title: Calcium-acting drugs modulate expression and development of chronic tolerance to nicotine-induced antinociception in mice.
abstract: Initial studies in our laboratory suggested that tolerance to nicotine is thought to involve neuronal adaptation not only at the level of the drug-receptor interaction but at postreceptor events such as calcium-dependent second messengers. The present study was undertaken to investigate the hypothesis that L-type calcium channels and calcium-dependent calmodulin protein kinase II are involved in the development and expression of nicotine tolerance. To that end, the effects of modulation of L-type calcium channels (through the use of inhibitors or activators) as well as calcium-dependent calmodulin protein kinase II inactivation were studied in a mouse model of tolerance where mice were infused with nicotine in minipumps (24 mg/kg/day) for 14 days. In addition, the activity of calcium-dependent calmodulin protein kinase II in the lumbar spinal cord region obtained from nicotine-tolerant mice was measured. Our data showed that chronic administration of L-type calcium channel antagonists nimodipine (1 and 5 mg/kg) and verapamil (10 mg/kg) prevented the development of tolerance to nicotine-induced antinociception. In contrast, chronic exposure of BAYK8644 [(+/-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester], a calcium channel activator, enhanced nicotine's tolerance. Moreover, a significant increase in both dependent and independent calcium-dependent calmodulin protein kinase II activity was seen in the spinal cord in nicotine-tolerant mice. Finally, spinal administration of 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenylpiperazine (KN-62), a calcium-dependent calmodulin protein kinase II antagonist, reduced the expression of tolerance to nicotine-induced antinociception in mice. In conclusion, our data indicate that calcium-dependent mechanisms such as L-type calcium channels and calcium-dependent calmodulin protein kinase II activation are involved in the expression and development of nicotine tolerance.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, 23298-0613, USA. mdamaj@hsc.vcu.edu
authors.forename: M I
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000700:Analgesics; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004361:Drug Tolerance; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009553:Nimodipine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000700:Analgesics; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D018722:Nicotinic Agonists; D009553:Nimodipine; C063302:KN 62; D009538:Nicotine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D014700:Verapamil; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium