The menthol receptor TRPM8 is considered the principal cold sensor in mammalian sensory neurons as animals lacking TRPM8 function are deficient in cold and cold pain behaviors. However some residual cold sensitivity remains, indicating the possible presence of TRPM8-independent cold transduction mechanisms. Other cell types, such as those expressing TRPV1 and TRPA1 channels, are critical for somatosensory signaling, and have been implicated in certain aspects of cold sensation. Genetic approaches to determine the role of these channels and cell-types are complicated by the fact that the resulting phenotypes are investigated either many days after manipulation, or in developmentally disparate backgrounds. An elegant approach has recently been devised that targets cell impermeant sodium (Na+) channel blockers to only primary sensory neurons mediating pain (nociceptors). Specifically, when stimulated with agonists for nociceptor-specific TRPV1 and TRPA1 channels, large molecules such as the charged lidocaine derivative QX-314 permeate through these channels, thereby selectively blocking nerve conduction in just these neuronal populations. Previous reports failed to find large molecule entry through TRPM8 channels, suggesting that TRPM8 neurons cannot be targeted in this manner. Our underlying hypothesis, supported by our novel preliminary data, is that large molecules permeate cells through TRPM8 when the channel is activated by potent agonists, and we propose to determine if cold and cold pain can be ameliorated by selectively blocking nerve conduction of these and other neuronal populations.
Aim 1 will determine the mechanisms whereby TRPM8 channels permeate large cations in vitro and be used as a means to target Na+-channel blockers to TRPM8 neurons.
Aim 2 will determine if targeting Na+-channel blockers in TRPM8 neurons alters cold sensation in mice, and determine if other primary sensory neurons also contribute to cold.
Aim 3 will extend these behavioral analyses to determine if chronic cold pain induced by injury can be ameliorated by targeting Na+-channel blockers to TRPM8, TRPV1, or TRPA1 neurons. With these studies we will determine if cold and cold pain can be specifically inhibited by the selective entry of large, cell impermeant anesthetics, as well as use this novel approach to further define the cellular basis for cold and cold pain, including identifying TRPM8-independent neuronal populations that contribute to this somatosensory modality.

Public Health Relevance

This project will determine the mechanisms whereby TRPM8 ion channels permeate large molecules, and if this is a suitable approach to target local anesthetics to cold-sensitive afferents. The project will also determine the contribution of other afferents subtypes to cold sensation, thereby identifying neuronal targets to treat cold pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Gnadt, James W
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University of Southern California
Schools of Arts and Sciences
Los Angeles
United States
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Ongun, Serra; Sarkisian, Angela; McKemy, David D (2018) Selective cold pain inhibition by targeted block of TRPM8-expressing neurons with quaternary lidocaine derivative QX-314. Commun Biol 1:53
McCoy, Daniel D; Palkar, Radhika; Yang, Yuening et al. (2017) Cellular permeation of large molecules mediated by TRPM8 channels. Neurosci Lett 639:59-67
Lippoldt, Erika K; Ongun, Serra; Kusaka, Geoffrey K et al. (2016) Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFR?3. Proc Natl Acad Sci U S A 113:4506-11
Palkar, Radhika; Lippoldt, Erika K; McKemy, David D (2015) The molecular and cellular basis of thermosensation in mammals. Curr Opin Neurobiol 34:14-9
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von B├╝dingen, H-Christian; Mei, Feng; Greenfield, Ariele et al. (2015) The myelin oligodendrocyte glycoprotein directly binds nerve growth factor to modulate central axon circuitry. J Cell Biol 210:891-8