AN EVALUATION OF THE GABA UPTAKE BLOCKER TIAGABINE IN ANIMAL-MODELS OF NEUROPATHIC AND NOCICEPTIVE PAIN

Tiagabine HCl [(R]-N-[4,4-bis(3-methyl-2-thienyl]-3-butenyl] nipecotic acid hydrochloride], a potent and selective GABA uptake inhibitor, wa s evaluated for potential anti-allodynic effects in a rodent model of neuropathic pain and for antinociceptive activity in rodent models of acute and persistent pain. The effect of tiagabine on neuropathic pain was evaluated in rats that developed allodynia after tight ligation o f L5 and L6 spinal nerves. The anti-allodynic effects of tiagabine wer e dose-dependent, with significant increases in response threshold to tactile stimulation occurring at 72.8 mu moles/kg, ip, but not at lowe r doses of 7.2 and 24.3 mu moles/kg, ip. In the hot-plate test in mice , tiagabine significantly increased foot-licking latency at 7.2 and 24 .3 mu moles/kg, ip, and jump latency at 24.3 mu moles/kg, ip. After tw ice daily dosing with 72.8 mu moles/kg, ip, of tiagabine for 4 days, m ice showed a tolerance to the antinociceptive effect of the 7.2 mu mol es/kg, ip, dose of tiagabine in the hot-plate test. Tolerance did not occur after twice daily dosing of the 7.2 mu moles/kg, ip, dose of tia gabine. Tiagabine did not have significant effects on the tail-flick l atency of rats at doses of 0.7 to 72.8 mu moles/kg, ip. Doses of 7.2 a nd 24.3 mu moles/kg, ip, of tiagabine significantly reduced the number of acetic acid-induced stretches in mice. In rats, tiagabine signific antly decreased the number of paw flinches in the early phase of the f ormalin test at 24.3 and 72.8 mu moles/kg, ip, and in the late phase o f the test at 72.8 mu moles/kg, ip. Tiagabine had no significant effec ts on carrageenan-induced paw edema at doses of 0.7 to 72.8 mu moles/k g, ip. Taken together, the results of these experiments revealed the p otential anti-allodynic and antinociceptive pharmacology of tiagabine. Drug Dev. Res. 44:106-113, 1998. (C) 1998 Wiley-Liss, Inc.