Antiallodynic effect of intrathecal gabapentin and its interaction with clonidine in a rat model of postoperative pain.
BACKGROUND
Systemic administration of gabapentin was shown previously to attenuate mechanical allodynia in a rat model of postoperative pain. Because intrathecal administration of gabapentin is effective in other hypersensitivity states, the authors tested its effect in the postoperative model, its interaction with another antiallodynic agent (clonidine), and a possible mechanism of gabapentin action (entry into sites of action via an L-amino acid transporter).


METHODS
Male Sprague-Dawley rats were anesthetized with halothane, and an incision of the plantaris muscle of right hind paw induced punctate mechanical allodynia. Withdrawal threshold to von Frey filament application near the incision site was determined before and 2 h after surgery. Then, an intrathecal injection was performed and thresholds were determined every 30 min for 3 h thereafter.


RESULTS
Paw incision induced a mechanical hypersensitivity (mechanical threshold > 25 g before incision and < 5 g after). Intrathecal gabapentin dose-dependently (10-100 microg) reduced mechanical allodynia. Intrathecal injection of an inhibitor of L-amino acid transporters or a competitor for this transporter, L-leucine, did not reverse the intrathecal effect of gabapentin. The ED50 of intrathecal gabapentin, clonidine, and their combination were 51, 31, and 9 microg, respectively, and isobolographic analysis showed synergy between gabapentin and clonidine.


CONCLUSIONS
Intrathecal gabapentin is effective against tactile allodynia that occurs after paw incision, and interacts synergistically with clonidine. Unlike results in vitro, gabapentin does not obligatorily need to enter cells via the L-amino acid transporter mechanism to achieve its effects in vivo.
Cheng
J K
JK
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. jkcheng@usa.net
Pan
H L
HL
Eisenach
J C
JC
D000085:Acetates / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000588:Amines; D000596:Amino Acids / Q000494:pharmacology; D000598:Amino Acids, Cyclic; D000700:Analgesics / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D007278:Injections, Spinal; D007930:Leucine / Q000494:pharmacology; D008297:Male; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000316:Adrenergic alpha-Agonists; D000588:Amines; D000596:Amino Acids; D000598:Amino Acids, Cyclic; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D007930:Leucine; D003000:Clonidine