Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release

Aristos J. Alexandrou, Adam R. Brown, Mark L. Chapman, Mark Estacion, Jamie Turner, Malgorzata A. Mis, Anna Wilbrey, Elizabeth C. Payne, Alex Gutteridge, Peter John Cox, Rachel Doyle, David Printzenhoff, Zhixin Lin, Brian E. Marron, Christopher West, Nigel A. Swain, R. Ian Storer, Paul A. Stupple, Neil A. Castle, James A. HounshellMirko Rivara, Andrew Randall, Sulayman D. Dib-Hajj, Douglas S. Krafte, Stephen G. Waxman, Manoj K. Patel, Richard P. Butt, Edward B. Stevens

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Abstract

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.

Original languageEnglish
Article numbere0152405
Number of pages22
JournalPLoS ONE
Volume11
Issue number4
DOIs
Publication statusPublished - 1 Apr 2016

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