doi: 10.1111/j.1472-8206.2011.01018.x ORIGINAL ARTICLE The mechanisms of antihyperalgesic effect of topiramate in a rat model of inflammatory hyperalgesia Sonja Lj. Paranos, Maja A. Tomic ´, Ana M. Micov, Radica M. Stepanovic ´-Petrovic ´ * Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, PO Box 146, 11221 Belgrade, Serbia INTRODUCTION In recent years, topiramate, a structurally novel anti- convulsant, has been reported to be useful in migraine prophylaxis and in the treatment of neuropathic pain in humans [1,2]. In animals, topiramate produces antino- ciceptive/antihyperalgesic effects in models of neuro- pathic [3–5], acute somatic [6], and visceral pain [7]. Despite the substantial evidence that several other anticonvulsants exert antihyperalgesia in animal inflam- matory pain models [8–11], the effect of topiramate against hyperalgesia in inflammation has not been explored. The mechanisms by which topiramate produces anal- gesia are poorly understood. Using the formalin test in mice, Lopes et al. [6] demonstrated that endogenous Keywords a 2 -adrenoceptors, GABA A receptors, inflammatory hyperalgesia, opioid receptors, topiramate Received 25 February 2011; revised 14 October 2011; accepted 8 November 2011 *Correspondence and reprints: racabbr@eunet.rs ABSTRACT 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 GABA A receptor antagonist), naloxone (nonselective opioid receptor antagonist), and yohimbine (selective a 2 -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 hyperal- gesia 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 GABA A and opioid receptors and by peripheral and most probably central a 2 -adrenergic receptors. These findings contribute to better understanding of topiramate’s action in pain states involving inflammation. ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Socie ´ te ´ Franc ¸aise de Pharmacologie et de The ´ rapeutique Fundamental & Clinical Pharmacology 1 Fundamental & Clinical Pharmacology