Selective keratinocyte stimulation is sufficient to evoke nociception in mice

Pain. 2015 Apr;156(4):656-665. doi: 10.1097/j.pain.0000000000000092.


The skin epidermis is densely innervated by peripheral sensory nerve endings. Nociceptive neurons, whose terminals are in close contact with epidermal keratinocytes, can be activated directly by noxious physical and chemical stimuli to trigger pain. However, whether keratinocytes can signal acutely to sensory nerve terminals to initiate pain in vivo remains unclear. Here, using the keratin 5 promoter to selectively express the capsaicin receptor TRPV1 in keratinocytes of TRPV1-knockout mice, we achieved specific stimulation of keratinocytes with capsaicin. Using this approach, we found that keratinocyte stimulation was sufficient to induce strong expression of the neuronal activation marker, c-fos, in laminae I and II of the ipsilateral spinal cord dorsal horn and to evoke acute paw-licking nocifensive behavior and conditioned place aversion. These data provide direct evidence that keratinocyte stimulation is sufficient to evoke acute nociception-related responses.

Publication types

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

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Capsaicin / pharmacology
  • Cells, Cultured
  • Conditioning, Operant / drug effects
  • Estrogen Antagonists / pharmacology
  • Female
  • Gene Expression Regulation / drug effects
  • Keratinocytes / drug effects
  • Keratinocytes / physiology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Pathways / drug effects
  • Neural Pathways / physiology*
  • Nociception / drug effects
  • Nociception / physiology*
  • Pain Measurement / drug effects
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / physiology*
  • Spinal Cord / metabolism
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Time Factors


  • Estrogen Antagonists
  • Luminescent Proteins
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Tamoxifen
  • afimoxifene
  • Calcitonin Gene-Related Peptide
  • Capsaicin