An evaluation of the GABA uptake blocker tiagabine in animal models of neuropathic and nociceptive pain

Abstract

Tiagabine HCl [(R]-N-[4,4-bis(3-methyl-2-thienyl]-3-butenyl] nipecotic acid hydrochloride], a potent and selective GABA uptake inhibitor, was 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 of L5 and L6 spinal nerves. The anti-allodynic effects of tiagabine were dose-dependent, with significant increases in response threshold to tactile stimulation occurring at 72.8 μmoles/kg, ip, but not at lower doses of 7.2 and 24.3 μmoles/kg, ip. In the hot-plate test in mice, tiagabine significantly increased foot-licking latency at 7.2 and 24.3 μmoles/kg, ip, and jump latency at 24.3 μmoles/kg, ip. After twice daily dosing with 72.8 μmoles/kg, ip, of tiagabine for 4 days, mice showed a tolerance to the antinociceptive effect of the 7.2 μmoles/kg, ip, dose of tiagabine in the hot-plate test. Tolerance did not occur after twice daily dosing of the 7.2 μmoles/kg, ip, dose of tiagabine. Tiagabine did not have significant effects on the tail-flick latency of rats at doses of 0.7 to 72.8 μmoles/kg, ip. Doses of 7.2 and 24.3 μmoles/kg, ip, of tiagabine significantly reduced the number of acetic acid-induced stretches in mice. In rats, tiagabine significantly decreased the number of paw flinches in the early phase of the formalin test at 24.3 and 72.8 μmoles/kg, ip, and in the late phase of the test at 72.8 μmoles/kg, ip. Tiagabine had no significant effects on carrageenan-induced paw edema at doses of 0.7 to 72.8 μmoles/kg, ip. Taken together, the results of these experiments revealed the potential anti-allodynic and antinociceptive pharmacology of tiagabine. Drug Dev. Res. 44:106–113, 1998. © 1998 Wiley-Liss, Inc.