The antiallodynic action target of intrathecal gabapentin: Ca2+ channels, KATP channels or N-methyl-d-aspartic acid receptors?
Gabapentin is a novel analgesic whose mechanism of action is not known. We investigated in a postoperative pain model whether adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channels, N-methyl-d-aspartic acid (NMDA) receptors, and Ca2+ channels are involved in the antiallodynic effect of intrathecal gabapentin. Mechanical allodynia was induced by a paw incision in isoflurane-anesthetized rats. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before and after incision and after intrathecal drug administration. The antiallodynic effect of gabapentin (100 mug) was not affected by intrathecal pretreatment with antagonists of K(ATP) channels, NMDA receptors or gamma-aminobutyric acid (GABA)(A) receptors. K(ATP) channel openers and GABA(A) receptor agonist, per se, had little effect on the postincision allodynic response. The Ca2+ channel blocker of N-type (omega-conotoxin GVIA, 0.1-3 microg), but not of P/Q-type (omega-agatoxin IVA), L-type (verapamil, diltiazem or nimodipine), or T-type (mibefradil), attenuated the incision-induced allodynia, as did gabapentin. Both the antiallodynic effects of gabapentin and omega-conotoxin GVIA were attenuated by Bay K 8644, an L-type Ca2+ channel activator. These results provide correlative evidence to support the contention that N-type Ca2+ channels, but not K(ATP) channels or NMDA or GABA(A) receptors, might be involved in the antiallodynic effect of intrathecal gabapentin.
Cheng
Jen-Kun
JK
Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan.
Chen
Chien-Chuan
CC
Yang
Jia-Rung
JR
Chiou
Lih-Chu
LC
D000255:Adenosine Triphosphate / Q000502:physiology*; D000588:Amines / Q000008:administration & dosage*; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D015220:Calcium Channels / Q000502:physiology*; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D000077206:Gabapentin; D007278:Injections, Spinal; D008297:Male; D010147:Pain Measurement / Q000379:methods*; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage*
D000588:Amines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D015221:Potassium Channels; D016194:Receptors, N-Methyl-D-Aspartate; C117780:mitochondrial K(ATP) channel; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000255:Adenosine Triphosphate