The role of nitric oxide in anticonvulsant and proconvulsant effects of morphine in mice.
Acute subcutaneous 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.
Homayoun
Houman
H
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran.
Khavandgar
Simin
S
Namiranian
Khodadad
K
Gaskari
Seyed Ali
SA
Dehpour
Ahmad Reza
AR
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D003292:Convulsants / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009270:Naloxone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*
D000701:Analgesics, Opioid; D000927:Anticonvulsants; D003292:Convulsants; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D009569:Nitric Oxide; D009270:Naloxone; D009020:Morphine; D019331:NG-Nitroarginine Methyl Ester