Home LiteratureArticle Details
PMID: 20424317 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

The Journal of clinical investigation ·Vol. 120 ·No. 5 ·2010-05-00 ·Pages 1617-26

Patwardhan AM, Akopian AN, Ruparel NB, Diogenes A, Weintraub ST, Uhlson C, Murphy RC, Hargreaves KM

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.

MeSH Terms
Animals Fatty Acids, Unsaturated/metabolism Hot Temperature Ligands Linoleic Acid/metabolism Male Mice Mice, Inbred C57BL Models, Biological Oxygen/chemistry,metabolism Pain Rats Rats, Sprague-Dawley TRPV Cation Channels/metabolism
Chemicals
Fatty Acids, Unsaturated Ligands TRPV Cation Channels TRPV1 protein, mouse Trpv1 protein, rat hydroxyoctadecadienoic acid Linoleic Acid Oxygen
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Patwardhan Amol M
Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78227, USA.
Akopian Armen N
Ruparel Nikita B
Diogenes Anibal
Weintraub Susan T
Uhlson Charis
Murphy Robert C
Hargreaves Kenneth M
References (37)
37 references, click to expand
  1. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels.
    Nature. 2003 Jul 24;424(6947):434-8 PMID: 12879072
  2. New bis-catechols 5-lipoxygenase inhibitors.
    Bioorg Med Chem. 2001 Feb;9(2):229-35 PMID: 11249115
  3. Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia.
    Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18820-4 PMID: 19843694
  4. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.
    Eur J Pharmacol. 1998 Jul 17;353(1):23-31 PMID: 9721036
  5. Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2.
    J Neurosci. 2008 Dec 17;28(51):13727-37 PMID: 19091963
  6. The capsaicin receptor: a heat-activated ion channel in the pain pathway.
    Nature. 1997 Oct 23;389(6653):816-24 PMID: 9349813
  7. The identification of hydroxy fatty acids in psoriatic skin.
    Prostaglandins. 1983 Sep;26(3):431-47 PMID: 6419288
  8. Increased levels of lipid oxidation products in low density lipoproteins of patients suffering from rheumatoid arthritis.
    Chem Phys Lipids. 1997 May 30;87(1):81-9 PMID: 9219348
  9. Mechanisms of sensory transduction in the skin.
    Nature. 2007 Feb 22;445(7130):858-65 PMID: 17314972
  10. Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization.
    J Physiol. 2007 Aug 15;583(Pt 1):175-93 PMID: 17584831
  11. Low-energy fast atom bombardment tandem mass spectrometry of monohydroxy substituted unsaturated fatty acids.
    Biol Mass Spectrom. 1993 Aug;22(8):465-73 PMID: 8357860
  12. Impaired nociception and pain sensation in mice lacking the capsaicin receptor.
    Science. 2000 Apr 14;288(5464):306-13 PMID: 10764638
  13. Biochemical pharmacology of the vanilloid receptor TRPV1. An update.
    Eur J Biochem. 2004 May;271(10):1814-9 PMID: 15128291
  14. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels.
    Nature. 2004 Aug 12;430(7001):748-54 PMID: 15306801
  15. Hydroxyoctadecadienoic acid and oxidatively modified peroxiredoxins in the blood of Alzheimer's disease patients and their potential as biomarkers.
    Neurobiol Aging. 2009 Feb;30(2):174-85 PMID: 17688973
  16. Hypotensive effect of 13-hydroxylinoleic acid in the rat: mediation via the release of a CGRP-like mediator from capsaicin-sensitive nerves.
    Br J Pharmacol. 1995 Jul;115(5):835-9 PMID: 8548184
  17. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels.
    EMBO J. 2005 Dec 21;24(24):4211-23 PMID: 16319926
  18. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation.
    Inflamm Res. 2000 Oct;49(10):497-505 PMID: 11089900
  19. Nordihydroguaiaretic acid protects hippocampal neurons against amyloid beta-peptide toxicity, and attenuates free radical and calcium accumulation.
    Brain Res. 1994 Aug 15;654(1):171-6 PMID: 7982093
  20. PAR-2 agonists activate trigeminal nociceptors and induce functional competence in the delta opioid receptor.
    Pain. 2006 Nov;125(1-2):114-24 PMID: 16781076
  21. The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation.
    J Neurosci. 2007 Mar 28;27(13):3366-74 PMID: 17392452
  22. The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies.
    J Neurosci. 1998 Aug 15;18(16):6081-92 PMID: 9698303
  23. Single-channel properties of native and cloned rat vanilloid receptors.
    J Physiol. 2002 Nov 15;545(1):107-17 PMID: 12433953
  24. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress.
    J Neurosci. 2008 Mar 5;28(10):2485-94 PMID: 18322093
  25. Molecular basis for species-specific sensitivity to "hot" chili peppers.
    Cell. 2002 Feb 8;108(3):421-30 PMID: 11853675
  26. Actions of two naturally occurring saturated N-acyldopamines on transient receptor potential vanilloid 1 (TRPV1) channels.
    Br J Pharmacol. 2004 Sep;143(2):251-6 PMID: 15289293
  27. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin.
    Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15435-9 PMID: 8986829
  28. The cloned capsaicin receptor integrates multiple pain-producing stimuli.
    Neuron. 1998 Sep;21(3):531-43 PMID: 9768840
  29. Homologous and heterologous desensitization of capsaicin and mustard oil responses utilize different cellular pathways in nociceptors.
    Pain. 2008 Apr;135(3):271-279 PMID: 17590514
  30. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.
    Pain. 1988 Jan;32(1):77-88 PMID: 3340425
  31. Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation.
    J Neurosci. 2008 Jan 30;28(5):1064-75 PMID: 18234885
  32. Generation and metabolism of lipoxygenase products in normal and membrane-damaged cultured human keratinocytes.
    J Invest Dermatol. 1989 Oct;93(4):486-91 PMID: 2476511
  33. A hot-sensing cold receptor: C-terminal domain determines thermosensation in transient receptor potential channels.
    J Neurosci. 2006 May 3;26(18):4835-40 PMID: 16672657
  34. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1.
    Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13519-24 PMID: 17684094
  35. Bio-markers of lipid peroxidation in vivo: hydroxyoctadecadienoic acid and hydroxycholesterol.
    Biofactors. 2006;27(1-4):195-202 PMID: 17012775
  36. Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats.
    J Pharmacol Exp Ther. 2008 Jul;326(1):218-29 PMID: 18420600
  37. Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells.
    J Biol Chem. 2002 Dec 6;277(49):47044-51 PMID: 12354759
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI41678
Published
2010-05-00
Epub
2010-00-26
Pages
1617-26
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2860941
Subset
IM
Grants
NIGMS NIH HHS · GM069338 · United States
NIDCR NIH HHS · R01 DE017696 · United States
NIDCR NIH HHS · R01 DE019311 · United States
NIGMS NIH HHS · U54 GM069338 · United States
NIDCR NIH HHS · DE019311 · United States
NIDCR NIH HHS · DE017696 · United States
NCRR NIH HHS · U54RR02438 · United States
NIDA NIH HHS · R01 DA019585 · United States
NIDA NIH HHS · DA019585 · United States
Corrections
CommentIn
PMID: 20424321
External Links
PubMed source DOI: 10.1172/JCI41678 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2