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Anesthesiology and Pain Management - Neurological Disorders - Neuroscience - Physiology

Role of Peptidergic Nerve Terminals in the Skin: Reversal of Thermal Sensation by Calcitonin Gene-Related Peptide in TRPV1-Depleted Neuropathy
Published: Tuesday, November 27, 2012
Author: Yu-Lin Hsieh et al.

by Yu-Lin Hsieh, Chih-Lung Lin, Hao Chiang, Yaw-Syan Fu, June-Horng Lue, Sung-Tsang Hsieh

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.