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PLoS One. 2016 Apr 6;11(4):e0152405. doi: 10.1371/journal.pone.0152405. eCollection 2016.

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

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Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
Pfizer Neusentis, 4222 Emperor Boulevard, Durham, North Carolina, 27703, United States of America.
Center for Neuroscience & Regeneration Research, Yale Medical School and Veterans Affairs Hospital, West Haven, CT, 06516, United States of America.
Pfizer Global R&D, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom.
Worldwide Medicinal Chemistry, Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
Dept. Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, 22911, United States of America.
Medical School, Hatherly Building, University of Exeter, Prince of Wales Road, Exeter, EX4 4PS, United Kingdom.


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.

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