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

• Published in: PloS one Vol. 7; no. 11; p. e50805
• Main Authors: Hsieh, Yu-Lin, Lin, Chih-Lung, Chiang, Hao, Fu, Yaw-Syan, Lue, June-Horng, Hsieh, Sung-Tsang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.11.2012; Public Library of Science (PLoS)
• Subjects: Analgesics; Animals; Biology; Botulinum toxin; Botulinum toxin type A; Calcitonin; Calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - metabolism; Capsaicin receptors; Depletion; Dorsal root ganglia; Ganglia, Spinal - cytology; Genes; Immunohistochemistry; Innervation; Laboratory animals; Localization; Male; Medicine; Mice; Migraine; Nerve endings; Neurons; Neurons - metabolism; Neuropathy; Neuropeptides; Pain; Pain perception; Peptides; Resiniferatoxin; Skin; Skin - innervation; Skin - metabolism; Studies; Substance P; Terminals; Thermosensing - physiology; Transient receptor potential proteins; TRPV Cation Channels - metabolism; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0050805

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.