Influence of calcium channel blockers on anticonvulsant and antinociceptive activities of valproic acid in pentylenetetrazole-kindled mice

Abstract

BackgroudComorbidities of epilepsy comprise some pain disorders, including acute nociceptive pain, therefore, antiepileptic drugs can prove efficacy in the management of this kind of pain albeit with several adverse reactions. The current study aimed to evaluate the modulatory effects of calcium channel blockers on the anticonvulsant and antinociceptive effects of valproic acid (VPA) in pentylenetetrazole (PTZ)-kindled mice. MethodsKindled mice were treated with 20mg/kg (ip) of diltiazem, nifedipine, or verapamil, then VPA (200mg/kg, ip) at 30min intervals before PTZ administration (35mg/kg, ip). ResultsOur data demonstrated that the three calcium channel blockers afforded a protection against sub-convulsive doses of PTZ. Their protective effects were comparable to that exerted by the standard antiepileptic drug, VPA. The anticonvulsant activity of VPA was further enhanced by its combination with diltiazem. Also, PTZ-kindling reduced pain-threshold as evaluated by hot plate anal-gesimeter and acetic acid-induced writhing test. Although the repeated administration of VPA significantly increased pain-threshold in kindled mice, it was not able to normalize it. Similar results were obtained with diltiazem and nifedipine. Interestingly, combination of diltiazem or nifedipine with VPA elicited the most profound antinociceptive effect in kindled mice. ConclusionsThese results demonstrate for the first time the beneficial role of some calcium channel blockers in combination with VPA in the management of acute nociceptive pain. Therapeutically, this enhancing profile for calcium channel blockers fosters a safer and more effective drug-combination regimen than valproic acid alone.