Abstract

(±)-Epibatidine (EPIB) and A-85380 are nicotinic acetylcholine receptor (nAChR) agonists that bind to the agonist ([³H]cytisine) binding site with 40 to 50 pM affinity but have different affinities in nAChR subtype selective functional receptor assays. In vivo EPIB was more (23-fold) potent than A-85380 in reducing open field activity and more (12-fold) potent in reducing nociception in the formalin test of persistent chemical pain. In the rat hot box test of thermal acute pain, both compounds produced antinociception, as indicated by an increase in the paw withdrawal latency, however EPIB was a ∼33-fold more potent than A-85380 (ED₅₀ = 0.004 and 0.11 μmol/kg, i.p., respectively). The systemic effects of both nAChR agonists were blocked by central (i.c.v.) administration of the nAChR antagonist chlorisondamine suggesting a central site of action for these compounds. Injections of EPIB (0.0013 to 0.013 nmol) and A-85380 (0.013 to 0.13 nmol) directly into the nucleus raphe magnus (NRM) were also effective in the hot box and could be blocked by coadministration of the nAChR antagonists chlorisondamine (0.23 nmol) or mecamylamine (0.8 nmol). The NRM was found to be critical for the antinociceptive effects of systemic EPIB but not for A-85380 in that NRM injections of either mecamylamine (0.8 nmol) or lidocaine (74 nmol) blocked the antinociceptive effects of systemic (i.p.) EPIB but not those of A-85380. These results suggest that A-85380 may act at multiple sites both within and outside the NRM, whereas EPIB acts largelyvia descending inhibitory pathways arising from the NRM.