Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors

doi:10.1073/pnas.0608715103

Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors

*Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157; and
Departments of ^†Biology and
^‡Psychiatry, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112

Communicated by Mario R. Capecchi, University of Utah, Salt Lake City, UT, October 4, 2006 (received for review August 12, 2006)

Abstract

α9α10 nicotinic acetylcholine receptors (nAChRs) have been identified in a variety of tissues including lymphocytes and dorsal root ganglia; except in the case of the auditory system, the function of α9α10 nAChRs is not known. Here we show that selective block (rather than stimulation) of α9α10 nAChRs is analgesic in an animal model of nerve injury pain. In addition, blockade of this nAChR subtype reduces the number of choline acetyltransferase-positive cells, macrophages, and lymphocytes at the site of injury. Chronic neuropathic pain is estimated to affect up to 8% of the world's population; the numerous analgesic compounds currently available are largely ineffective and act through a small number of pharmacological mechanisms. Our findings not only suggest a molecular mechanism for the treatment of neuropathic pain but also demonstrate the involvement of α9α10 nAChRs in the pathophysiology of peripheral nerve injury.

Footnotes

^§To whom correspondence should be sent at the ‡ address. E-mail: mcintosh.mike{at}gmail.com
Author contributions: M.V. and J.M.M. designed research; S.W., R.P., and M.E. performed research; B.M.O. contributed new reagents/analytic tools; M.V. and J.M.M. analyzed data; and M.V., B.M.O., and J.M.M. wrote the paper.
Conflict of interest statement: B.M.O. has been a consultant and officer of Cognetix. J.M.M. has been a consultant and officer of Cognetix.
Abbreviations:

ACh,

acetylcholine;

nAChR,

nicotinic ACh receptor;

CCI,

chronic constriction injury;

PWT,

paw withdrawal threshold;

ChAT,

choline acetyltransferase;

PBS+T,

0.01 M PBS with 0.15% Triton X-100
Freely available online through the PNAS open access option.