Peripheral neuropathy is one of the most debilitating diseases that significantly impacts patient's quality of life with recurring pain and imposes staggering economic burdens to our society. Neuropathic pain also represents a critical unmet medical need because it tends to respond poorly to traditional analgesics and the most commonly used pain medicines produce serious side effects. Therefore, it is important to identify cells, molecules, and neural circuits specifically involved at different stages of the pathogenesis of neuropathic pain to help develop mechanism-based therapies. Transient receptor potential (TRP) channels are a group of ion channels serving as cellular sensors expressed by many cell types. TRPV4 is a polymodal sensory transducer integrating a variety of thermal, mechanical and chemical stimuli. Based on pilot studies, we hypothesize that TRPV4 is required for inflammatory responses that dynamically catalyze neuropathic pain in the spinal cord. To determine the cellular mechanisms underlying TRPV4-mediated neuropathic pain we will use a multidisciplinary approach combining generation of cell- specific TRPV4 mutant mice and bone marrow chimeras, optogenetic activation of TRPV4-expressing cells in the spinal cord, and neuropathic pain behavioral testing. We will also determine if pharmacological inhibition of TRPV4 channels and optogenetic inhibition of TRPV4-expressing spinal cells ameliorate peripheral nerve injury-induced neuropathic pain. This proposal will establish the cellular basis of TRPV4-dependent immune activation during neuropathic pain and explore the potential for pharmacological modulation of neuro-inflammation via inhibition of TRPV4 function. Thus, this study advances a unique opportunity to identify unique molecular and cellular targets for rational design of treatment for neuro-inflammatory diseases resulting in neuropathic pain.

Public Health Relevance

Chronic neuropathic pain is a significant clinic problem and significantly impacts quality of life and productivity. No efficient treatments are available for chronic neuropathic pain due to a lack of effective medicines and deleterious side effects accompanying currently recommended treatments. The current proposal aims to understand the cellular and molecular mechanisms underlying dynamic neuroimmune interactions during peripheral nerve injury-induced chronic neuropathic pain and facilitate identification of novel drug targets for treating chronic neuropathic pain.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Cui, Changhai
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Washington University
Schools of Medicine
Saint Louis
United States
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Lakk, Monika; Young, Derek; Baumann, Jackson M et al. (2018) Polymodal TRPV1 and TRPV4 Sensors Colocalize but Do Not Functionally Interact in a Subpopulation of Mouse Retinal Ganglion Cells. Front Cell Neurosci 12:353
Xie, Zili; Hu, Hongzhen (2018) TRP Channels as Drug Targets to Relieve Itch. Pharmaceuticals (Basel) 11: