Nicotinic agonists have demonstrated antinociceptive effects in a wide range of acute, tonic, and chronic pain models. However, their effectiveness is limited by their side effects. This study investigated the effects of two nicotinic partial agonists, varenicline [7,8,9,10-tetrahydro-6,10-methano-6H-pyrzino(2,3-h)(3)benzazepine] and sazetidine-A [6-[5-[(2S)-2-azetidinylmethoxy]-3-pyridinyl]-5-hexyn-1-ol]. Compared with full agonists, neither of the partial agonists had analgesic effects in acute thermal mouse pain models. Both compounds blocked the analgesic effect of nicotine in the tail-flick assay. However, initial evidence that these two partial agonists were different was demonstrated when only sazetidine-A blocked the analgesic effect of nicotine in the hot-plate assay. When investigated in tonic pain, both compounds dose-dependently induced an analgesic effect in the mouse formalin model. Interestingly, the fact that the β2 subunit is not required for varenicline's efficacy was demonstrated when the formalin test was conducted in β2 subunit knockout mice. In contrast, sazetidine was not effective in β2 subunit knockout mice. Both compounds were effective without significant effects on motor coordination. In summary, these studies demonstrate that both partial agonists are effective in tonic pain but not acute pain. However, they appear to be efficacious via different nicotinic subtypes.
See article at J Pharmacol Exp Ther 2012, 342:742–749.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics