Involvement of the nitric oxide pathway in the anticonvulsant effect of tramadol on pentylenetetrazole-induced seizures in mice

In the present study, the effects of tramadol on pentylenetetrazole (PTZ)-induced seizures and involvement of nitric oxide (NO) were assessed in mice. To determine the threshold for clonic seizures, PTZ was administered intravenously. Tramadol was administered intraperitoneally (0.5–50 mg/kg) 30 minutes prior to induction of seizures. The effects of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 0.5, 1, 5, and 10 mg/kg), the nitric oxide precursor L-arginine (10, 30, and 60 mg/kg), and the nonspecific opioid receptor antagonist naloxone (0.1, 0.5, 1, and 5 mg/kg) on the anticonvulsant effect of tramadol were investigated. Administration of tramadol (1 mg/kg) increased the threshold for seizures induced with PTZ in a monophasic, dose-independent, and time-dependent manner. Acute administration of L-NAME (5 and 10 mg/kg) inhibited the anticonvulsant effect of tramadol (1 mg/kg), whereas L-arginine, in the noneffective dose range (30 and 60 mg/kg), potentiated the seizure threshold when co-administered with a subeffective dose of tramadol (0.5 mg/kg). Naloxone partially and dose-independently antagonized the anticonvulsant effect of tramadol (1 mg/kg). These results indicate that the anticonvulsant effect of tramadol is mediated by the nitric oxide pathway and also by classic opioid receptors.

Research Highlights
► Tramadol has a monophasic anticonvulsant effect on pentylenetetrazole-induced clonic seizure in a dose-independent and time-dependent manner.
► This anticonvulsant effect is completely reversed by a non-specific NOS inhibitor (L-NAME).
► A NO precursor (L-arginine) potentiates the anticonvulsive effect of tramadol.
► A non-specific opioid receptor antagonist (naloxone) reduced tramadol-induced enhancing effect on seizure threshold in a dose-independent manner.