title: Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release.
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.
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Aristos J
authors.initials: AJ
authors.lastname: Alexandrou
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Brown
authors.affiliation: Pfizer Neusentis, 4222 Emperor Boulevard, Durham, North Carolina, 27703, United States of America.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Chapman
authors.affiliation: Center for Neuroscience & Regeneration Research, Yale Medical School and Veterans Affairs Hospital, West Haven, CT, 06516, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Estacion
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Jamie
authors.initials: J
authors.lastname: Turner
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Malgorzata A
authors.initials: MA
authors.lastname: Mis
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilbrey
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Payne
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Gutteridge
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cox
authors.affiliation: Pfizer Global R&D, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Doyle
authors.affiliation: Pfizer Neusentis, 4222 Emperor Boulevard, Durham, North Carolina, 27703, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Printzenhoff
authors.affiliation: Pfizer Neusentis, 4222 Emperor Boulevard, Durham, North Carolina, 27703, United States of America.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Pfizer Neusentis, 4222 Emperor Boulevard, Durham, North Carolina, 27703, United States of America.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Marron
authors.affiliation: Pfizer Neusentis, 4222 Emperor Boulevard, Durham, North Carolina, 27703, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: West
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Swain
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: R Ian
authors.initials: RI
authors.lastname: Storer
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Stupple
authors.affiliation: Pfizer Neusentis, 4222 Emperor Boulevard, Durham, North Carolina, 27703, United States of America.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Castle
authors.affiliation: Dept. Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, 22911, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: Hounshell
authors.affiliation: Dept. Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, 22911, United States of America.
authors.forename: Mirko
authors.initials: M
authors.lastname: Rivara
authors.affiliation: Medical School, Hatherly Building, University of Exeter, Prince of Wales Road, Exeter, EX4 4PS, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Randall
authors.affiliation: Center for Neuroscience & Regeneration Research, Yale Medical School and Veterans Affairs Hospital, West Haven, CT, 06516, United States of America.
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: Pfizer Neusentis, 4222 Emperor Boulevard, Durham, North Carolina, 27703, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Krafte
authors.affiliation: Center for Neuroscience & Regeneration Research, Yale Medical School and Veterans Affairs Hospital, West Haven, CT, 06516, United States of America.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.affiliation: Dept. Anesthesiology, University of Virginia Health System, Charlottesville, Virginia, 22911, United States of America.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Patel
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Butt
authors.affiliation: Pfizer Neusentis, The Portway Buiding, Granta Park, Great Abington, Cambridge, CB21 6GS, United Kingdom.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stevens
mesh_terms: D000200:Action Potentials; D000818:Animals; D001369:Axons / Q000502:physiology*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010647:Phenyl Ethers / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; D010647:Phenyl Ethers; D013449:Sulfonamides; C000618268:PF-05089771; D000096926:Benzenesulfonamides