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


METHODS
Kindled mice were treated with 20 mg/kg (ip) of diltiazem, nifedipine, or verapamil, then VPA(200 mg/kg, ip) at 30 min intervals before PTZ administration (35 mg/kg, ip).


RESULTS
Our 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 analgesimeter 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.


CONCLUSIONS
These 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.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt. melazab@georgiahealth.edu
Mona F
MF
El-Azab
Yasser M
YM
Moustafa
D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007274:Injections, Intraperitoneal; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D010146:Pain / Q000150:complications / Q000188:drug therapy*; D010147:Pain Measurement; D017288:Pain Threshold; D010433:Pentylenetetrazole / Q000494:pharmacology; D012640:Seizures / Q000150:complications / Q000188:drug therapy*; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use*
D000700:Analgesics; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D014635:Valproic Acid; D010433:Pentylenetetrazole