• Journal Article

The Antinociceptive Effects of Nicotinic Receptors alpha 7-Positive Allosteric Modulators in Murine Acute and Tonic Pain Models

Citation

Freitas, K., Carroll, F., & Damaj, M. I. (2013). The Antinociceptive Effects of Nicotinic Receptors alpha 7-Positive Allosteric Modulators in Murine Acute and Tonic Pain Models. Journal of Pharmacology and Experimental Therapeutics, 344(1), 264-275. DOI: 10.1124/jpet.112.197871

Abstract

The alpha 7 nicotinic acetylcholine receptor (nAChR) subtype is abundantly expressed in the central nervous system and in the periphery. Recent evidence suggests that alpha 7 nAChR subtypes, which can be activated by an endogenous cholinergic tone, comprising acetylcholine and the alpha 7 nAChR agonist choline, play an important role in subchronic pain and inflammation. This study's objective was to test whether alpha 7 nAChR positive allosteric modulators (PAMs) produce antinociception in in vivo mouse models of acute and persistent pain. Testing type I [N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl) phenyl] (NS1738)] and type II [1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl) (PNU-120596)] alpha 7 nAChR PAMs in acute and persistent pain, we found that, although neither reduced acute thermal pain, only PNU-120596 dose-dependently attenuated paw-licking behavior in the formalin test. The long-acting effect of PNU-120596 in this test was in discordance with its pharmacokinetic profile in mice, which suggests the involvement of postreceptor signaling mechanisms. Our results with selective mitogen-activated protein kinase kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene monoethanolate (U0126) argues for an important role of extracellular signal-regulated kinase-1/2 pathways activation in PNU-120596's antinociceptive effects. The alpha 7 antagonist MLA, administered intrathecally, reversed PNU-120596's effects, confirming PNU-120596's action, in part, through central alpha 7 nAChRs. Importantly, tolerance to PNU-120596 was not developed after subchronic treatment of the drug. Surprisingly, PNU-120596's antinociceptive effects were blocked by NS1738. Our results indicate that type II alpha 7 nAChR PAM PNU-120596, but not type I alpha 7 nAChR PAM NS1738, shows significant antinociception effects in persistent pain models in mice