Differences between the antinociceptive effects of the cholinergic channelactivators A-85380 and (+/-)-epibatidine in rats

(+/-)-Epibatidine (EPIB) and A-85380 are nicotinic acetylcholine receptor ( nAChR) agonists that bind to the agonist (H-3]cytisine) binding site with 4 0 to 50 pM affinity but have different affinities in nAChR subtype selectiv e 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 reducin g 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 w as a similar to 33-fold more potent than A-85380 (ED50 = 0.004 and 0.11 mu mol/kg, i.p., respectively). The systemic effects of both nAChR agonists we re blocked by central (i.c.v.) administration of the nAChR antagonist chlor isondamine suggesting a central site of action for these compounds. Injecti ons of EPIB (0.0013 to 0.013 nmol) and A-85380 (0.013 to 0.13 nmol) directl y into the nucleus raphe magnus (NRM) were also effective in the hot box an d could be blocked by coadministration of the nAChR antagonists chlorisonda mine (0.23 nmol) or mecamylamine (0.8 nmol). The NRM was found to be critic al 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 b oth within and outside the NRM, whereas EPIB acts largely via descending in hibitory pathways arising from the NRM.