The involvement of spinal Ca2+/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 Ca2+ fluxes in the response to nicotine. In order to assess Ca2+-dependent mechanisms in nicotine-induced antinociception, the Ca2+ 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 [Ca2+](i) and CaM kinase II activity in spinal cord tissues. Nicotine increased [Ca2+](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 Ca2+ ions, which would reach sufficient levels to activate Ca2+-dependent/CaM kinase II. Neuronal Ca2+ acting via Ca2+-dependent CaM kinase IT, appears to mediate nicotine-induced antinociception at the spinal level. (C) 2000 Elsevier Science B.V. All rights reserved.