title: The antinociceptive effects of nicotinic receptors α7-positive allosteric modulators in murine acute and tonic pain models.
abstract: The α7 nicotinic acetylcholine receptor (nAChR) subtype is abundantly expressed in the central nervous system and in the periphery. Recent evidence suggests that α7 nAChR subtypes, which can be activated by an endogenous cholinergic tone, comprising acetylcholine and the α7 nAChR agonist choline, play an important role in subchronic pain and inflammation. This study's objective was to test whether α7 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)] α7 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 α7 antagonist MLA, administered intrathecally, reversed PNU-120596's effects, confirming PNU-120596's action, in part, through central α7 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 α7 nAChR PAM PNU-120596, but not type I α7 nAChR PAM NS1738, shows significant antinociception effects in persistent pain models in mice.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613, USA.
authors.forename: Kelen
authors.initials: K
authors.lastname: Freitas
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: M Imad
authors.initials: MI
authors.lastname: Damaj
mesh_terms: D000700:Analgesics; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde; D006358:Hot Temperature; D007278:Injections, Spinal; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D010671:Phenylurea Compounds / Q000378:metabolism / Q000494:pharmacology; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D011930:Reaction Time; D011978:Receptors, Nicotinic / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C523981:1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea; D000700:Analgesics; D002070:Butadienes; D018678:Cholinergic Agents; C579166:Chrna7 protein, mouse; D007555:Isoxazoles; D009570:Nitriles; D010671:Phenylurea Compounds; D011978:Receptors, Nicotinic; C113580:U 0126; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005557:Formaldehyde