The management of chronic pain is a major health care problem due, in part, to an incomplete understanding of persistent pain mechanisms. Available chronic pain treatments are often limited by poor efficacy, side effects, or risks of dependency, therefore fundamental research into molecular mechanisms of chronic pain are critical in order to develop more efficacious analgesics. Nerve growth factor (NGF) is a neurotrophin that is released under inflammatory conditions and modulates the transmission of nociceptive or pain signals. NGF has been demonstrated to acutely sensitize transient receptor potential vanilloid 1 (TRPV1), a ligand gated ion channel expressed on a major subpopulation of nociceptive afferent neurons. Endogenous NGF is elevated in several chronic pain conditions, and a single administration of NGF to healthy humans produced a prolonged pain state that persisted up to 4-7 weeks. Although the link between NGF and pain is well recognized, there is a gap in understanding of the mechanisms mediating persistent pain. The majority of preclinical NGF studies focus on the acute effects (seconds to hours) of NGF, while the mechanisms underlying persistent NGF effects remain unknown. Towards this objective, we have developed a rodent model of NGF-induced persistent thermal allodynia (a reduced nociceptive threshold) and demonstrated that antagonism of TRPV1 was able to immediately reverse allodynia at a time point long after the NGF was physically eliminated from the animals. More recent preliminary studies suggest that persistent activation of TRPV1 by endogenous oxidized lipid agonists, including oxidized linoleic acid metabolites (OLAMs), may be a peripheral mechanism contributing towards a persistent, long-term nociceptive state after NGF administration. Therefore, this proposal will test the central hypothesis that NGF causes persistent thermal allodynia via increased activities of TRPV1 channels and increased production of endogenous oxidized lipid TRPV1 agonists, including OLAMs. The following aims will test this hypothesis:
Specific Aim #1 : Determine NGF-induced changes in TRPV1 activity in rats during persistent NGF- induced thermal allodynia.
Specific Aim #2 : Define the effect of NGF on levels of oxidized lipids, including OLAMs, and their activation of TRPV1 in rats during persistent NGF-induced thermal allodynia. The proposed studies test an innovative and significant hypothesis and provide a multidisciplinary approach to develop my career as an independent investigator in pain pharmacology.
Chronic pain management is a major health care problem because available treatments often do not provide adequate pain relief. Our lab has preliminary data demonstrating that a protein called nerve growth factor causes persistent pain through activation of the pain receptor TRPV1 by oxidized lipids, including a class of linoleic acid metabolites (OLAMs). Here we propose to investigate the cellular effect of nerve growth factor on TRPV1 and oxidized lipid production with the potential for developing novel chronic pain treatments.
|Eskander, Michael A; Ruparel, Shivani; Green, Dustin P et al. (2015) Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms. J Neurosci 35:8593-603|
|Rowan, Matthew P; Bierbower, Sonya M; Eskander, Michael A et al. (2014) Activation of mu opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) via Î²-arrestin-2-mediated cross-talk. PLoS One 9:e93688|
|Ruparel, Shivani; Hargreaves, Kenneth M; Eskander, Michael et al. (2013) Oxidized linoleic acid metabolite-cytochrome P450 system (OLAM-CYP) is active in biopsy samples from patients with inflammatory dental pain. Pain 154:2363-71|