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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 Article has an altmetric score of 32

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 2

Heating increases oxidized linoleic acid metabolites in skin.

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Heating increases oxidized linoleic acid metabolites in skin.
(A) HPLC c...
(A) HPLC comparison of unique substances in superfusates collected from mouse skin biopsies (1.5 × 1.5 cm) after exposure to noxious heat (48°C for 20 min) or control temperatures (37°C for 20 min). The TRPV1 activity of each fraction was evaluated using calcium imaging of TG neurons cultured from rats and CHO cells expressing TRPV1 (data not shown). cps, counts per second. (B) Evaluation of product ions formed from HPLC fraction 22 following collisional activation of the [M-H]_ ion at m/z 295 with tandem quadrupole mass spectrometer monitoring of either m/z 171 (9-HODE) or m/z 195 (13-HODE). (C and D) Temperature-dependent release of 9-HODE (C) and 13-HODE (D) into mouse skin superfusates collected after 20 minutes exposure to a given temperature. 9- and 13-HODE were detected by HPLC/MS as described (x axis has a logarithmic scale).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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