Nociceptive and antinociceptive responses to intrathecally administered nicotinic agonists.
Activation of spinal nicotinic receptors evokes a prominent algogenic response. Recently, epibatidine, a potent nicotinic agonist, was found to display an antinociceptive response after systemic administration. To examine the spinal component of this action, effects of three nicotinic agonists epibatidine, cytisine and nicotine--were given intrathecally (IT) and their antinociceptive activity was subsequently assessed. All agents elicited dose-dependent algogenic activity, characterized at lower doses by touch-evoked hyperactivity and at higher doses by intermittent vocalization and marked behavioral activity, with the rank order of potency being epibatidine > cytisine > nicotine. In addition, intrathecal epibatidine elicited a short-lasting, dose-dependent thermal antinociception. In contrast, the other nicotinic agonists at the highest usable dose failed to produce a significant antinociception. 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 responses, but methyllycaconitine inhibited only the algogenic effects of epibatidine. Dihydro-beta-erythroidine, also a competitive antagonist, had no effect on the initial intense algogenic responses. The analgesic response to epibatidine was neither inhibited by naloxone nor by atropine. 2-Amino-5-phosphopentanoic acid, a competitive N-methyl-D-aspartate receptor antagonist, did not affect the analgesic response to intrathecal epibatidine or the intense initial algogenic response. Upon repeated administration (30-min interval), epibatidine (1 microg, IT) exhibited marked and rapid desensitization to both the analgesic and algogenic responses which recovered within 8 h. Pretreatment with two consecutive doses of cytisine (5 microg, IT, 30-min apart) inhibited the agitation and analgesic actions of intrathecal epibatidine. Thus, we contend that in addition to the typical nociceptive response elicited by spinal nicotinic agonists, intrathecal epibatidine also exhibits a pronounced but short-lasting antinociception. The analgesic and algogenic responses to intrathecal epibatidine may be mediated by distinct subtypes of spinal nicotinic receptors as suggested by the antagonist studies.
Khan
I M
IM
Department of Pharmacology, University of California, San Diego 92093-0818, USA.
Buerkle
H
H
Taylor
P
P
Yaksh
T L
TL
D000470:Alkaloids / Q000008:administration & dosage / Q000494:pharmacology; D000698:Analgesia; D000818:Animals; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology; D004924:Escape Reaction; D006614:Hindlimb; D006358:Hot Temperature; D007278:Injections, Spinal; D008120:Lobeline / Q000494:pharmacology; D008297:Male; D008464:Mecamylamine / Q000008:administration & dosage / Q000494:pharmacology; D008845:Microinjections; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011807:Quinolizines; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014828:Vocalization, Animal; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008120:Lobeline; D008464:Mecamylamine; D009538:Nicotine; D018722:Nicotinic Agonists; D011725:Pyridines; D011807:Quinolizines; D016194:Receptors, N-Methyl-D-Aspartate; D014633:Valine; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C056639:2-amino-5-phosphopentanoic acid; C082748:epibatidine