Melatonin enhances the anticonvulsant and proconvulsant effects of morphine in mice: role for nitric oxide signaling pathway.
Melatonin has different interactions with opioids including enhancing their analgesic effect and reversal of opioid tolerance and dependence. Opioids are known to exert dose-dependent anti- and proconvulsant effects in different experimental seizure paradigms. This study investigated the effect of melatonin on biphasic modulation of seizure susceptibility by morphine, in mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. We further investigated the involvement of the nitric oxidergic pathway in this interaction, using a nitric oxide synthase inhibitor, NG-nitro-L-arginine-methyl-ester (L-NAME). Melatonin exerted anticonvulsant effect with doses as high as 40-80 mg/kg, but with a dose far bellow that amount (10 mg/kg), it potentiated both the anticonvulsant and proconvulsant effects of morphine on the PTZ-induced clonic seizures. Possible pharmacokinetic interaction of melatonin and morphine cannot be ruled out in the enhancement of two opposing effects of morphine on seizure threshold. L-NAME (1 mg/kg) reversed the anticonvulsant property of the combination of melatonin (10 mg/kg) plus morphine (0.5 mg/kg). Moreover, L-NAME (5 mg/kg) blocked the enhancing effect of melatonin (10 mg/kg) on proconvulsant activity of morphine (60 mg/kg). Our results indicate that co-administration of melatonin enhances both anti- and proconvulsant effects of morphine via a mechanism that may involve the nitric oxidergic pathway.
Yahyavi-Firouz-Abadi
Noushin
N
Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran, P.O. Box 13145-784, Tehran, Iran.
Tahsili-Fahadan
Pouya
P
Riazi
Kiarash
K
Ghahremani
Mohammad Hossein
MH
Dehpour
Ahmad R
AR
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012640:Seizures / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000927:Anticonvulsants; D000975:Antioxidants; D003292:Convulsants; D009569:Nitric Oxide; D009020:Morphine; D019001:Nitric Oxide Synthase; D008550:Melatonin; D019331:NG-Nitroarginine Methyl Ester