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PNAS 106 (44): 18820-18824

Copyright © 2009 by the National Academy of Sciences.

From the Cover


Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Amol M. Patwardhana, Phoebe E. Scotlandb, Armen N. Akopiana, and Kenneth M. Hargreavesa,b,1

Departments of aEndodontics and bPharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229

Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved September 16, 2009

Received for publication May 15, 2009.

Abstract: Transient receptor potential vanilloid 1 (TRPV1) plays a major role in hyperalgesia and allodynia and is expressed both in the peripheral and central nervous systems (CNS). However, few studies have evaluated mechanisms by which CNS TRPV1 mediates hyperalgesia and allodynia after injury. We hypothesized that activation of spinal cord systems releases endogenous TRPV1 agonists that evoke the development of mechanical allodynia by this receptor. Using in vitro superfusion, the depolarization of spinal cord triggered the release of oxidized linoleic acid metabolites, such as 9-hydroxyoctadecadienoic acid (9-HODE) that potently activated spinal TRPV1, leading to the development of mechanical allodynia. Subsequent calcium imaging and electrophysiology studies demonstrated that synthetic oxidized linoleic acid metabolites, including 9-HODE, 13-HODE, and 9 and 13-oxoODE, comprise a family of endogenous TRPV1 agonists. In vivo studies demonstrated that intrathecal application of these oxidized linoleic acid metabolites rapidly evokes mechanical allodynia. Finally, intrathecal neutralization of 9- and 13-HODE by antibodies blocks CFA-evoked mechanical allodynia. These data collectively reveal a mechanism by which an endogenous family of lipids activates TRPV1 in the spinal cord, leading to the development of inflammatory hyperalgesia. These findings may integrate many pain disorders and provide an approach for developing analgesic drugs.

Key Words: inflammation • pain

Freely available online through the PNAS open access option.

Author contributions: A.M.P., A.N.A., and K.M.H. designed research; A.M.P., P.E.S., and A.N.A. performed research; A.M.P., P.E.S., A.N.A., and K.M.H. analyzed data; and A.M.P., A.N.A., and K.M.H. wrote the paper.

Conflict of interest statement: The University of Texas has claimed intellectual property on this discovery.

This article is a PNAS Direct Submission.

See Commentary on page 18435.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: hargreaves{at}

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