The involvement of spinal Ca(2+)/calmodulin-protein kinase II in nicotine-induced antinociception in mice.
The nature of the signaling process activated by neuronal nicotinic receptors has not been fully defined; however, several recent studies have implicated the involvement of Ca(2+) fluxes in the response to nicotine. In order to assess Ca(2+)-dependent mechanisms in nicotine-induced antinociception, the Ca(2+) channel antagonist nimodipine and several calcium/calmodulin-protein kinase II (CaM kinase II) inhibitors were evaluated for their effects on nicotine-induced antinociception. The results indicate that both of these antagonists dose-dependently blocked nicotine-induced antinociception after intrathecal (i.t.) injection. Indeed, three structurally unrelated CaM kinase II inhibitors blocked nicotine's effects in the tail-flick test in a dose-related manner. A second series of experiments assessed the effect of acute nicotine exposure on [Ca(2+)](i) and CaM kinase II activity in spinal cord tissues. Nicotine increased [Ca(2+)](i) in a concentration-dependent manner after application of the drug to spinal synaptosomes. Furthermore, a dose-dependent increase in the spinal cord membrane CaM kinase II activity was seen after acute injection of nicotine in mice. Taken together, these results are consistent with the hypothesis that nicotine binding to nicotinic receptors leads to channel opening and depolarization responses with an influx of Ca(2+) ions, which would reach sufficient levels to activate Ca(2+)-dependent/CaM kinase II. Neuronal Ca(2+), acting via Ca(2+)-dependent CaM kinase II, appears to mediate nicotine-induced antinociception at the spinal level.
Damaj
M I
MI
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA. mdamaj@hsc.vcu.edu
D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D009538:Nicotine / Q000494:pharmacology* / Q000627:therapeutic use; D009553:Nimodipine / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000700:Analgesics; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D009553:Nimodipine; D009538:Nicotine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium