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Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain

Kesingland, A. C.a; Gentry, C. T.a; Panesar, M. S.a; Bowes, M. A.a; Vernier, J.-Mb; Cube, R.b; Walker, K.a; Urban, L.a,*

doi: 10.1016/S0304-3959(00)00233-5
Article

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.

a Novartis Institute of Medical Sciences, 5 Gower Place, London, WC1E 6BT, UK

b SIBIA Neurosciences Inc., 505 Coast Boulevard South, La Jolla, CA 92037-4631, USA

*Corresponding author. Tel.: +44-171-387-4445; fax: +44-171-387-4116

E-mail: laszlo.urban@pharma.novartis.com

Received 14 July 1999; received in revised form 2 December 1999; accepted 23 December 1999.

© 2000 Lippincott Williams & Wilkins, Inc.
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