title: The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil.
abstract: The purpose of the present study was to explore the analgesic effects of the low voltage-activated T-type Ca2+ channel blockers ethosuximide, trimethadione, and mibefradil in persistent and acute nociceptive tests. The anticonvulsant effects of the compounds were also determined in the intravenous pentylenetetrazol seizure model. Following intraperitoneal administration, ethosuximide and trimethadione dose-dependently reversed capsaicin-induced mechanical hyperalgesia. Similarly, the highest dose of mibefradil tested (30 microg, intracisternal) reversed capsaicin-induced mechanical hyperalgesia. Ethosuximide and mibefradil produced statistically significant analgesic effects in both early and late phase formalin-induced behaviors and trimethadione reduced late phase behaviors. Additionally, ethosuximide and trimethadione produced antinociceptive effects in the rat-tail flick reflex test. In contrast, following intracisternal administration, mibefradil had no effect in the tail flick reflex test. In addition, the anticonvulsants ethosuximide and trimethadione increased the doses of pentylenetetrazol required to produce both first twitch and clonic seizures. In contrast however, mibefradil had no anticonvulsant effect. The present results demonstrate that the clinically used anticonvulsants ethosuximide and trimethadione provide analgesic effects at doses, which are anticonvulsant. Furthermore, the data further supports the idea that T-type Ca2+ channels may be important targets for treating persistent pain syndromes.
authors.affiliation: Neuroscience Research Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Barton
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Eberle
authors.forename: Harlan E
authors.initials: HE
authors.lastname: Shannon
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005013:Ethosuximide / Q000494:pharmacology; D006930:Hyperalgesia / Q000517:prevention & control*; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014293:Trimethadione / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D020748:Mibefradil; D005013:Ethosuximide; D014293:Trimethadione