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PNAS 105 (25): 8784-8789

Copyright © 2008 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / PHARMACOLOGY

General anesthetics activate a nociceptive ion channel to enhance pain and inflammation

José A. Matta*, Paul M. Cornett*, Rosa L. Miyares*, Ken Abe{dagger}, Niaz Sahibzada*, and Gerard P. Ahern*,{ddagger}

Departments of *Pharmacology and {dagger}Physiology and Biophysics, Georgetown University, 3900 Reservoir Road, NW, Washington, DC 20007

Edited by Ramón Latorre, Centro de Neurociencias, Universidad de Valparaíso, Valparaíso, and approved April 21, 2008

Received for publication November 21, 2007.

Abstract: General anesthetics (GAs) have transformed surgery through their actions to depress the central nervous system and blunt the perception of surgical insults. Counterintuitively, many of these agents activate peripheral nociceptive neurons. However, the underlying mechanisms and significance of these effects have not been explored. Here, we show that clinical concentrations of noxious i.v. and inhalation GAs excite sensory neurons by selectively activating TRPA1, a key ion channel in the pain pathway. Further, these GAs induce pain-related responses in mice that are abolished in TRPA1-null animals. Significantly, TRPA1-dependent neurogenic inflammation is greater in mice anesthetized with pungent compared with nonpungent anesthetics. Thus, our results show that TRPA1 is essential for sensing noxious GAs. The pronociceptive effects of GAs combined with surgical tissue damage could lead to a paradoxical increase in postoperative pain and inflammation.

Key Words: TRPA1 • TRPV1 • isothiocyanate • mustard oil • isoflurane

Author contributions: J.A.M., P.M.C., and G.P.A. designed research; J.A.M., P.M.C., R.L.M., K.A., N.S., and G.P.A. performed research; J.A.M., P.M.C., R.L.M., N.S., and G.P.A. analyzed data; and J.A.M., R.L.M., and G.P.A. wrote the paper.

Conflict of interest: Georgetown University has filed a provisional patent relating to this study.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0711038105/DCSupplemental.

{ddagger}To whom correspondence should be addressed. E-mail: gpa3{at}georgetown.edu

© 2008 by The National Academy of Sciences of the USA

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