The role of nitric oxide in anticonvulsant and proconvulsant effects of morphine in mice

Abstract Acute subcutanous administration of lower doses of morphine (0.5, 1 and 3 mg/kg) increase the threshold of seizures induced by pentylenetetrazole (PTZ) in mice, whereas higher doses of morphine (15, 30 and 60 mg/kg) have proconvulsant effects. The effect of systemic administration of nitric oxide synthase (NOS) inhibitors N G -nitro- l -arginine methyl ester ( l -NAME) and N G -nitro- l -arginine ( l -NNA) and nitric oxide synthase (NOS) l -arginine on biphasic effect of morphine was investigated. Acute administration of both l -NAME (1, 3 and 10 mg/kg) and l -NNA (1 and 10 mg/kg) as well as chronic pretreatment with l -NAME (1 and 10 mg/kg, 4 days) dose-dependently inhibited both the anticonvulsant and proconvulsant effects of morphine (1 and 30 mg/kg, respectively). The inhibition was complete for anticonvulsant effect while partial for proconvulsant effect. l -arginine at doses that did not affect seizure threshold per se (acute, 30 and 60 mg/kg; chronic, 60 mg/kg) potentiated both anticonvulsant and proconvulsant properties of less potent doses of morphine (0.5 and 15 mg/kg, respectively). The l -arginine induced potentiation of both phases of morphine effect was blocked by l -NAME (0.5–30 mg/kg). Moreover, low and per se non-effective doses of naloxone (0.1 mg/kg) and l -NAME (0.3, 0.5 or 1 mg/kg) showed additive effects in inhibiting both phases of morphine effects. These results support the involvement of l -arginine/nitric oxide pathway in the modulation of seizure threshold by morphine.