Role of endogenous TRPV1 agonists in a postburn pain model of partial-thickness injury

Research output: Contribution to journalArticle

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Abstract

Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous transient receptor potential vanilloid 1 (TRPV1) channel agonists released on exposure of tissue to transient noxious temperatures. These lipid compounds also contribute to inflammatory and heat allodynia. Because persistent pain after a burn injury represents a significant clinical challenge for treatment, we developed an in vivo rat model of partial-thickness cutaneous thermal injury and examined whether TRPV1 and specific OLAM metabolites play a role in mediating postburn pain injury. This peripheral model of burn injury had marked thermal allodynia peaking at 24 h after thermal injury, with allodynia being maintained for up to 7 d. Immunohistochemical characterization of tissue taken from injury sites revealed an increase in leukocyte/macrophage infiltration that was colocalized with TRPV1-positive fibers. Using this peripheral thermal injury model, we found that pharmacological blockade of peripheral TRPV1 receptors reduced thermal allodynia by about 98%. Moreover, there was a significant increase in OLAM levels compared to naive controls in hind paw skin biopsies. Additional studies of the metabolism of [C14]-linoleic acid in skin biopsies revealed the role of the cytochrome P450 (CYP) system in mediating the metabolism of linoleic acid after thermal injury. Finally, we demonstrated that direct inhibition of OLAMs using OLAM antibodies and indirect inhibition using the CYP inhibitor ketoconazole significantly reduced postburn thermal allodynia. Collectively, these findings point to a novel role of the OLAMs and CYP-related enzymes in generating postburn allodynia via activation of peripheral TRPV1. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Original languageEnglish (US)
Pages (from-to)2512-2520
Number of pages9
JournalPain
Volume154
Issue number11
DOIs
StatePublished - Nov 2013

Fingerprint

TRPV Cation Channels
Linoleic Acid
Pain
Wounds and Injuries
Hyperalgesia
Hot Temperature
Cytochrome P-450 Enzyme System
Skin
Biopsy
Inhibition (Psychology)
Ketoconazole
Leukocytes
Macrophages
Pharmacology
Lipids
Temperature
Antibodies

Keywords

  • Burn
  • Cytochrome P450
  • Linoleic acid
  • OLAM
  • Pain
  • TRPV1

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine
  • Neurology
  • Pharmacology
  • Medicine(all)

Cite this

Role of endogenous TRPV1 agonists in a postburn pain model of partial-thickness injury. / Green, Dustin P.; Ruparel, Shivani; Roman, Linda; Henry, Michael A.; Hargreaves, Kenneth M.

In: Pain, Vol. 154, No. 11, 11.2013, p. 2512-2520.

Research output: Contribution to journalArticle

Green, Dustin P.; Ruparel, Shivani; Roman, Linda; Henry, Michael A.; Hargreaves, Kenneth M. / Role of endogenous TRPV1 agonists in a postburn pain model of partial-thickness injury.

In: Pain, Vol. 154, No. 11, 11.2013, p. 2512-2520.

Research output: Contribution to journalArticle

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abstract = "Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous transient receptor potential vanilloid 1 (TRPV1) channel agonists released on exposure of tissue to transient noxious temperatures. These lipid compounds also contribute to inflammatory and heat allodynia. Because persistent pain after a burn injury represents a significant clinical challenge for treatment, we developed an in vivo rat model of partial-thickness cutaneous thermal injury and examined whether TRPV1 and specific OLAM metabolites play a role in mediating postburn pain injury. This peripheral model of burn injury had marked thermal allodynia peaking at 24 h after thermal injury, with allodynia being maintained for up to 7 d. Immunohistochemical characterization of tissue taken from injury sites revealed an increase in leukocyte/macrophage infiltration that was colocalized with TRPV1-positive fibers. Using this peripheral thermal injury model, we found that pharmacological blockade of peripheral TRPV1 receptors reduced thermal allodynia by about 98%. Moreover, there was a significant increase in OLAM levels compared to naive controls in hind paw skin biopsies. Additional studies of the metabolism of [C14]-linoleic acid in skin biopsies revealed the role of the cytochrome P450 (CYP) system in mediating the metabolism of linoleic acid after thermal injury. Finally, we demonstrated that direct inhibition of OLAMs using OLAM antibodies and indirect inhibition using the CYP inhibitor ketoconazole significantly reduced postburn thermal allodynia. Collectively, these findings point to a novel role of the OLAMs and CYP-related enzymes in generating postburn allodynia via activation of peripheral TRPV1. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.",
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N2 - Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous transient receptor potential vanilloid 1 (TRPV1) channel agonists released on exposure of tissue to transient noxious temperatures. These lipid compounds also contribute to inflammatory and heat allodynia. Because persistent pain after a burn injury represents a significant clinical challenge for treatment, we developed an in vivo rat model of partial-thickness cutaneous thermal injury and examined whether TRPV1 and specific OLAM metabolites play a role in mediating postburn pain injury. This peripheral model of burn injury had marked thermal allodynia peaking at 24 h after thermal injury, with allodynia being maintained for up to 7 d. Immunohistochemical characterization of tissue taken from injury sites revealed an increase in leukocyte/macrophage infiltration that was colocalized with TRPV1-positive fibers. Using this peripheral thermal injury model, we found that pharmacological blockade of peripheral TRPV1 receptors reduced thermal allodynia by about 98%. Moreover, there was a significant increase in OLAM levels compared to naive controls in hind paw skin biopsies. Additional studies of the metabolism of [C14]-linoleic acid in skin biopsies revealed the role of the cytochrome P450 (CYP) system in mediating the metabolism of linoleic acid after thermal injury. Finally, we demonstrated that direct inhibition of OLAMs using OLAM antibodies and indirect inhibition using the CYP inhibitor ketoconazole significantly reduced postburn thermal allodynia. Collectively, these findings point to a novel role of the OLAMs and CYP-related enzymes in generating postburn allodynia via activation of peripheral TRPV1. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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