A collaborative study by clinicians and scientists at Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge has explored the genetic underpinnings of pain in the context of childbirth. Their findings are published in the journal Cell Biology.
Pain is a complex phenomenon
Delivering a child is a complex and subjective experience that is different for every woman; there are various options for delivery methods, delivery locations, approaches to breathing and so on.
Regardless of these different variables, childbirth is widely recognized as ranking highly on the pain rating scale compared to other life experiences, and the fear of such pain can discourage women from wanting to carry and deliver a child.
The level of discomfort experienced during labor varies largely between individuals, with some requiring pain relief and others not. Pain is multifaceted – it has physiological and psychological components, and as such, it's quite tricky to research. Over recent years, scientists have gained a deeper understanding of pain at the molecular level, exploring which proteins and complexes are required for pain signals to be transmitted throughout the body, and how they work.
Genetics is important here. Our genetic code essentially acts as a blueprint which provides the instructions for these molecular workhorses to be built and to function. Variations in the genetic code can lead to variations in the subsequent proteins, which might alter their function. If these proteins are involved in pain signals, it can lead to variations in pain phenotypes, i.e. how much pain we feel compared to the next person.
Take the SCN9A gene, for example, which provides the blueprint for building a specific part of a sodium channel known as NaV1.7. This channel is found in nociceptors – the sensory neurons that transmit pain signals from the periphery to the brain. Several mutations in SCN9A have been identified as causing a congenital insensitivity to pain, in which a carrier of the mutation cannot physically perceive pain.
In a study published in Cell Biology a team of researchers led by Dr Michael Lee decided to explore how genetic variations might influence a mother's experience of pain during labor.
Exploring pain thresholds in labor
The researchers recruited a cohort of 189 women that had carried their first-born child to full term and did not request pain relief during their uncomplicated vaginal delivery. A control group were also recruited, comprising 33 women that were matched by age of delivery and location of maternity service, but who had decided to use analgesics during labor. Psychometric testing revealed no significant differences in psychological or cognitive measures between each group.
First, the researchers subjected the cohort to an array of tests that assessed their pain thresholds and tolerance. It revealed the test group had higher pain thresholds for heat, cold and mechanical pressure. “It is unusual for women to not request gas and air, or epidural for pain relief during labor, particularly when delivering for the first time,” said Lee in a press release. "When we tested these women, it was clear their pain threshold was generally much higher than it was for other women.” This data, coupled with the lack of significant difference in cognitive measures, suggested that the pain threshold variability was due to an intrinsic difference.
Nature's own analgesic?
The next step was genetic analysis, conducted by Geoff Woods and colleagues at the Cambridge Institute for Medical Research. Of the 189 women in the control group, 158 provided high-quality DNA that was subjected to genetic analysis. One hundred women formed the discovery cohort that underwent exome sequencing, and 58 were allocated to a replication cohort that underwent genome-wide single nucleotide polymorphism (SNP) frequency assessment.
Woods and team discovered that a rare allele (rs140124801) in the KCNG4 gene was over-represented in the discovery cohort, estimated to be carried by 1 in 100 women. There were four heterozygotes who possessed this rare allele in the women that had not required pain relief during labor, and quantitative sensory and pain testing were available for three of them. In the paper, the authors said: "We found that women who possess the rare allele showed a significantly increased cuff pressure pain threshold compared with controls."
The mechanism behind this increased pain threshold was next explored. KCNG4 is a gene that encodes the KV6.4 protein which acts as a "gate", controlling the electric signal flowing along our nerve cells that transmits pain. John Smith, senior co-author of the study commented, “The genetic variant that we found in women who feel less pain during childbirth leads to a “defect” in the formation of the switch on the nerve cells. In fact, this defect acts like a natural epidural. It means it takes a much greater signal – in other words, stronger contractions during labor – to switch it on. This makes it less likely that pain signals can reach the brain.”
New avenues for analgesics
In the paper, the authors note that their data warrants further exploration into pharmacological manipulation of KV6.4 – if the protein is druggable, it could be a potential target to modulate labor pain without side effects associated with other analgesic interventions.
“Not only have we identified a genetic variant in a new player underlying different pain sensitivities,” senior co-author Professor Frank Reimann said, “but we hope this can open avenues to the development of new drugs to manage pain.”
One potential caveat to the study is the fact that blinding was not a feasible option, and social desirability bias could explain the findings of overall increased threshold and tolerance to pain. However, the authors note that this bias might also be expected to lower scores in self-report measures, which was not observed.
The applications of this research may also expand beyond the realms of childbirth, as the authors explain in their discussion: "Our data also raise the question of whether KV6.4 has roles in other painful visceral disorders within and outside the female genital tract. One closely related context would be primary dysmenorrhea, which is characterized by severe pain associated with uterine contraction during menstruation."
Lee et al (2020). Human labour pain is influenced by the voltage-gated potassium channel Kv6.4 subunit. Cell Reports. DOI: 10.1016/j.celrep.2020.107941