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.
Highlights
Numerous genetic studies implicate Nav1.7 in the pathogenesis of distinct pain states
Previous studies have suggested that Nav1.7 contributes to electrogenesis by increasing the probability that the cell will reach action potential threshold [24] [20] [25]
Nav1.7 has been suggested to amplify the generator potential at the peripheral terminals acting a s a threshold channel [24], we propose that another principal role for Nav1.7 in nociceptors is in action potential electrogenesis
Summary
Numerous genetic studies implicate Nav1.7 in the pathogenesis of distinct pain states (for reviews see [1] [2]). Expression of Nav1.7 in DRG neurons extends from the peripheral terminals in the skin to the central terminals in the dorsal horn [9]. These studies present a clear link between Nav1.7 function and pain sensation and raise the possibility that selective Nav1.7 inhibitors might hold therapeutic potential as novel analgesics. Despite the strong evidence implicating Nav1.7 in human pain genetic studies, a detailed investigation of the role of Nav1.7 in nociception remains an important area of investigation. Given the participation of multiple Navs in pain signalling, progress in delineating the individual roles of specific Nav isoforms in DRG neurons would be accelerated if subtype-selective inhibitors were available
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