Transient Receptor Potential Vanilloid-1 Sensitization in Inflammation

Harvard Medical School, Boston MA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Peripheral sensitization is a process by which pain fibers become sensitized to innocuous stimuli (allodynia) or more sensitive to noxious stimuli (hyperalgesia). This process occurs through a variety of inflammatory mediators and signaling pathways, with downstream targets including several receptors important for signal transduction. Transient receptor potential vanilloid 1 (TRPV1) is an important non-selective cation channel and receptor in this process. It is sensitive to heat, acid, and vanilloids, includig the 'hot' component of chili peppers, capsaicin. Several inflammatory compounds and pathways can affect its sensitivity to its known ligands. To date, most studies have focused on the individual compounds and the pathways by which they affect TRPV1. This study aims to show that TRPV1 sensitization can be more accurately modeled by using a multi-pronged sensitization approach. Through in vitro calcium-based imaging and electrophysiological techniques, we will explore the characteristics of TRPV1 sensitization including characteristics of particular neuronal sub-populations within dorsal root and trigeminal ganglia. Short- and long-term models will be used to assess these differences and then applied as systems for screening therapeutics. We will begin with compounds that are known to block important signaling molecules such as PKA, PKC, PI3K, and p38 MAPK with the objective of finding key pathways important for TRPV1 sensitization. Finally, high throughput identification screen data will be applied to this model to more closely mimic the inflammatory milieu in vitro and show novel TRPV1-modifying inflammatory compounds.