Role of peptidergic nerve terminals in the skin: reversal of thermal sensation by calcitonin gene-related peptide in TRPV1-depleted neuropathy

PLoS One. 2012;7(11):e50805. doi: 10.1371/journal.pone.0050805. Epub 2012 Nov 27.


To investigate the contribution of peptidergic intraepidermal nerve fibers (IENFs) to nociceptive responses after depletion of the thermal-sensitive receptor, transient receptor potential vanilloid subtype 1 (TRPV1), we took advantage of a resiniferatoxin (RTX)-induced neuropathy which specifically affected small-diameter dorsal root ganglion (DRG) neurons and their corresponding nerve terminals in the skin. Thermal hypoalgesia (p<0.001) developed from RTX-treatment day 7 (RTXd7) and became normalized from RTXd56 to RTXd84. Substance P (SP)(+) and TRPV1(+) neurons were completely depleted (p = 0.0001 and p<0.0001, respectively), but RTX had a relatively minor effect on calcitonin gene-related peptide (CGRP)(+) neurons (p = 0.029). Accordingly, SP(+) (p<0.0001) and TRPV1(+) (p = 0.0008) IENFs were permanently depleted, but CGRP(+) IENFs (p = 0.012) were only transiently reduced and had recovered by RTXd84 (p = 0.83). The different effects of RTX on peptidergic neurons were attributed to the higher co-localization ratio of TRPV1/SP than of TRPV1/CGRP (p = 0.029). Thermal hypoalgesia (p = 0.0018) reappeared with an intraplantar injection of botulinum toxin type A (botox), and the temporal course of withdrawal latencies in the hot-plate test paralleled the innervation of CGRP(+) IENFs (p = 0.0003) and CGRP contents in skin (p = 0.01). In summary, this study demonstrated the preferential effects of RTX on depletion of SP(+) IENFs which caused thermal hypoalgesia. In contrast, the skin was reinnervated by CGRP(+) IENFs, which resulted in a normalization of nociceptive functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism*
  • Ganglia, Spinal / cytology
  • Immunohistochemistry
  • Male
  • Mice
  • Neurons / metabolism
  • Skin / innervation*
  • Skin / metabolism*
  • TRPV Cation Channels / metabolism*
  • Thermosensing / physiology


  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Calcitonin Gene-Related Peptide

Grant support

This work was supported by grants from the National Health Research Institute (NHRIEX98-9736NI), the National Science Council (NSC97-2320-B-002-042-MY3 and NSC100-2320-B-037-018), the Excellent Translational Medicine Research Projects of National Taiwan University Medical Center and National Taiwan University Hospital (98C101-201), and Kaohsiung Medical University Research Foundation (KMU-Q098015, KMUQ099005, and KMU-M100004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.