NaV1.1 inhibition can reduce visceral hypersensitivity

Area of Science:

• Neuroscience
• Gastroenterology
• Pharmacology

Background:

• Functional bowel disorders often involve chronic abdominal pain due to visceral hypersensitivity.
• Current treatments for this pain are varied and not always effective, highlighting a need for better understanding and targeted therapies.

Purpose of the Study:

• To investigate the role of the voltage-gated sodium channel subtype 1.1 (NaV1.1) in chronic visceral hypersensitivity (CVH) and associated abdominal pain.
• To determine if inhibiting NaV1.1 can alleviate pain in preclinical models of functional bowel disorders.

Main Methods:

• Utilized three distinct mouse models of chronic pain.
• Examined the functional expression and activity of NaV1.1 in sensory neurons.
• Administered a selective NaV1.1 inhibitor and assessed its effects on neuronal excitability and pain behaviors.

Main Results:

• NaV1.1 was found to be functionally upregulated in conditions mimicking CVH.
• Selective inhibition of NaV1.1 reduced sodium currents in colon-innervating neurons.
• NaV1.1 inhibition decreased mechanical responses in colonic nociceptors and normalized pain responses in irritable bowel syndrome models.

Conclusions:

• NaV1.1 channel activity is implicated in the development and maintenance of chronic abdominal pain associated with functional bowel disorders.
• Targeting NaV1.1 represents a promising therapeutic strategy for managing pain in these conditions.