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

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 1

Heated skin evokes endogenous TRPV1 ligand(s).

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Heated skin evokes endogenous TRPV1 ligand(s). (A) Effect of superfusate...
(A) Effect of superfusates, collected from 6 mouse skin biopsies (1.5 × 1.5 cm) after exposure to noxious (48°C for 20 min) or control temperatures (37°C for 20 minutes), to TG neurons from WT mice (positive control: capsaicin [Cap], 100 nM) using single-cell calcium imaging. Superfusates were applied after cooling to room temperature. Results are plotted as the 340/380 ratio. (B) The effect of same superfusate (1A) on calcium levels in TG neurons from TRPV1 KO mice. Positive control: MO (50 μM). (C) Graph summarizing comparison of heated skin superfusate application to WT or TRPV1 KO neurons (n = 48 for WT and 36 for TRPV1 KO; P = 0.00001). Mean ± SEM. Results are plotted as Δ ratio 340/380 (Δ = maximum peak 340/380 – baseline 340/380). (D) Temperature dependence of endogenous TRPV1 agonist(s) release (no. of responder/total no. of neurons). (E) Effect of I-RTX (200 nM) pretreatment on superfusate-evoked (mouse skin, heated at 48°C for 20 minutes) responses in TG neurons from WT mice (n = 44 for vehicle [Veh], 31 for I-RTX; P = 0.0003). (F) Heated skin superfusate applied to TRPV1 CHO cells. Positive control: capsaicin (100 nM). (G) Graph summarizing comparison of heated skin superfusate effect on CHO cells expressing TRPV1 (n = 56 for TRPV1, 43 for GFP, negative control; P = 0.00001). (H) Representative inward current in rat TG neuron by heated mouse skin superfusate and capsaicin. (I) Nocifensive behavior (WT vs. TRPV1 KO mice) evoked by hind paw injection of compound(s) isolated from previously heated skin biopsies (n = 5–6 per group; P = 0.0003). ***P < 0.001.