It has been estimated that 2 million burn injuries occur yearly in the US, with ~15% of these injuries requiring hospitalization. The primary complaint of burn victims is an intense, often devastating spontaneous pain, with persistence of both mechanical and thermal allodynia and hyperalgesia. Thus, there is a compelling need for fundamental research aimed at understanding mechanisms of burn pain and in identifying potentially novel therapeutic approaches for treating it. A prominent member of the family of transient receptor potential (TRP) ligand-gated ion channels is the TRP vanilloid subfamily 1 (TRPV1) ion channel, and is expressed on a major subpopulation of nociceptive neurons. TRPV1 transduces various noxious physical and chemical stimuli applied to peripheral tissues. The TRPV1 ion channel plays a critical role in detecting many of these stimuli, including noxious heat, and contributes to heat hyperalgesia. The role of the TRPV1 receptor in mediating pain post burn injury is incompletely understood. Thus, further research on the mechanisms by which TRPV1 contributes to post-burn pain addresses an important gap in knowledge and may offer innovative approaches for treating the post-burn patient. Our lab has previously published data revealing a novel class of endogenous TRPV1 agonists, the oxidized linoleic acid metabolites (OLAMs), which are released upon thermal and inflammatory tissue injury. More recent preliminary studies have identified the cytochrome P450 (CYP) enzyme system in mediating the release of OLAMs from cultured neurons exposed to linoleic acid. Based upon these studies, as well as additional results presented as Preliminary Data, we propose that thermal injury leads to persistent activation of a CYP system leading to generation of oxidative metabolites of linoleic acid (OLAMs) and activation of TRPV1. The following specific aims will test this innovative hypothesis:
Specific Aim 1 Determine whether thermal injury activates capsaicin-sensitive nociceptors via CYP mediated release of OLAMs.
Specific Aim 1 uses in vitro cellular methods to evaluate the hypothesis that the OLAM system activates TRPV1 after peripheral burn injury.
Aim 1 affords the opportunity to learn patch clamp electrophysiology, a method providing a valuable tool in my future career as a neurobiologist.
Specific Aim 2 Identify CYP enzymes that is up-regulated in sensory neurons after thermal injury.
Specific Aim 2 will identify and characterize CYP isoforms that are up-regulated in sensory neurons after burn injury.
This Aim provides an excellent opportunity to learn both qRT-PCR as well as intracellular immunoneutralization, two techniques which will strengthen my future career as a neurobiologist.
It has been estimated that 2 million burn injuries occur yearly in the US, with ~15% of these injuries requiring hospitalization. Our lab has previously published data revealing a novel class of linoleic acid metabolites (OLAMs), released upon thermal and inflammatory tissue injury that activate the pain receptor TRPV1. Here we propose to investigate the enzymatic system that metabolizes linoleic acid in thermal injuries with the potential for therapeutic applications in burn pain.
|Green, Dustin P; Patil, Mayur J; Akopian, Armen N (2016) Influence of hypophysectomy, ovariectomy and gonadectomy on postoperative hypersensitivity in rats. Glob Anesth Perioper Med 2:171-175|
|Green, Dustin; Ruparel, Shivani; Gao, Xiaoli et al. (2016) Central activation of TRPV1 and TRPA1 by novel endogenous agonists contributes to mechanical allodynia and thermal hyperalgesia after burn injury. Mol Pain 12:|
|Green, Dustin P; Ruparel, Shivani; Roman, Linda et al. (2013) Role of endogenous TRPV1 agonists in a postburn pain model of partial-thickness injury. Pain 154:2512-20|
|Patil, M J; Green, D P; Henry, M A et al. (2013) Sex-dependent roles of prolactin and prolactin receptor in postoperative pain and hyperalgesia in mice. Neuroscience 253:132-41|
|Ruparel, Shivani; Green, Dustin; Chen, Paul et al. (2012) The cytochrome P450 inhibitor, ketoconazole, inhibits oxidized linoleic acid metabolite-mediated peripheral inflammatory pain. Mol Pain 8:73|