Thermo- and Mechano-sensory Components of Pain

Our work is focused on the thermo- and mechano-sensory components of pain, with an emphasis on transduction and transmission of sensory stimuli by peripheral sensory neurons of the dorsal root ganglia (DRG). Of primary interest to us are the “thermoTRPs,” a subset of TRP ion channels gated by thermal, mechanical and chemical stimuli. At the molecular level, these channels enable specific subsets of DRG neurons to excite in response to heat, cold and mechanical force.

One line of investigation in our lab is focused on TRPA1, a thermoTRP gated by noxious (painful) cold and a variety of pungent chemicals, such as those derived from mustard and cinnamon oils. Typically, TRPA1 ligands induce burning sensations in humans and promote nociceptive behavior in mice. However, we have recently shown that a specific TRPA1 ligand is able to induce long-term mechanical and cold analgesia in inflammatory and neuropathic pain models. Our data support that the mechanism of analgesia is due, in part, to initial activation followed by long-term inhibition of TRPA1. We are currently engaged in biochemical and cellular experiments to determine the mechanisms whereby TRPA1 is modulated differentially by various exogenous and endogenous agonists. We are intrigued that differential, ligand-mediated effects on the channel can result in both pro- and anti-nociceptive effects on behavior. Our goal is to identify modulators of TRPA1 as candidate molecules to aid in the design of peripherally acting pain therapeutics.

At home, in the work place and on trips by automobile, many of us notice a gender difference in preferred environmental temperature. We are not alone. A second line of investigation in our lab has identified striking differences in behavioral responses of male vs. female mice to a broad range of temperatures. Overall, we find that female mice prefer ~6°C warmer surface temperatures compared to males and exhibit more robust escape behaviors when exposed to noxious cold surface temperatures (?15°C). In order to identify the molecular substrates underlying sexually dimorphic cold nociception, we have investigated male vs. female differences in response to icilin, a synthetic, cold-mimetic ligand of TRPM8 (the “cool” and menthol receptor) and TRPA1. Using icilin as a pharmacological tool to activate peripheral cold-sensing pathways, we employ further manipulation of peripheral, central and hormonal signaling to dissect the mechanisms underlying sex differences in cold nociception. A goal of our work is to leverage these sex differences in mice in order to uncover the cause(s) of hypersensitivity to cold in both men and women. Cold hypersensitivity burdens many chronic pain patients and results from certain diseases (such as Fibromyalgia) and nerve injury.