Effects of Nicotinic Acetylcholine Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behaviors in Rats

Abstract

Agonists at nicotinic acetylcholine receptors (nAChRs) constitute one drug class being evaluated as candidate analgesics. Previous preclinical studies have implicated alpha 4 beta 2 and alpha 7 nAChRs as potential mediators of the antinociceptive effects of (-)-nicotine hydrogen tartrate (nicotine) and other nAChR agonists; however, these studies have relied exclusively on measures of pain-stimulated behavior, which can be defined as behaviors that increase in frequency, rate, or intensity after presentation of a noxious stimulus. Pain is also associated with depression of many behaviors, and drug effects can differ in assays of pain-stimulated versus pain-depressed behavior. Accordingly, this study compared the effects of nicotine, the selective alpha 4/6 beta 2 agonist 5-(123I) iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5-I-A-85380), and the selective alpha 7 agonist N-(3R)-1-azabicyclo(2.2.2) oct-3-yl-4-chlorobenzamide in assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to either stimulate a stretching response or depress the operant responding, which is maintained by electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. Nicotine produced a dose-dependent, time-dependent, and mecamylamine-reversible blockade of both acid-stimulated stretching and acid-induced depression of ICSS. 5-I-A-85380 also blocked both acid-stimulated stretching and acid-induced depression of ICSS, whereas N-(3R)-1-azabicyclo(2.2.2) oct-3-yl-4-chlorobenzamide produced no effect in either procedure. Both nicotine and 5-I-A-85380 were >= 10-fold more potent in blocking the acid-induced depression of ICSS than in blocking the acid-induced stimulation of stretching. These results suggest that stimulation of alpha 4 beta 2 and/or alpha 6 beta 2 nAChRs may be especially effective to alleviate the signs of pain-related behavioral depression in rats; however, nonselective behavioral effects may contribute to apparent antinociception.