Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release

PLoS ONE, 2016 · DOI: 10.1371/journal.pone.0152405 · Published: April 6, 2016

Simple Explanation

This study investigates the role of Nav1.7, a sodium channel, in pain sensation using selective inhibitors. Researchers found that Nav1.7 is crucial for initiating and conducting electrical signals in pain-sensing neurons. The research confirms Nav1.7's involvement in transmitting signals in the spinal cord and releasing neuropeptides in the skin, highlighting its multiple contributions to pain signaling. By using specific inhibitors, the study sheds light on how Nav1.7 contributes to both peripheral and central transmission of noxious signals, offering a mechanistic basis for its role in pain.

Study Duration

Not specified

Participants

Mice and human DRG samples

Evidence Level

Not specified

Key Findings

1
Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors, contributing to the initiation and upstroke phase of the nociceptor action potential.
2
Nav1.7 influences synaptic transmission in the dorsal horn of the spinal cord, as well as peripheral neuropeptide release in the skin.
3
Selective Nav1.7 inhibitors, PF-05198007 and PF-05089771, demonstrate high potency and a high degree of Nav subtype selectivity.

Research Summary

This study identifies and characterizes two potent and selective arylsulfonamide Nav1.7 inhibitors, PF-05198007 and PF-05089771, to investigate Nav1.7's role in nociceptor physiology. The findings demonstrate that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and is involved in action potential initiation and upstroke. The study also confirms Nav1.7's role in synaptic transmission in the spinal cord's dorsal horn and peripheral neuropeptide release, providing a mechanistic basis for its contribution to pain signaling.

Practical Implications

Analgesic Development

Selective Nav1.7 inhibitors might hold therapeutic potential as novel analgesics.

Targeted Pain Treatment

Understanding Nav1.7's specific roles can lead to more targeted pain therapies.

Nociceptor Function

Further research on Nav1.7 can improve our understanding of nociceptor signaling in acute and chronic pain states.

Study Limitations

1
Lack of validated heterologous expression system for Nav1.9 prohibited evaluation of the potency of PF-05089771 against this channel
2
Study focused on specific Nav1.7 inhibitors; other mechanisms may also be relevant
3
In vivo studies were limited to the capsaicin flare response; other pain models may yield different results

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