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

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 α7nAChR 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 α7-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%).PerspectiveThese studies provide good rationale for the utility of selective, central nervous system penetrant agonists at the α7-nicotinic receptor for the treatment of inflammatory pain.