDUCED LETHALITY IN MICE I. DOKMECI, A. ULUGOL, A. TUNCER, T. DOST, D. DOKMECI, H. KARADAG Department of Pharmacology, Faculty of Medicine, Trakya University, 22030-Edirne, Turkey Objective: The contribution of N-methyl-D-aspartate (NMDA) receptors and nitric oxide (NO) to the effect of morphine on hypoxia-induced lethality was investigated in the present experiments. Methods: Mice were subjected to hypoxia by putting them in a tightly closed glass container. The latencies for death were recorded. Results: MK-801 (0.25 mg/kg, i.p.) and N G -nitro-L-arginine-methyl ester (L-NAME, 10 mg/kg, i.p.), at doses which themselves produced no effect on hypoxia-induced lethality, attenuated the hypoxic effect of morphine (10 mg/kg, i.p.) significantly, but not completely. Concomitant administrations of NMDA (10 mg/ kg) or L-arginine (500 mg/kg, i.p.), completely reversed the protective effects of MK-801 and L-NAME, indicating the possible involvement of NO-linked NMDA receptors in the hypoxic effect of morphine. Conclusion: Hypoxia induced lethality may be, at least partly, mediated through the NMDA-NO pathway. NMDA nitric oxide morphine hypoxic convulsions INTRODUCTION Recent evidence suggests the involvement of NO in NMDA receptor-mediated glutamate toxicity 1 . The role of NMDA receptors and NO in hypoxic convul- sions are also known 2 . Moreover, NMDA receptors and NO may be implicated in the actions of morphine, such as tolerance, analgesia, and abstinence syn- drome 3-8 . Thus, the present study was designed to investigate, whether NMDA receptors and NO are involved in the mechanisms that mediate the effect of morphine on hypoxia-induced lethality. MATERIALS AND METHODS Animals: Wistar mice of either sex (20-25 g, obtained from Eczacibasi-Turkey) maintained on a 12-h light and dark cycle were used. Animals were housed at constant room temperature (22 +1 o C), and received food and water ad libitum except during the experi- ments. The experiment was approved by Animal care Ethics Committee. Experimental Procedure: Animals were subjected to hypoxia by putting them individually in a tightly closed 300-ml glass container. The animals had con- vulsions and died from hypoxia. The latencies for death were recorded 9,10 . The animals died approxi- mately 2 min after they had convulsions, and great care was taken to determine the exact time of death. Mice were weighed and received either single i.p. injection of morphine (0.1, 1, 10, 100 mg/kg), the excitatory amino acid, NMDA (2.5, 5, 10, 20 mg/kg), the NO synthesis precursor, L-arginine (100, 500, 1000 mg/kg), the competitive NMDA antagonist, MK- 801 (0.1, 0.25, 0.5, 1 mg/kg), or the nitric oxide syn- thase (NOS) inhibitor, L-NAME (1, 3, 10, 30, 100 mg/ kg) 15 min before they were subjected to hypoxia. To investigate whether pretreatments with the agonists and the antagonists alter the effect of morphine, NMDA (10 mg/kg), L-arginine (500 mg/kg), MK-801 (0.25 mg/kg) and L-NAME (10 mg/kg), at doses which themselves produced no effect on hypoxia-induced lethality, were given 5 min prior the administration of morphine (10 mg/kg). Concomitant administrations of NMDA (10 mg/kg) or L-arginine (500 mg/kg) with MK-801 (0.25 mg/kg) and L-NAME (10 mg/kg) was also given 5 min prior the administration of morphine to observe the relationship between NO and NMDA receptors. Drugs: NMDA and L-NAME was obtained from Sigma Chemical Co., while L-arginine and MK-801 were purchased from Research Biochemicals Inc. Morphine hydrochloride (Morphine, Haver, Istanbul)