Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel K V 6.4 Subunit

By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4. The rare variant K 6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of K 2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (K 6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express K 2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a. In neurons overexpressing K 6.4-Met419, the voltage dependence of inactivation for K 2.1 is more depolarized compared with neurons overexpressing K 6.4. Finally, K 6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that K 6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.