TRPV1 activity and substance P release are required for corneal cold nociception

Nat Commun. 2019 Dec 12;10(1):5678. doi: 10.1038/s41467-019-13536-0.

Abstract

As a protective mechanism, the cornea is sensitive to noxious stimuli. Here, we show that in mice, a high proportion of corneal TRPM8+ cold-sensing fibers express the heat-sensitive TRPV1 channel. Despite its insensitivity to cold, TRPV1 enhances membrane potential changes and electrical firing of TRPM8+ neurons in response to cold stimulation. This elevated neuronal excitability leads to augmented ocular cold nociception in mice. In a model of dry eye disease, the expression of TRPV1 in TRPM8+ cold-sensing fibers is increased, and results in severe cold allodynia. Overexpression of TRPV1 in TRPM8+ sensory neurons leads to cold allodynia in both corneal and non-corneal tissues without affecting their thermal sensitivity. TRPV1-dependent neuronal sensitization facilitates the release of the neuropeptide substance P from TRPM8+ cold-sensing neurons to signal nociception in response to cold. Our study identifies a mechanism underlying corneal cold nociception and suggests a potential target for the treatment of ocular pain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cold Temperature
  • Cornea / metabolism*
  • Dry Eye Syndromes
  • Gene Expression Regulation
  • Hyperalgesia / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nociception / physiology*
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism*
  • Substance P / metabolism*
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Tamoxifen / pharmacology
  • Thermosensing / physiology*

Substances

  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Tamoxifen
  • Substance P