There are a limited number of robust animal models that can be used to assay phenotypic changes associated with acute and chronic pain. This is true not only for animal behaviors, but also with respect to mechanistic details of changes that occur in relevant tissues at the site of injury, including nociceptive nerve fibers. For a more in-depth understanding of how inflammation leads to pain and hyperexcitability, it will be informative to know how this type of pathology leads to molecular, cellular, and anatomical changes in specific cohorts of afferent neurons that mediate such sensitization. At the molecular level, members of the TRP family of ion channels play essential roles in the formation of both acute and persistent pain in vivo, particularly the irritant receptor channel TRPA1. TRPA1 is critical for the development of inflammatory hypersensitivity to both mechanical and thermal stimuli, implicating the afferent neurons expressing TRPA1 as being of equal importance in inflammatory signaling. Here we propose to address the property of these neurons, but not necessarily the channel itself, with the generation of two mouse models with which we will examine how their phenotype and morphology changes with inflammatory hypersensitivity, and through cell ablation, will determine their necessity in acute and inflammatory signaling. We have initiated the creation of transgenic mice in which neurons that express TRPA1 are labeled with a fluorescent axonal tracer which we will use to establish the neurochemical phenotype and morphology of the peripheral and central terminations of TRPA1 neurons in vivo. These analyses will be done under normal conditions and in the context of mouse models of inflammatory injury. Next, using this newly developed transgenic strategy, we will target TRPA1 neurons for conditional ablation and determine their role in acute and persistent pain in vivo. As whole, these exploratory studies will tease out the role of this specific neuronal population in somatosensory signaling and the formation of inflammatory hypersensitivity, as well as develop novel animal models that selectively target TRPA1 neurons for future studies into their physiology and function.
Our studies will provide insights into the neuronal mechanisms that lead to the persistent pain associated with inflammation by characterizing the morphological changes induced in specific afferent cell types by tissue injury. Moreover, we will determine the necessity of a specific afferent population in the formation and maintenance of inflammatory pain, thereby providing novel therapeutic targets that can be used to alleviate these debilitating conditions.
|Lippoldt, Erika K; Elmes, Russell R; McCoy, Daniel D et al. (2013) Artemin, a glial cell line-derived neurotrophic factor family member, induces TRPM8-dependent cold pain. J Neurosci 33:12543-52|
|McKemy, David D (2013) The molecular and cellular basis of cold sensation. ACS Chem Neurosci 4:238-47|
|Osborne, Melissa; Gomez, Daniel; Feng, Zhihua et al. (2012) Characterization of behavioral and neuromuscular junction phenotypes in a novel allelic series of SMA mouse models. Hum Mol Genet 21:4431-47|