Reversal of experimental neuropathic pain by T-type calcium channel blockers.
Experimental nerve injury results in exaggerated responses to tactile and thermal stimuli that resemble some aspects of human neuropathic pain. Neuronal hyperexcitability and neurotransmitter release have been suggested to promote such increased responses to sensory stimuli. Enhanced activity of Ca(2+) current is associated with increased neuronal activity and blockade of N- and P-types, but not L-type, calcium channels have been found to block experimental neuropathic pain. While T-type currents are believed to promote neuronal excitability and transmitter release, it is unclear whether these channels may also contribute to the neuropathic state. Rats were prepared with L(5)/L(6) spinal nerve ligation, and tactile and thermal hypersensitivities were established. Mibefradil or ethosuximide was administered either intraperitoneally, intrathecally (i.th.), or locally into the plantar aspect of the injured hindpaw. Systemic mibefradil or ethosuximide produced a dose-dependent blockade of both tactile and thermal hypersensitivities in nerve-injured rats; responses of sham-operated rats were unchanged. Local injection of mibefradil also blocked both end points. Ethosuximide, however, was inactive after local administration, perhaps reflecting its low potency when compared with mibefradil. Neither mibefradil nor ethosuximide given i.th. produced any blockade of neuropathic behaviors. The results presented here suggest that T-type calcium channels may play a role in the expression of the neuropathic state. The data support the view that selective T-type calcium channel blockers may have significant potential in the treatment of neuropathic pain states.
D000287:Administration, Topical; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005013:Ethosuximide / Q000008:administration & dosage*; D005528:Foot; D006358:Hot Temperature; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D020748:Mibefradil / Q000008:administration & dosage*; D009437:Neuralgia / Q000209:etiology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000293:injuries; D014110:Touch; D014949:Wounds, Nonpenetrating / Q000150:complications
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D020748:Mibefradil; D005013:Ethosuximide