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 μg for intrathecal and 185 mg/kg for intraperitoneal administration. S(+)-3- isobutyl-γ-aminobutyric acid, but not R(-)-3-isobutyl-γaminobutyric acid, also produced dose-dependent reversal of the intrathecal substance P-induced thermal hyperalgesia (intrathecal ED100, 65 μg and intraperitonal ED100, 31 mg/kg). The effects of intraperitoneally administered gabapentin and 3-isobutyl-γaminobutyric acid were reversed by intrathecal pretreatment with D-serine (100 μg) 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- γaminobutyric acid (30 mg/kg intraperitoneally). Conclusions: The structure- activity relationship and the stereospecificity noted after intrathecal delivery suggest that gabapentin and S(+)-3-isobutyl-γaminobutyric acid act at a common spinal locus to modulate selectively a facilitated state of nociceptive processing.
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