Unraveling the Role of NaV1.7 in Visceral and Somatic Pain Pathways: Insights into Nociceptive Mechanisms

Voltage-gated sodium channels are crucial for neuronal excitability, with a specific subtype, NaV1.7, implicated in acute and inflammatory pain in mice and humans. However, the role of NaV1.7 in visceral pain has not been fully understood. This study investigates its involvement in visceral pain and the development of referred hyperalgesia using a knockout mouse model and a selective antagonist, PF-5198007.

The research utilized behavioral models to compare responses to both somatic and visceral pain. The knockout mice exhibited typical responses to noxious stimuli in visceral pain models, indicating that NaV1.7 does not play a role in visceral pain signaling. Additionally, nerve-gut preparations and human appendix tissue studies showed no effect on afferent responses when NaV1.7 was absent or blocked.

Expression analysis revealed the presence of NaV1.7 mRNA in colon neurons, suggesting a possible functional redundancy. In contrast, the same genetic deletion in somatic pain models showed that NaV1.7 does regulate the threshold for noxious heat pain, which was also observable with the use of the selective antagonist.

The findings indicate that NaV1.7 contributes to pain pathways in a modality-specific manner, affecting somatic pain but not visceral pain. This insight suggests that targeting NaV1.7 alone may not be effective for treating chronic visceral pain and highlights the need for a nuanced approach to pain research and drug development for novel visceral analgesics.