Promotion of thermal analgesia and neuropeptidergic skin reinnervation by 4‐methylcatechol in resiniferatoxin‐induced neuropathy

Abstract

To investigate whether 4-methylcatechol (4MC) could decrease the duration of the thermosensation disorder and promote the innervation of peptidergic intraepidermal nerve fibers (IENFs), we developed a resiniferatoxin (RTX)-induced neuropathic mouse model with thermal analgesia and skin denervation that was followed by daily 4MC treatment. On day 7 after RTX administration (RTXd7), the substance P (SP)(+) IENFs were completely depleted compared with the vehicle group (p < 0.0001), whereas the calcitonin gene-related peptide (CGRP)(+) IENFs were dramatically, but not completely, depleted (p < 0.0001). While SP(+) IENFs remained depleted (p = 0.0043), CGRP(+) IENFs were recovered by RTXd84 (p = 0.78). 4MC had no effect on the reinnervation of SP(+) IENFs, but markedly promoted the reinnervation of CGRP(+) IENFs on RTXd35 (p = 0.035). On RTXd56, CGRP(+) IENFs were comparable with the vehicle group (p = 0.39). In addition, 4MC normalized thermal analgesia on RTXd35 compared with RTX group (p = 0.007). In the current study, the significant promotion of reinnervation of CGRP(+) IENFs and thermal latencies on RTXd35 by 4MC indicated that CGRP(+) IENFs were responsible for the thermal transmission in chronic phase of RTX-induced neuropathy.

Establishing a Mouse Model of a Pure Small Fiber Neuropathy with the Ultrapotent Agonist of Transient Receptor Potential Vanilloid Type 1

“…Moreover, this current model induced the typical neuropathology and neuropathic pain profile of small fiber neuropathy and the effects lasted for 8 weeks post RTX treatment 6,18,19 . The durations of neuropathology and neuropathic pain were equivalent and could be reversed by promoting the synthesis of nerve growth factor (NGF) 18,40,41 . Collectively, this protocol both established a pure small fiber neuropathy model and highlighted the possible therapeutic potential of NGF.…”

Transient receptor potential vanilloid subtype 1 depletion mediates mechanical allodynia through cellular signal alterations in small-fiber neuropathy

“…Notably, the neurophysiological functions of small-diameter nociceptors depend on the regulation of neurotrophin signals; the reinnervation of CGRP (+) peptidergic IENFs normalizes the thermal noxious sensation that underlies the activation of NGF-TrkA signaling. 48 , 52 , 53 TrkA is the high-affinity receptor of NGF that regulates the neurophysiological functions of peptidergic nociceptors. NGF-TrkA signaling also regulates the neurophysiological functions of nonpeptidergic PAP (+) nociceptors through high PAP/TrkA colocalization ratios (approximately 70%).…”