Characterization of the effects of gabapentin and 3-isobutyl-gamma-aminobutyric acid on substance P-induced thermal hyperalgesia.
BACKGROUND
The authors sought to characterize the pharmacologic characteristic and site of action of gabapentin (Neurontin) in a model of thermal hyperalgesia induced by intrathecal substance P administration.


METHODS
Rats were prepared with long-term lumbar intrathecal catheters. Hind paw withdrawal latency was determined using a radiant heat stimulus focused through a glass surface onto the plantar surface of the paw.


RESULTS
Within 5 min after intrathecal injection of substance P (30 nmol), hind paw withdrawal latency fell from 11 to 8 s. Gabapentin given intrathecally or intraperitoneally produced dose-dependent reversal of the thermal hyperalgesia, with complete reversal (ED100) occurring at 163 microg for intrathecal and 185 mg/kg for intraperitoneal administration. S(+)-3-isobutyl-gamma aminobutyric acid, but not R(-)-3-isobutyl-gamma aminobutyric acid, also produced dose-dependent reversal of the intrathecal substance P-induced thermal hyperalgesia (intrathecal ED100, 65 microg and intraperitonal ED100, 31 mg/kg). The effects of intraperitoneally administered gabapentin and 3-isobutyl-gamma aminobutyric acid were reversed by intrathecal pretreatment with D-serine (100 microg) but not by L-serine. All effects were observed at doses that had little effect on motor function or spontaneous activity. Intrathecal N-methyl-D-aspartate (2 nmol) induced thermal hyperalgesia, which was blocked by gabapentin (100 mg/kg intraperitoneally) and S(+)-3-isobutyl-gamma aminobutyric acid (30 mg/kg intraperitoneally).


CONCLUSIONS
The structure-activity relationship and the stereospecificity noted after intrathecal delivery suggest that gabapentin and S(+)-3-isobutyl-gamma aminobutyric acid act at a common spinal locus to modulate selectively a facilitated state of nociceptive processing.
Partridge
B J
BJ
Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0818, USA.
Chaplan
S R
SR
Sakamoto
E
E
Yaksh
T L
TL
D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects; D012694:Serine / Q000494:pharmacology; D013237:Stereoisomerism; D013373:Substance P / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D013373:Substance P; D012694:Serine; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D000077206:Gabapentin