• Guangyou Duan, Chongyang Han, Qingli Wang, Shanna Guo, Yuhao Zhang, Ying Ying, Penghao Huang, Li Zhang, Lawrence Macala, Palak Shah, Mi Zhang, Ningbo Li, Sulayman D Dib-Hajj, Stephen G Waxman, and Xianwei Zhang.
• Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China.
• Mol Pain. 2016 Jan 1; 12.

BackgroundNav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined.ResultsCandidate single nucleotide polymorphism association approach together with experimental pain testing in human subjects was used to explore possible common SCN10A missense variants that might affect human pain sensitivity. We demonstrated an association between rs6795970 (G > A; p.Ala1073Val) and higher thresholds for mechanical pain in a discovery cohort (496 subjects) and confirmed it in a larger replication cohort (1005 female subjects). Functional assessments showed that although the minor allele shifts channel activation by -4.3 mV, a proexcitatory attribute, it accelerates inactivation, an antiexcitatory attribute, with the net effect being reduced repetitive firing of dorsal root ganglion neurons, consistent with lower mechanical pain sensitivity.ConclusionsAt the association and mechanistic levels, the SCN10A single nucleotide polymorphism rs6795970 biases human pain sensitivity.© The Author(s) 2016.

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