Role of Endogenous TRPV1 Agonists in a Post-Burn Pain Model of Partial-Thickness Injury

摘要

Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous transient receptor potential vanilloid 1 (TRPV1) channel agonists released upon exposure of tissue to transient noxious temperatures. These lipid compounds also contribute to inflammatory and heat allodynia. As 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 post-burn pain injury. This peripheral model of burn injury had marked thermal allodynia peaking at 24 hours post thermal injury, with allodynia being maintained for up to 7 days. Immunohistochemical characterization of tissue taken from injury site revealed an increase of leukocyte/macrophage infiltration that was co-localized with TRPV1-positive fibers. Utilizing this peripheral thermal injury model we found that pharmacological blockade of peripheral TRPV1 receptors reduced thermal allodynia by about 67%. Moreover, there was a significant increase in OLAM levels compared to naïve controls in hindpaw skin biopsies. Additional studies on metabolism of [C¹⁴]-linoleic acid in skin biopsies revealed the role of the cytochrome P450 (CYP) system in mediating the metabolism of linoleic acid post thermal injury. Finally, we demonstrated direct inhibition of OLAMs using OLAM antibodies and indirect inhibition using the CYP inhibitor ketoconazole significantly reduced post-burn thermal allodynia. Collectively, these findings point to a novel role of the OLAMs and CYP-related enzymes in generating post-burn allodynia via activation of peripheral TRPV1.