Activation of the alpha7-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 alpha(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 alpha(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%).


CONCLUSIONS
These studies provide good rationale for the utility of selective, central nervous system penetrant agonists at the alpha(7)-nicotinic receptor for the treatment of inflammatory pain.
Medhurst
Stephen J
SJ
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, United Kingdom. Stephen.j.medhurst@gsk.com
Hatcher
Jon P
JP
Hille
Christopher J
CJ
Bingham
Sharon
S
Clayton
Nick M
NM
Billinton
Andy
A
Chessell
Iain P
IP
D000157:Aconitine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008297:Male; D008464:Mecamylamine / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology*; D016474:Weight-Bearing / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001572:Benzofurans; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; C520027:N-(1-azabicyclo(2.2.2)oct-3-yl)-7-(2-(methoxy)phenyl)-1-benzofuran-2-carboxamide; D018733:Nicotinic Antagonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D008464:Mecamylamine; D005620:Freund's Adjuvant; D000157:Aconitine