Involvement of calcium and L-type channels in nicotine-induced antinociception.
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 calcium ion fluxes in the response to nicotine on a cellular level. Alteration of nicotine-induced antinociception in mice after systemic administration was therefore investigated in the presence of several drugs that increase intracellular calcium. Calcium, (+/-)-BAYK 8644, thapsigargin, glyburide and A23187 administered intrathecally (i.t.) were found to enhance nicotine-induced antinociception by shifting its dose-response curve to the left. Conversely, i.t. administration of agents which decrease intracellular calcium, such as EGTA and alpha-calcitonin gene-related peptide, blocked nicotine-induced antinociception. These findings support a role for spinal intracellular calcium in the pharmacological effects of nicotine. Additionally, blockade of antinociception by nimodipine and nifedipine indicates that a L-type calcium channel is involved in nicotine's effect. However, nicotine did not compete for [3H] nitrendipine binding. Intrathecal administration of mecamylamine, a nicotinic antagonist, resulted in a blockade of antinociception produced by the i.t. injection of thapsigargin, A23187, calcium and (+/-)-BAYK 8644. The mechanism of mecamylamine's antagonism of nicotine is uncertain. However, these results suggest that mecamylamine blocks the effects of drugs which increase intracellular calcium by either a modulation of intracellular calcium-dependent mechanisms or a blockade of calcium channels. Thus, mecamylamine could modulate a calcium signaling process secondary to receptor activation resulting in blockade of antinociception produced by diverse agents.
Damaj
M I
MI
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Welch
S P
SP
Martin
B R
BR
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000698:Analgesia; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D007278:Injections, Spinal; D007424:Intracellular Fluid / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009538:Nicotine; D009568:Nitrendipine / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D014316:Tritium
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011978:Receptors, Nicotinic; D013729:Terpenes; D014316:Tritium; D000001:Calcimycin; D019284:Thapsigargin; D008464:Mecamylamine; D009538:Nicotine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009568:Nitrendipine; D002118:Calcium