Nav1.5 in the dorsal root ganglion plays a crucial role in mechanical hypersensitivity.

Voltage-gated sodium channels in primary sensory neurons are essential mediators of nociceptive signal transmission and represent promising therapeutic targets for pain management. Here, we demonstrate that Nav1.5, which is traditionally known to be a cardiac sodium channel, as a major determinant of mechanical sensitivity in the somatosensory system. Immunostaining and single-cell RNA sequencing analyses revealed that Nav1.5 is predominantly expressed in myelinated TrkB-positive A-fibre neurons within the dorsal root ganglion. Through conditional knockout studies, we found that Nav1.5 deletion in TrkB neurons or dorsal root ganglion tissue specifically impairs mechanical sensitivity while preserving other sensory and motor functions. Notably, Nav1.5 ablation significantly attenuated mechanical hypersensitivity in both neuropathic and visceral pain models. Mechanistically, Nav1.5 contributes to action potential generation and firing patterns in TrkB-positive neurons. In summary, these findings establish Nav1.5 as a critical regulator of mechanical hypersensitivity.