INVOLVEMENT OF CALCIUM AND L-TYPE CHANNELS IN NICOTINE-INDUCED ANTINOCICEPTION

The nature of the signaling process activated by neuronal nicotinic re ceptors has not been fully defined; however, several recent studies ha ve implicated the involvement of calcium ion fluxes in the response to nicotine on a cellular level. Alteration of nicotine-induced antinoci ception in mice after systemic administration was therefore investigat ed in the presence of several drugs that increase intracellular calciu m. Calcium, (+/-)-BAYK 8644, thapsigargin, glyburide and A23187 admini stered intrathecally (i.t.) were found to enhance nicotine-induced ant inociception by shifting its dose-response curve to the left. Converse ly, i.t. administration of agents which decrease intracellular calcium , such as EGTA and alpha-calcitonin gene-related peptide, blocked nico tine-induced antinociception. These findings support a role for spinal intracellular calcium in the pharmacological effects of nicotine. Add itionally, blockade of antinociception by nimodipine and nifedipine in dicates that a L-type calcium channel is involved in nicotine's effect . However, nicotine did not compete for [H-3] nitrendipine binding. In trathecal administration of mecamylamine, a nicotinic antagonist, resu lted in a blockade of antinociception produced by the i.t. injection o f thapsigargin, A23187, calcium and (+/-)-BAYK 8644. The mechanism of mecamylamine's antagonism of nicotine is uncertain. However, these res ults suggest that mecamylamine blocks the effects of drugs which incre ase intracellular calcium by either a modulation of intracellular calc ium-dependent mechanisms or a blockade of calcium channels. Thus, meca mylamine could modulate a calcium signaling process secondary to recep tor activation resulting in blockade of antinociception produced by di verse agents.