The mechanisms of antihyperalgesic effect of topiramate in a rat model of inflammatory hyperalgesia

Recent studies have shown that topiramate, a structurally novel anticonvulsant, exerts antinociceptive activity in animal models of neuropathic, acute somatic, and visceral pain. This study was aimed to examine: (i) the effects of systemically and locally peripherally administered topiramate in the rat inflammatory pain model and (ii) the potential role and site(s) of gamma-aminobutyric acid (GABA), opioid, and adrenergic receptors in topiramate's antihyperalgesia. Rats received intraplantar (i.pl.) injections of the pro-inflammatory compound carrageenan. A paw pressure test was used to determine: (i) the effect of systemic and local peripheral topiramate on carrageenan-induced hyperalgesia and (ii) the effects of systemic and local peripheral bicuculline (selective GABAA receptor antagonist), naloxone (nonselective opioid receptor antagonist), and yohimbine (selective α2-adrenergic receptor antagonist) on topiramate-induced antihyperalgesia. Systemic topiramate (40-160 mg/kg; p.o.) produced a significant dose-dependent reduction in the paw inflammatory hyperalgesia induced by carrageenan. The antihyperalgesic effect of systemic topiramate was significantly decreased by systemic bicuculline (0.5-1 mg/kg; i.p.), naloxone (2-5 mg/kg; i.p.), and yohimbine (1-3 mg/kg; i.p.). Local peripheral topiramate (0.03-0.34 mg/paw; i.pl.) also produced significant dose-dependent antihyperalgesia, which was significantly depressed by local peripheral yohimbine (0.05-0.2 mg/paw; i.pl.) but not by local peripheral bicuculline (0.15 mg/paw; i.pl.) or naloxone (0.1 mg/paw; i.pl.). The results suggest that topiramate produces systemic and local peripheral antihyperalgesia in an inflammatory pain model, which is, at least partially, mediated by central GABAA and opioid receptors and by peripheral and most probably central α2-adrenergic receptors. These findings contribute to better understanding of topiramate's action in pain states involving inflammation.