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

Yu-Lin Hsieh,Yaw-Syan Fu,Hao Chiang,Chih-Lung Lin,Sung-Tsang Hsieh,June-Horng Lue,Alice Y W Chang

doi:10.1371/journal.pone.0050805

Abstract

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.

Highlights

Neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) are presumably responsible for transmitting nociceptive stimuli from sensory nerve terminals of the skin
Thermal hypoalgesia existed from RTX-treatment day 7 (RTXd7) to RTXd49 (15.565.3 s, p,0.01) and hot-plate withdrawal latencies had become normalized on RTXd56 (12.363.0 s, p.0.05) through RTXd84, the end point of the study period (11.363.5 s, p.0.05) (Fig. 1)
Differential Depletion of SP(+) and CGRP(+) dorsal root ganglion (DRG) Neurons To understand the effects of RTX on peptidergic neurons, we examined the co-expressions of neuropeptides with transient receptor potential vanilloid subtype 1 (TRPV1) on DRG neurons

Summary

Introduction

Neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) are presumably responsible for transmitting nociceptive stimuli from sensory nerve terminals of the skin. Nerve terminals of CGRP and SP phenotypes in the skin belong to smalldiameter neurons, the soma of which are located in dorsal root ganglia (DRGs) These neurons express transient receptor potential vanilloid subtype 1 (TRPV1) [8], which can be depleted by an ultrapotent capsaicin agonist, resiniferatoxin (RTX) [9,10]. To investigate pathophysiology of small-fiber sensory neuropathy, we and other groups previously established a system of RTXinduced neuropathy with thermal hypoalgesia due to cutaneous nerve terminal degeneration, peptidergic nerve terminals [11,12,13,14] In this model, there is a lack of systematic studies investigating the relationship between TRPV1 and neuropeptides and the influence of such changes on nociceptive functions after RTX-induced neuropathy, including the peptidergic profiles in DRG neurons and molecules compensating for the loss of TRPV1(+) neurons

Methods

Results

Conclusion