Abstracts

Rationale: Sumatriptan is an agonist of 5 hydroxytryptamine (5-HT) 1B/1D receptors, which are presented on serotonergic terminals and regulates serotonin (5-HT) release. Some studies reported that the extracellular level of serotonin modulates seizure activities. Opioids have been used by humans for pleasure and for treating several conditions especially pain for almost 6 millennia. One important and less known field of investigation is the modulatory effects of opioids on seizure susceptibility. Previous reports have indicated the heterogeneity of regulation by opioids of convulsive phenomena. It has been indicated that Sumatriptan and Morphine both have biphasic effects on the seizure threshold. Anti-convulsant impact in lower doses and pro-convulsant effect in higher doses on seizure induced by pentylenetetrazole. Nitric oxide (NO) is a neurotransmitter or neuronal messenger in the central and peripheral nervous system, which is synthesized by NO synthase (NOSs) from amino acid L-arginine. It has been postulated that NO modulates the susceptibility to seizure either anticonvulsant or proconvulsant effects. In the present study, we aimed to shed light on the effects of the co-treatment of sumatriptan and morphine on the seizure threshold and delineate the presumable role of NO pathway.

Methods: Clonic seizures were induced in male NMRI mice by intravenous administration of pentylenetetrazol (PTZ).

Results: The maximum anti-convulsive effect of sumatriptan was exhibited at the dose of (0.5 mg/kg, i.p), whereas sumatriptan at the dose of (20 mg/kg, i.p) demonstrated a pro-convulsive effect on seizure threshold. Morphine at the dose of (0.5 and 1 mg/kg, i.p) increased seizure thresholds. The maximum pro-convulsive effect of morphine was detected at the dose of (20 mg/kg, i.p). Co-administration of sub-effective dose of morphine (0.1 mg/kg) and sub-effective dose of sumatriptan (0.1 mg/kg) significantly increased the seizure thresholds. Treatment with L-arginine [NO precursor] and combined treatment with sumatriptan (0.1 mg/kg) + morphine (0.1 mg/kg) remarkably increased seizure threshold. On the other hand, combined treatment with [NOS inhibitors] L-NAME with sumatriptan (0.1 mg/kg) + morphine (0.1 mg/kg) remarkably enhanced the PTZ-induced seizure threshold. The administration of aminoguanidine [an inducible NOS inhibitor] along with combination of sumatriptan (0.1 mg/kg) and morphine (0.1 mg/kg) markedly increased seizure threshold compared with sumatriptan (0.1 mg/kg, i.p) and morphine (0.1 mg/kg, i.p) groups. The administration of 7-nitroindazole [NOS inhibitor] with co-treatment of sumatriptan (0.1 mg/kg) and morphine (0.1 mg/kg) significantly reduced seizure activity induced by PTZ in comparison with morphine (0.1 mg/kg) group; nevertheless, failed to detect any differences in PTZ-induced seizure thresholds in contrast to sumatriptan-treated group.

Conclusions: In conclusion, our findings demonstrated that the nitric oxide pathway can be involved in the anticonvulsant properties of morphine and sumatriptan combination therapy on the clonic seizures induced by PTZ in mice.

Funding: No funding was received.