title: Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain.
abstract: The anti-nociceptive and locomotor effects of the nicotinic acetylcholine receptor (nAChR) agonists (+)-epibatidine and ABT-594 were compared in the rat. Acute thermal nociception was measured using the tail flick test. Mechanical hyperalgesia was measured as paw withdrawal threshold (PWT) in response to a mechanical stimulus in two animal models of persistent pain; (1) 24 h following subplantar injections of Freund's complete adjuvant (FCA) into the left hind paw or (2) 11-15 days following a partial ligation of the left sciatic nerve. Disruption of locomotor function was assessed using an accelerating rotarod device. In all tests, (+)-epibatidine was significantly more potent than ABT-594. Both (+)-epibatidine and ABT-594 dose-dependently increased tail flick latencies but only at doses that also disrupted performance in the rotarod test. On the other hand, (+)-epibatidine and ABT-594 dose-dependently reversed inflammatory and neuropathic hyperalgesia at significantly lower doses than that needed to disrupt performance in the rotarod test. In summary, ABT-594 is less potent than (+)-epibatidine in assays of acute and persistent pain and in the rotarod assay. However, ABT-594 displayed a clearer separation between its motor and anti-hyperalgesic effects. This shows that nicotinic agonists with improved selectivity between the nicotinic receptor subtypes could provide strong analgesic effects with a much improved therapeutic window.
authors.affiliation: Novartis Institute of Medical Sciences, London, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Kesingland
authors.forename: C T
authors.initials: CT
authors.lastname: Gentry
authors.forename: M S
authors.initials: MS
authors.lastname: Panesar
authors.forename: M A
authors.initials: MA
authors.lastname: Bowes
authors.forename: J M
authors.initials: JM
authors.lastname: Vernier
authors.forename: R
authors.initials: R
authors.lastname: Cube
authors.forename: K
authors.initials: K
authors.lastname: Walker
authors.forename: L
authors.initials: L
authors.lastname: Urban
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications; D001384:Azetidines / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000188:drug therapy / Q000523:psychology; D007249:Inflammation / Q000150:complications*; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects*; D020426:Sciatic Neuropathy / Q000150:complications*
chemical_list: C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D018712:Analgesics, Non-Narcotic; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D005620:Freund's Adjuvant; C082748:epibatidine