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Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents
Amol M. Patwardhan, … , Robert C. Murphy, Kenneth M. Hargreaves
Amol M. Patwardhan, … , Robert C. Murphy, Kenneth M. Hargreaves
Published April 26, 2010
Citation Information: J Clin Invest. 2010;120(5):1617-1626. https://doi.org/10.1172/JCI41678.
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Research Article

Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents

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Abstract

The transient receptor potential vanilloid 1 (TRPV1) channel is the principal detector of noxious heat in the peripheral nervous system. TRPV1 is expressed in many nociceptors and is involved in heat-induced hyperalgesia and thermoregulation. The precise mechanism or mechanisms mediating the thermal sensitivity of TRPV1 are unknown. Here, we have shown that the oxidized linoleic acid metabolites 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE) are formed in mouse and rat skin biopsies by exposure to noxious heat. 9- and 13-HODE and their metabolites, 9- and 13-oxoODE, activated TRPV1 and therefore constitute a family of endogenous TRPV1 agonists. Moreover, blocking these substances substantially decreased the heat sensitivity of TRPV1 in rats and mice and reduced nociception. Collectively, our results indicate that HODEs contribute to the heat sensitivity of TRPV1 in rodents. Because oxidized linoleic acid metabolites are released during cell injury, these findings suggest a mechanism for integrating the hyperalgesic and proinflammatory roles of TRPV1 and linoleic acid metabolites and may provide the foundation for investigating new classes of analgesic drugs.

Authors

Amol M. Patwardhan, Armen N. Akopian, Nikita B. Ruparel, Anibal Diogenes, Susan T. Weintraub, Charis Uhlson, Robert C. Murphy, Kenneth M. Hargreaves

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Figure 8

Linoleic acid rescues the TRPV1-mediated heat responses in membrane patches.

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Linoleic acid rescues the TRPV1-mediated heat responses in membrane patc...
(A) The responsiveness of TRPV1-expressing CHO cells to 48°C is maintained in the cell-attached configuration but is lost by 3 minutes of washing the inside-out configuration. The application of heated linoleic acid (LA) (1 μM) rescues temperature responses (i.e., Po) in inside-out patches from TRPV1-expressing cells that were washed at least 3 minutes. Single-channel configurations and applied temperatures are indicated. (n = 4–8; P = 0.0001). ***P < 0.001. (B) Representative traces show single-channel recording at indicated temperatures in inside-out and cell-attached configurations. Inside-out patches were washed at least 3 minutes prior to the recording. (C) Representative traces illustrate the effects of application of 1 μM LA at indicated temperatures. Recordings were performed from inside-out patches washed at least 3 minutes. (D) Coapplication of 10 μM linoleic acid does not affect capsaicin-gated (100 nM) responses in TRPV1-expressing patches. Recordings were performed from inside-out patches washed at least 3 minutes. (E) Representative traces show single-channel recording for Cap and a mix of Cap and linoleic acid.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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