Antinociceptive responses to nicotinic acetylcholine receptor ligands after systemic and intrathecal administration in mice.
The objective of this study was to determine which nicotinic receptor subtypes are involved in antinociception and their site of action. For that, the antinociceptive effects of several nicotinic receptor ligands were evaluated in the tail-flick test both after s.c. and intrathecal (i.t.) administration. Nicotine and other nicotine agonists increased tail-flick latencies in a dose-dependent manner after both routes of administration. Epibatidine enantiomers were the most potent agonists examined. Cytisine, a potent nicotinic ligand, failed to elicit antinociception when injected either i.t. or s.c. Despite some similarities in the effects of nicotinic agonists after i.t. and s.c. injections, their rank-order potency was different. In contrast to the s.c. results, the stereoselectivity of nicotine's effect after i.t. administration was minimal. When various nicotinic antagonists were compared after i.t. and s.c. administration, the results showed that mecamylamine and dihydro-beta-erythroidine differ in potency and their degree of antagonism of some of the nicotinic agonists given i.t. These data suggest that different subtypes of nicotinic receptors may exist in the spinal cord. A good correlation was found between binding affinity to [3H]-nicotine binding sites and analgesic potency after i.t. (r = 0.82), suggesting the involvement of alpha 4 beta 2 receptor subunits. In contrast, studies with MLA and alpha-BGTX suggested a minimal role for alpha-BGTX-sensitive receptors in the antinociceptive effect of nicotinic agonists.
Damaj
M I
MI
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
Fei-Yin
M
M
Dukat
M
M
Glassco
W
W
Glennon
R A
RA
Martin
B R
BR
D000470:Alkaloids / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001392:Azocines; D002038:Bungarotoxins / Q000494:pharmacology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011807:Quinolizines; D011978:Receptors, Nicotinic / Q000145:classification / Q000502:physiology*; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D018712:Analgesics, Non-Narcotic; D001392:Azocines; D002038:Bungarotoxins; D004079:Dihydro-beta-Erythroidine; D008464:Mecamylamine; D018722:Nicotinic Agonists; D011807:Quinolizines; D011978:Receptors, Nicotinic; C004712:cytisine; D000093843:Quinolizidine Alkaloids