title: Role of peptidergic nerve terminals in the skin: reversal of thermal sensation by calcitonin gene-related peptide in TRPV1-depleted neuropathy.
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.
authors.affiliation: Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Hsieh
authors.forename: Chih-Lung
authors.initials: CL
authors.lastname: Lin
authors.forename: Hao
authors.initials: H
authors.lastname: Chiang
authors.forename: Yaw-Syan
authors.initials: YS
authors.lastname: Fu
authors.forename: June-Horng
authors.initials: JH
authors.lastname: Lue
authors.forename: Sung-Tsang
authors.initials: ST
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D012867:Skin / Q000294:innervation* / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*; D013697:Thermosensing / Q000502:physiology
chemical_list: D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D015740:Calcitonin Gene-Related Peptide