Abstract
SummaryBy 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 KV6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of KV2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (KV6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express KV2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a. In neurons overexpressing KV6.4-Met419, the voltage dependence of inactivation for KV2.1 is more depolarized compared with neurons overexpressing KV6.4. Finally, KV6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that KV6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.
Highlights
All eutherians experience contraction of the uterus and discomfort during parturition
We found that the voltage-gated potassium channel (KV) modifier KCNG4 (KV6.4) single nucleotide polymorphisms (SNPs) rs140124801 rare allele c.1255G>A p.(Val419Met) was over-represented
There are clearly other reasons for an increased cuff pressure pain threshold in individuals who do not carry the rare KCNG4 allele, these data suggest that the rare allele of KCNG4 may be related to the lack of analgesic requirement for the 3 subjects we identified in this study
Summary
All eutherians (placental mammals) experience contraction of the uterus and discomfort during parturition. This discomfort is universal in eutherians, it appears to be most marked in humans (Maul, 2007). Women with the very rare Mendelian disorder congenital insensitivity to pain due to bi-allelic non-functional mutations in SCN9A (MIM: 243000) do not report labor pain or require analgesics during labor (Haestier et al., 2012). SCN9A encodes for the voltage-gated sodium channel NaV1.7, expressed selectively in nociceptive and autonomic neurons, and mutations in SCN9A have well-documented roles in causing extremely painful or painless phenotypes (Bennett et al, 2019). The painlessness conferred by loss-of-function SCN9A mutations is clearly maladaptive and can be associated with severe injury during human parturition (Wheeler et al, 2014)
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