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

• Published in: PloS one Vol. 11; no. 4; p. e0152405
• Main Authors: Alexandrou, Aristos J, Brown, Adam R, Chapman, Mark L, Estacion, Mark, Turner, Jamie, Mis, Malgorzata A, Wilbrey, Anna, Payne, Elizabeth C, Gutteridge, Alex, Cox, Peter J, Doyle, Rachel, Printzenhoff, David, Lin, Zhixin, Marron, Brian E, West, Christopher, Swain, Nigel A, Storer, R Ian, Stupple, Paul A, Castle, Neil A, Hounshell, James A, Rivara, Mirko, Randall, Andrew, Dib-Hajj, Sulayman D, Krafte, Douglas, Waxman, Stephen G, Patel, Manoj K, Butt, Richard P, Stevens, Edward B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06-04-2016; Public Library of Science (PLoS)
• Subjects: Action potential; Action Potentials; Anesthesiology; Animals; Axons; Axons - physiology; Biology and Life Sciences; Brown, Mark; Conduction; Dorsal horn; Ganglia, Spinal - drug effects; Ganglia, Spinal - physiology; Genetic aspects; HEK293 Cells; Humans; Inhibitors; Male; Medical schools; Medicine and Health Sciences; Mice; Mutation; NAV1.7 Voltage-Gated Sodium Channel - drug effects; NAV1.7 Voltage-Gated Sodium Channel - physiology; Nerve conduction; Neurons; Neurosciences; Nociceptors; Pain; Pain perception; Patch-Clamp Techniques; Pharmaceutical sciences; Phenyl Ethers - pharmacology; Physical Sciences; Physiological aspects; Presynaptic Terminals - physiology; Propagation; Research and analysis methods; Rodents; Signal transmission; Signaling; Skin; Social Sciences; Sodium; Sodium channels (voltage-gated); Spinal cord; Studies; Sulfonamides - pharmacology; Synaptic transmission; Tetrodotoxin; Veterans; United States; North Carolina; United Kingdom > UK; United States > US; Virginia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0152405

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.