Systemic gabapentin and S(+)-3-isobutyl-gamma-aminobutyric acid block secondary hyperalgesia

Abstract

Gabapentin (GBP) and S(+)-3-isobutyl-gamma-aminobutyric acid (IBG) are anticonvulsant agents which are effective against many clinical and experimental neuropathic pain states. We examined the efficacy of these agents in a new rat model of secondary mechanical hyperalgesia generated by a mild thermal injury. Under brief halothane anesthesia, an injury was induced by applying one heel to a hot surface (52.5 degreesC) for 45 s. GBP, IBG or saline was injected i.p. just prior to the injury. Mean mechanical withdrawal threshold (MWT) was determined using von Frey hairs before and at 30 min intervals for 3 h following the injury. MWT outside the injury area decreased post-injury (secondary hyperalgesia, allodynia), but primary (site of injury) mechanical hyperalgesia was not observed. Secondary hyperalgesia exhibited a tendency toward recovery over time. Time to onset of the anti-allodynic effect of GBP was 30-60 min. The minimum effective GBP dose was 100 mg/kg; 300 mg/kg GBP totally inhibited the drop in MWT, but was accompanied by pronounced sedation. Anti-allodynic effects of IBG were apparent at the first post-injury measure of MWT (30 min). Thirty milligrams per kilogram was the minimum effective dose; 100 mg/kg IBG totally blocked the allodynia with minimal side effects. Our findings demonstrate a dose-dependent blockade of the mechanical sensitivity caused by a mild thermal injury by both GBP and IBG. Results indicate that IBG is more effective than GBP in this model at doses which do not cause sedation. These observations support the suggested use of these or related gamma-amino acid analogues as an effective treatment for post-operative pain.