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Selective Sensory Axon Reinnervation and TRPV1 Activation

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Abstract

Current strategies to enhance regeneration of peripheral neurons involve broad activation of sensory, autonomic, and motor axons. Peripheral neuron regeneration is limited in persons with damage or disease of peripheral axons. Here, we provide evidence that subtoxic activation of TRPV1 channels in sensory neurons is associated with activation of growth and subtle changes in skin reinnervation. We identify a bidirectional, dose-related impact of capsaicin, a TRPV1 agonist, on sensory neurons and their axons with rises in their outgrowth plasticity at low doses and toxic neurodegeneration at high doses. Moreover, its impact on growth added to that of preconditioning. Neither outcome was observed in TRPV1 null neurons. We confirmed that low dose activation was associated with rises in neuronal calcium, as well as rises in TRPV1 mRNA transcripts. In mice with a sciatic nerve crush followed by a single application of capsaicin directly to the injury site, there was no impact on motor or myelinated axon recovery but there was evidence of better recovery of thermal sensation toward baseline with hyperalgesia. Moreover, skin reinnervation by epidermal axons approached contralateral levels. TRPV1 null mice displayed loss of thermal sensation during later recovery. In sensory axons innervating the pinna of the ear, local capsaicin rendered early axon loss followed by later hyperinnervation. Taken together, TRPV1 activation alters the regenerative behavior of adult neurons and their axons both in vitro and during epidermal reinnervation in vivo. The findings identify a selective manipulation that augments cutaneous innervation by thermosensitive axons.

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Acknowledgements

Dr. Matt Larouche and Twinkle Joy provided valuable technical assistance.

Funding

The work was supported by an operating grant from the Canadian Institutes of Health Research (362082), by the Faculty of Medicine, Department of Medicine, Division of Neurology, University of Alberta, and by the University Hospital Foundation.

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Author notes

  1. T. Poitras and A. Chandrasekhar contributed equally to this work.

Authors and Affiliations

  1. Division of Neurology, Department of Medicine and the Neuroscience and Mental Health Institute, University of Alberta, 132A-Clinical Sciences Building, 11350 Ave, Edmonton, Alberta, T6G 2G3, Canada

    T. Poitras, A. Chandrasekhar, L. McCoy, P. Komirishetty, A. Areti & Douglas W. Zochodne

  2. Division of Anatomy, Department of Surgery and the Neuroscience and Mental Health Institute, University of Alberta, 11350 Ave, Edmonton, Alberta, T6G 2G3, Canada

    C. A. Webber

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  1. T. Poitras
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Correspondence to Douglas W. Zochodne.

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The protocols were reviewed and approved by the Animal Care Committee University of Alberta, adhering to guidelines of the Canadian Council of Animal Care.

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T. Poitras and A. Chandrasekhar are co-first author.

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Poitras, T., Chandrasekhar, A., McCoy, L. et al. Selective Sensory Axon Reinnervation and TRPV1 Activation. Mol Neurobiol 56, 7144–7158 (2019). https://doi.org/10.1007/s12035-019-1574-6

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