Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats.
1. Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage- and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. 2. We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na+ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 microg per 100 microl, respectively. 3. Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. 4. Hill slope coefficients for the tested anticonvulsants indicate that the dose-response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. 5. Our data strongly suggest that cellular targets like voltage-gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na+ and Ca2+ channels may be useful analgesics.
Todorovic
Slobodan M
SM
Department of Anesthesiology, University of Virginia Health System, Mail Box 800710, Charlottesville, VA 22908, U.S.A.
Rastogi
A J
AJ
Jevtovic-Todorovic
Vesna
V
D000085:Acetates / Q000494:pharmacology; D000588:Amines; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002220:Carbamazepine / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D005013:Ethosuximide / Q000494:pharmacology; D005260:Female; D000077206:Gabapentin; D006614:Hindlimb / Q000187:drug effects / Q000294:innervation; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement / Q000379:methods; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology / Q000517:prevention & control; D010672:Phenytoin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000700:Analgesics; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D003509:Cyclohexanecarboxylic Acids; D026941:Sodium Channel Blockers; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D005013:Ethosuximide; D010672:Phenytoin; D000077206:Gabapentin