Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain

Gao, BaoXi; Hierl, Markus; Clarkin, Kristie; Juan, Todd; Nguyen, Hung; Valk, Marissa van der; Deng, Hong; Guo, Wenhong; Lehto, Sonya G.; Matson, David; McDermott, Jeff S.; Knop, Johannes; Gaida, Kevin; Cao, Lei; Waldon, Dan; Albrecht, Brian K.; Boezio, Alessandro A.; Copeland, Katrina W.; Harmange, Jean-Christophe; Springer, Stephanie K.; Malmberg, Annika B.; McDonough, Stefan I.

doi:10.1016/j.pain.2010.01.007

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Volume 149, Issue 1 , Pages 33-49, April 2010

Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain

BaoXi Gao
- Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
- These authors contributed equally to this work.
Markus Hierl
- Department of Neuroscience, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
- Department of Lead Discovery, Amgen, Inc., Josef-Engert-St. 11, D-93053 Regensburg, Germany
- These authors contributed equally to this work.
Kristie Clarkin
- Department of Protein Sciences, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
Todd Juan
- Department of Protein Sciences, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
Hung Nguyen
- Department of Protein Sciences, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
Marissa van der Valk
- Department of Protein Sciences, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
Hong Deng
- Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
Wenhong Guo
- Department of Neuroscience, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Sonya G. Lehto
- Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
David Matson
- Department of Neuroscience, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Jeff S. McDermott
- Department of Neuroscience, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
- Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
Johannes Knop
- Department of Lead Discovery, Amgen, Inc., Josef-Engert-St. 11, D-93053 Regensburg, Germany
Kevin Gaida
- Department of Inflammation, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
Lei Cao
- Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Dan Waldon
- Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Brian K. Albrecht
- Department of Chemistry Research and Development, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Alessandro A. Boezio
- Department of Chemistry Research and Development, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Katrina W. Copeland
- Department of Chemistry Research and Development, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Jean-Christophe Harmange
- Department of Chemistry Research and Development, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Stephanie K. Springer
- Department of Chemistry Research and Development, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Annika B. Malmberg
- Department of Neuroscience, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
Stefan I. McDonough
- Department of Neuroscience, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA
- Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA
- Corresponding author. Tel.: +1 617 444 5580; fax: +1 617 494 1075.

Received 25 August 2009; received in revised form 16 December 2009; accepted 11 January 2010. published online 18 February 2010.

Abstract

Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for α4β2 or for α7 nAChRs were then tested in the formalin and complete Freund’s adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective α4β2 agonist ispronicline and a novel α4β2-selective potentiator did not appear to produce analgesia in either model. α7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective α7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by α4β2 and only minimally by α7 subtypes. Taken with previous studies, the results suggest that agonism of α4β2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia.

Keywords: ABT-594, Varenicline, Tropisetron, Ispronicline, SSR-180711, SSR-591813, TC-1734, TC-2696