Selective Sensory Axon Reinnervation and TRPV1 Activation
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.
KeywordsPeripheral nerve Regeneration Capsaicin TRPV1 Sensory neurons
Dr. Matt Larouche and Twinkle Joy provided valuable technical assistance.
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.
Compliance with Ethical Standards
The protocols were reviewed and approved by the Animal Care Committee University of Alberta, adhering to guidelines of the Canadian Council of Animal Care.
- 10.Frey E, Karney-Grobe S, Krolak T, Milbrandt J, DiAntonio A (2018) TRPV1 agonist, capsaicin, induces axon outgrowth after injury via Ca(2+)/PKA signaling. eNeuro 5(3)Google Scholar
- 11.Krishnan A, Purdy K, Chandrasekhar A, Martinez J, Cheng C, Zochodne DW (2017) A BRCA1-dependent DNA damage response in the regenerating adult peripheral nerve milieu. Mol Neurobiol 55:4051–4067Google Scholar
- 18.Cheng C, Guo GF, Martinez JA, Singh V, Zochodne DW (2010) Dynamic plasticity of axons within a cutaneous milieu. J Neurosci 30:13735–13744Google Scholar
- 25.Elitt CM, McIlwrath SL, Lawson JJ, Malin SA, Molliver DC, Cornuet PK, Koerber HR, Davis BM et al (2006) Artemin overexpression in skin enhances expression of TRPV1 and TRPA1 in cutaneous sensory neurons and leads to behavioral sensitivity to heat and cold. J Neurosci 26:8578–8587CrossRefGoogle Scholar
- 33.Al-Majed AA, Neumann CM, Brushart TM, Gordon T (2000) Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J Neurosci 20:2602–2608Google Scholar