The Effect Of SCN10A Polymorphism On Human Pain Sensitivity In The General Population And Its Mechanism

BackgroundThe biophysical properties of Nav1.8, encoded by SCN10A, its critical role in repetitive firing, and its presence in free nerve endings, suggest that Navl.8 can significantly influence excitability of nociceptor especially dorsal root ganglion (DRG) neurons, thus contributing to pain. Indeed, relatively rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies. However, whether more common variants in SCN10A can have an effect at the channel level and at the DRG neuronal level leading to a pain disorder or an altered normal pain threshold have not been determined. This study aimed to explore the possible associations of two SCN10A single nucleotide polymorphism (SNPs), whose minor allele causes a non-synonymous substitution, and human pain sensitivity and tested its possible function in DRG neurons.MethodsFirst, we enrolled 508 healthy undergraduates of Han Chinese ethnic origin in the primary study to explore possible associations of the SCN10A SNPs with experimental mechanical and heat pain sensitivity. Following informed consent, we measured dull pressure pain threshold and tolerance (D-PPT and D-PTO), sharp pressure pain threshold and tolerance (S-PPT and S-PTO), and quantitative pricking pain threshold (QPT) to assess the subjects'mechanical pain sensitivity. Withdrawal latency time (WLT) was measured to evaluate heat pain sensitivity. Genotyping of the SCN10A SNPs for all subjects was performed using ligase detection reactions. Second, we included 1025 female patient subjects with experimental mechanical pain sensitivity testing for replication the primary results. Then we tested the hypothesis that the positive SNP may alter channel properties and firing properties of DRG neurons through voltage and current clamp experiments.ResultsIn the primary sample, the subjects who carried the minor homozygote allele of rs6795970 showed higher D-PPT and D-PTO (P< 0.05) than those who carried major homozygote or heterozygote alleles, whereas the other three types of mechanical pain measures showed non-significant but similar trends. The replication study showed that the mean mechanical pain thresholds in carriers of the minor homozygote allele were higher than those in carriers of the other genotypes, indicating that minor allele of rs6795970 is associated with a decrease in human mechanical pain sensitivity. The significance values (P values) for the differences of D-PPT and S-PPT between carriers of the minor homozygote alleles and those with the two other genotypes in the replication cohort reached (1.7-2.4) x10-4and (7.6-7.8)×10-6. No other SNP was found to have significant association with pain sensitivity in both two populations. In the electrophysiological analysis, although compared to major allele (Navl.8-Ala 1073) the minor allele (Nav1.8-Val 1073) shifts channel activation by-4.3 mV, a pro-excitatory attribute, it accelerates inactivation and decreases persistent currents, both anti-excitatory attributes, with the net effect being reduced repetitive firing of DRG neurons, consistent with higher thresholds for mechanical pain in the general population.ConclusionsOur results support a role for Navl.8 not only in pathological pain conditions, but also in modulating human pain sensitivity in the general population. Demonstration of a role of this common variant in biasing pain sensitivity may facilitate the deep insight of the mechanism of individualized pain, and support targeting of this channel for treatment of pain.