Activation of the α7-Nicotinic Acetylcholine Receptor Reverses Complete Freund Adjuvant–Induced Mechanical Hyperalgesia in the Rat Via a Central Site of Action

Abstract The role of specific nicotinic receptor (nAChR) subtypes in antinociception has not been fully elucidated because of the lack, until recently, of selective tool compounds. (R)- N -(1-azabicyclo[2.2.2] oct -3- yl )(5-(2-pyridyl)thiopene-2-carboxamide) (compound B) is reported to be an agonist selective for the α 7 nAChR and in the present study was found to be efficacious in inflammatory pain models in 2 species. Compound B reversed complete Freund adjuvant–induced reductions in paw withdrawal thresholds in rat and mouse in a dose-related manner, producing maximum reversals of 65% ± 4% at 10 mg/kg and 87% ± 15% at 20 mg/kg. When rats and mice were predosed with the centrally penetrant, broad-spectrum nicotinic receptor antagonist mecamylamine, the efficacy of the agonist was significantly inhibited, producing reversals of only 11% ± 5% at 10 mg/kg and 5% ± 13% at 20 mg/kg, confirming activity via nicotinic receptors. Rats were also predosed systemically with the selective low-brain penetrant α 7 -antagonist methyllycaconitine, which had no effect on agonist activity (90% ± 18% at 10 mg/kg), suggesting a central involvement. This hypothesis was further established with methyllycaconitine completely inhibited the agonist effect when dosed intrathecally (1% ± 7%). Perspective These studies provide good rationale for the utility of selective, central nervous system penetrant agonists at the α 7 -nicotinic receptor for the treatment of inflammatory pain.