Nociceptive and antinociceptive responses to intrathecally administered nicotinic agonists

Activation of spinal nicotinic receptors evokes a prominent algogenic respo nse. Recently, epibatidine. a potent nicotinic agonist, was found to displa y an antinociceptive response after systemic administration. To examine the spinal component of this: action, effects of three nicotinic agonists-epib atidine. cytisine and nicotine-were given intrathecally (IT) and their anti nociceptive activity was subsequently assessed. All agents elicited dose-de pendent algogenic activity, characterized at lower doses by touch-evoked hy peractivity and at higher doses by intermittent vocalization and marked beh avioral activity, with the rank order of potency being epibatidine > cytisi ne > nicotine. In addition, intrathecal epibatidine elicited a short-lastin g, dose-dependent thermal antinociception. In contrast, the other nicotinic agonists at the highest usable dose failed to produce a significant antino ciception. Mecamylamine, a nicotinic channel blocker, completely abolished the antinociceptive and algogenic responses of epibatidine. The competitive antagonist, alpha-lobeline, blocked both the analgesic and algogenic respo nses, but methyllycaconitine inhibited only the algogenic effects of epibat idine. Dihydro-beta-erythroidine, also a competitive antagonist, had no eff ect on the initial intense algogenic responses. The analgesic response to e pibatidine was neither inhibited by naloxone not by atropine. 2-Amino-5-pho sphopentanoic acid, a competitive N-methyl-D-aspartate receptor antagonist, did not affect the analgesic response to intrathecal epibatidine or the in tense initial algogenic response. Upon repeated administration (30-min inte rval), epibatidine(1 mu g, IT exhibited marked and rapid desensitization to both the analgesic and algogenic responses which recovered within 8 h. Pre treatment with two consecutive doses of cytisine (5 mu g, IT, 30-min apart) inhibited the agitation and analgesic actions of intrathecal epibatidine. Thus, we contend that in addition to the typical nociceptive response elici ted by spinal nicotinic agonists, intrathecal epibatidine also exhibits a p ronounced but short-lasting antinociception. The analgesic and algogenic re sponses to intrathecal epibatidine may be mediated by distinct subtypes of spinal nicotinic receptors as suggested by the antagonist studies. (C) 1998 Elsevier Science Ltd. All rights reserved.