Abstracts

Rationale: Hyperexcitability of the peripheral and central nervous system may contribute to pain sensitization (Woolf , CJ and Decosterd, I. Pain 1999; 82(Suppl. 6): S141-S147.) Thus, drugs with efficacy at reducing hyperexcitability have been investigated and, in the case of gabapentin, carbamazepine, and mexiletine, validated clinically for their ability to treat chronic neuropathic pain (Hord AH, et al., Anesth Analg 2003; 96:1700-1706). This investigation assessed the effects of amygdala kindling on mechanical allodynia in rats and determined if treatment with carisbamate, (RWJ 333369) (S)-2-O-carbamoyl-1-O-chlorophenyl-ethanol, during kindling acquisition can prevent the development of mechanical allodynia.Methods: A bipolar electrode was implanted into the basolateral amygdala of 48 adult male Sprague-Dawley rats. Rats in each of three groups were kindled with a suprathreshold (200 μA, 2 sec) daily stimulation 15 minutes after i.p. administration of vehicle or drug (25 mg/kg or 40 mg/kg carisbamate) until the vehicle-treated rats reached a stable kindled state. Mechanical allodynia was assessed with von Frey monofilaments by measuring the 50% threshold for paw withdrawal using the “up and down” step procedure (Chaplan, SR et al., J. Neurosci. Methods 1994; 53(1):55-63) one day before the initiation of kindling and two days after the last kindling stimulation. Following a one week stimulation- and drug-free period, rats in all three groups were then rechallenged (in the absence of drug) daily with the original kindling stimulus until all carisbamate-treated rats reached a stable kindled state. Mechanical allodynia was then re-assessed several days post-rechallenge.Results: When the vehicle-treated rats reached the fully kindled state, the threshold for mechanical allodynia was significantly reduced to 47 + 8% (n=16) of the pre-kindling threshold. These results demonstrate that amygdala kindling produced a sensitization to punctate tactile stimulation, otherwise referred to as mechanical allodynia. Carisbamate dose-dependently inhibited the development of kindling-induced allodynia in the rats. The 50% paw withdrawal thresholds were 79 + 10% (n=14) and 91 + 19% (n=16) of pre-kindling threshold for 25 mg/kg and 40 mg/kg carisbamate, respectively. Following rechallenge, the threshold for mechanical allodynia was lowered for the groups previously treated with carisbamate (12 + 2% and 51 + 16%, respectively) while remaining unchanged for the vehicle-treated rats (44 + 12 %).Conclusions: This study is the first to show that amygdala kindling produces mechanical allodynia in rats. Carisbamate at both doses tested prevented the kindling induced mechanical allodynia. These results support previous findings suggesting that carisbamate possesses disease modifying properties in the post-status epilepticus rat (François J, et al., Epilepsia 2005; 46(Suppl. 6):215) and suggest that treatment with carisbamate may be effective in preventing the development of neuropathic pain. (Supported by a grant from Johnson & Johnson Pharmaceutical Research and Development, L.L.C.)