Abstract
Nicotinic agonists display a wide-range profile of antinociceptive activity in acute, tonic, and chronic pain models. However, their effectiveness is limited by their unacceptable side effects. We investigated the antinociceptive effects of two new α4β2* nicotinic partial agonists, varenicline and sazetidine-A, in acute thermal and tonic pain mouse models. Both drugs failed to induce significant effects in the tail-flick and hot-plate tests after subcutaneous administration. However, they blocked nicotine's effects in these tests at very low doses. In contrast to acute pain tests, varenicline and sazetidine-A dose-dependently induced an analgesic effect in the mouse formalin test after systemic administration. Their antinociceptive effects were mediated, however, by different nicotinic acetylcholine receptor (nAChR) subtypes. Sazetidine-A effects were mediated by β2* nAChR subtypes, whereas varenicline actions were attributed to α3β4 nAChRs. Moreover, low inactive doses of varenicline blocked nicotine's actions in phase II of the formalin test. Overall, our results suggest that the antagonistic actions of varenicline at low doses are mediated by β2*-nAChRs and at higher doses as an agonist by α3β4*-nAChRs. In contrast, both actions of sazetidine-A are mediated by β2*-nAChR subtypes. These results suggest that nicotinic partial agonists possess analgesic effects in a rodent tonic pain model and may provide a potential treatment for the treatment of chronic pain disorders.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA-019377 (to M.I.D.), DA12001 (to F.I.C.)]; the National Institutes of Health National Institute of Mental Health [Grant MH53631] (to J.M.M.); and the National Institutes of Health National Institute of General Medical Sciences [Grant GM48677] (to J.M.M.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- nAChR
- nicotinic acetylcholine receptor
- DHβE
- dihydro-β-erythroidine
- WT
- wild type
- KO
- knockout
- MEC
- mecamylamine
- MLA
- methyllycaconitine
- CNS
- central nervous system
- Var
- varenicline
- Saz
- sazetidine-A
- Veh
- vehicle
- Nic
- nicotine
- MPE
- maximum possible effect
- AD50
- antagonist dose at 50%
- α-ctx AuIB
- α-conotoxin AuIB.
- Received March 17, 2012.
- Accepted June 6, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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