Nicotinic agonists display a wide-range profile of antinociceptive activity in acute, tonic, and
chronic pain models. However, their effectiveness is limited by their unacceptable side effects. We investigated the antinociceptive effects of two new α4β2* nicotinic partial agonists,
varenicline and
sazetidine-A, in acute thermal and tonic
pain mouse models. Both drugs failed to induce significant effects in the tail-flick and hot-plate tests after subcutaneous administration. However, they blocked
nicotine's effects in these tests at very low doses. In contrast to
acute pain tests,
varenicline and
sazetidine-A dose-dependently induced an
analgesic effect in the mouse
formalin test after systemic administration. Their antinociceptive effects were mediated, however, by different
nicotinic acetylcholine receptor (nAChR) subtypes.
Sazetidine-A effects were mediated by β2* nAChR subtypes, whereas
varenicline actions were attributed to α3β4 nAChRs. Moreover, low inactive doses of
varenicline blocked
nicotine's actions in phase II of the
formalin test. Overall, our results suggest that the antagonistic actions of
varenicline at low doses are mediated by β2*-nAChRs and at higher doses as an agonist by α3β4*-nAChRs. In contrast, both actions of
sazetidine-A are mediated by β2*-nAChR subtypes. These results suggest that nicotinic partial agonists possess
analgesic effects in a rodent tonic
pain model and may provide a potential treatment for the treatment of
chronic pain disorders.