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

Abstract

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.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…In a rat model of partial-thickness cutaneous thermal injury, pharmacological blockade of TRPV1 728 almost completely (by 98%) blocked thermal allodynia (Green et al, 2013), indicating that pain evoked by a second-degree burn is predominantly TRPV1 mediated. This observation implies a clinical benefit for TRPV1 antagonist-containing lotions in the pain control of burn patients.…”

Lipids as central modulators of sensory TRP channels

“…Intraplantar injection of these lipids causes enhanced thermal hyperalgesia through TRPV1 activation and/or sensitization [111;112]. More recently, HODEs were also shown to be upregulated in murine skin biopsies in a post-burn pain model [113].…”

Nerve reinnervation and itch behavior in a rat burn wound model

“…Iodine was applied and lidocaine was administered subcutaneously. A customized copper soldering stamp (2 × 1 cm), connected to a temperature‐controlled soldering station, was heated to 100 °C and applied to the dorsolateral skin for 15 seconds to induce a full thickness thermal injury . It was ascertained that this region was easily accessible by the unilateral hindpaw for scratching.…”

“…A customized copper soldering stamp (2 3 1 cm), connected to a temperature-controlled soldering station, was heated to 100 8C and applied to the dorsolateral skin for 15 seconds to induce a full thickness thermal injury. 20,21 It was ascertained that this region was easily accessible by the unilateral hindpaw for scratching. Immediately postburn the rats received subcutaneous buprenorfine (0.05 mg/kg, Temgesic; Schering-Plough BV, Utrecht, The Netherlands) as an analgesic, and after that every 12-14 hours up to 72 hours.…”