Amplified cold transduction in native nociceptors by M-channel inhibition

J Neurosci. 2013 Oct 16;33(42):16627-41. doi: 10.1523/JNEUROSCI.1473-13.2013.

Abstract

Topically applied camphor elicits a sensation of cool, but nothing is known about how it affects cold temperature sensing. We found that camphor sensitizes a subpopulation of menthol-sensitive native cutaneous nociceptors in the mouse to cold, but desensitizes and partially blocks heterologously expressed TRPM8 (transient receptor potential cation channel subfamily M member 8). In contrast, camphor reduces potassium outward currents in cultured sensory neurons and, in cold nociceptors, the cold-sensitizing effects of camphor and menthol are additive. Using a membrane potential dye-based screening assay and heterologously expressed potassium channels, we found that the effects of camphor are mediated by inhibition of Kv7.2/3 channels subtypes that generate the M-current in neurons. In line with this finding, the specific M-current blocker XE991 reproduced the cold-sensitizing effect of camphor in nociceptors. However, the M-channel blocking effects of XE991 and camphor are not sufficient to initiate cold transduction but require a cold-activated inward current generated by TRPM8. The cold-sensitizing effects of XE991 and camphor are largest in high-threshold cold nociceptors. Low-threshold corneal cold thermoreceptors that express high levels of TRPM8 and lack potassium channels are not affected by camphor. We also found that menthol--like camphor--potently inhibits Kv7.2/3 channels. The apparent functional synergism arising from TRPM8 activation and M-current block can improve the effectiveness of topical coolants and cooling lotions, and may also enhance TRPM8-mediated analgesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Camphor / pharmacology
  • Cold Temperature
  • Female
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism
  • Male
  • Menthol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Nerve Fibers, Unmyelinated / drug effects
  • Nerve Fibers, Unmyelinated / metabolism
  • Nociceptors / metabolism
  • Nociceptors / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*
  • Thermoreceptors / metabolism
  • Thermoreceptors / physiology*
  • Thermosensing / drug effects
  • Thermosensing / physiology*

Substances

  • TRPM Cation Channels
  • TRPM8 protein, mouse
  • Menthol
  • Camphor