1. Activation of the alpha7-nicotinic acetylcholine receptor reverses complete freund adjuvant-induced mechanical hyperalgesia in the rat via a central site of action.
- Author
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Medhurst SJ, Hatcher JP, Hille CJ, Bingham S, Clayton NM, Billinton A, and Chessell IP
- Subjects
- Aconitine administration & dosage, Aconitine analogs & derivatives, Aconitine pharmacology, Animals, Behavior, Animal drug effects, Benzofurans administration & dosage, Dose-Response Relationship, Drug, Female, Freund's Adjuvant, Hyperalgesia chemically induced, Hyperalgesia physiopathology, Inflammation chemically induced, Inflammation metabolism, Inflammation physiopathology, Injections, Intraperitoneal, Male, Mecamylamine administration & dosage, Mecamylamine pharmacology, Mice, Mice, Inbred C57BL, Models, Animal, Nicotinic Antagonists administration & dosage, Nicotinic Antagonists pharmacology, Pain drug therapy, Pain metabolism, Pain physiopathology, Pain Measurement methods, Quinuclidines administration & dosage, Rats, Weight-Bearing physiology, alpha7 Nicotinic Acetylcholine Receptor, Benzofurans pharmacology, Hyperalgesia drug therapy, Quinuclidines pharmacology, Receptors, Nicotinic physiology
- Abstract
Unlabelled: 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%)., Perspective: 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.
- Published
- 2008
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