The effect of intrathecal gabapentin and 3-isobutyl gamma-aminobutyric acid on the hyperalgesia observed after thermal injury in the rat

Abstract

Gabapentin is an anticonvulsant that may represent a novel class of drugs, which has novel spinal antihyperalgesic activity. We sought to characterize this spinal action in a model of hyperalgesia that involves a mild thermal injury to the hind paw of the rat. Rats were prepared with chronic spinal catheters. Under brief halothane anesthesia, a thermal injury was induced by applying the left hind paw to a thermal surface (52.5 degrees C) for 45 s. This exposure results in mild erythema but no blistering. Thermal escape latency of the hind paw was determined using an underglass thermal stimulus with which response latencies of the injured and uninjured (normal) paw could be obtained. Thirty minutes after thermal injury, the response latency in all groups decreased from 10-12 s to 5-7 s. Uninjured paw withdrawal latency was unaltered. The intrathecal injection of gabapentin (30-300 microg) produced a dose-dependent reversal of the hyperalgesia but had no effect on the response latency of the normal hind paw, even at the largest doses. A similar reversal was observed after intrathecal delivery of the structural analog S(+)-3-isobutyl gamma-aminobutyric acid (GABA) (30-300 microg), but not after the largest dose of its stereoisomer R(-)-3-isobutyl GABA (300 microg). The effects of both intrathecal gabapentin and S(+)-3-isobutyl GABA were reversed by intrathecal D-serine, but not L-serine. All effects were observed at doses that had no significant effect on motor function. These observations, in conjunction with the accumulating data on binding and transmitter release, emphasize that these gabapentinoids can selectively modulate the facilitation of spinal nociceptive processing otherwise generated by persistent small afferent input generated by tissue injury.

Implications: Gabapentin and its analog, 3-isobutyl gamma-aminobutyric acid, given spinally, produce a dose-dependent, D-serine-sensitive reversal of the thermal hyperalgesia evoked by mild thermal injury.