TTX-R and TTX-S Sodium Channels in CGRP-Positive Dorsal Root Ganglia Neurons Mediate Referred Somatic Hyperalgesia in Ulcerative Colitis Mice.

BACKGROUND

Ulcerative colitis (UC) frequently co-exists with referred somatic hyperalgesia in clinical presentations. However, the peripheral neurophysiological mechanisms of visceral referred pain remain unclear. This study aimed to clarify the neurobiological mechanisms that underpin the referred somatic hyperalgesia associated with UC.

METHODS

A UC mouse model was constructed via the administration of dextran sulfate sodium (DSS). Referred somatic regions in these mice were identified by measuring the number of Evans blue extravasations and pain threshold levels. Electrophysiological and immunofluorescent staining approaches were applied to evaluate the alterations in kinetic properties and expression of TTX-R (Nav1.8) and TTX-S (Nav1.7) channels in calcitonin gene-related peptide (CGRP)-positive dorsal root ganglion (DRG) neurons in the referred regions. Pharmacological methods were utilized to elucidate the necessary role of the Nav1.8 and Nav1.7 channels in somatic referred hyperalgesia.

KEY

RESULTS

Oral administration of DSS to mice for 7 days resulted in significant colon damage, neurogenic inflammation, and referred somatic hyperalgesia. The mechanisms underlying these effects may involve the activation of TTX-R and TTX-S channels, and the upregulation of co-expressed Nav1.8 and Nav1.7 with CGRP, resulting in an increased excitability of CGRP+ DRG neurons in sensitized regions. Selectively inhibiting either Nav1.8 or Nav1.7 channels could mitigate the referred somatic hyperalgesia induced by DSS.

CONCLUSIONS AND INFERENCES: The functional alterations in Nav1.8 and Nav1.7 channels within CGRP+ DRG neurons are pivotal to the development of neurogenic inflammation and referred somatic hyperalgesia. These findings lay a foundation for exploring novel therapeutic targets to relieve visceral referred pain.