Novel agonist of α 4 β 2 neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain

• Published in: Journal of pain research 2018, Vol.11, p.2453-2462
• Main Authors: Sudo, Roberto T, Hayashida, Kenichiro, Santos, Aluizio N, Kawatani, Masahito, Monteiro, Carlos Es, Moreira, Roberto D, Trachez, Margarete M, Montes, Guilherme C, Zapata-Sudo, Gisele
• Format: Article
• Language: English
• ISSN: 1178-7090; 1178-7090
• DOI: 10.2147/JPR.S169637

To demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl}piperidine), a novel selective α β * nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models. Hot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods. Cris-104 effects on spontaneous locomotion were examined in an open-field test. Cris-104 induced dose-dependent antinociception effects in hot-plate and formalin tests, and these effects were blocked by the general nAChR antagonist mecamylamine, the selective α β * nAChR antagonist dihydro-beta-erythroidine, and the α -adrenoceptor antagonist yohimbine, but not by the α -adrenoceptor antagonist prazosin. Systemic and spinally perfused Cris-104 increased NE concentrations in microdialysates from the spinal cord in both normal and SNL rats. Systemic Cris-104 increased neuronal activity in the LC of normal rats. Mecamylamine blocked the effects of Cris-104 on spinal NE release and LC neuronal activity. Systemic Cris-104 did not affect locomotor activity significantly. The α β neuronal nAChR agonist, Cris-104, was effective for treatment of pain via descending noradrenergic inhibition of pain signaling.