Published December 20, 2020
The American actress Danica McKellar, best known for her role as Winnie Cooper in the hit television series The Wonder Years, once said: “My hope is to go fully natural during childbirth – no epidural, no interventions. Wish me luck.” A recent study shows that luck of a sort – genetic luck, in this case – may indeed have something to do with whether childbirth is painful or not.
Research led by a collaboration at the University of Cambridge, UK, has identified a subset of women who have reduced pain during labor because of a mutation in a gene called KCNG4. This gene makes a protein, called Kv6.4, that controls the electrical excitability of nerve cells.
Taking this finding into animals to learn more, the researchers then found that the KCNG4 mutation made mouse sensory neurons in the uterus less sensitive to painful stimuli.
“This paper is a beautiful example of how interdisciplinary research can reveal something so fundamental as human labor pain,” said Rajesh Khanna, a pain researcher at the University of Arizona, US, who was not part of the study. “It is a landmark paper in its ability to show how a marriage of different fields – clinical, genetic, physiological, molecular – can come together to find a new gene mutation that explains a type of pain resilience in childbirth,” Khanna said.
The study was published on July 21, 2020, in the journal Cell Reports.
Resilience to labor pain in a lucky few
Geoffrey Woods, one of four senior study authors including Ewan St. John Smith, Frank Reimann, and David Menon, explained how the collaboration came together to find new genetic mutations that might explain differences people have in their experience of pain.
“Patients with pain insensitivity are very important to study pain mechanisms in humans, but because they are extremely rare, we wanted to look at more common variances of pain. We aimed to investigate if there were genetic predispositions that made people less likely to experience pain in common circumstances,” Woods said.
They chose to look for healthy women who did not require analgesia (pain relief) during full-term delivery of their firstborn child.
“From local health records, we estimated that about 1% of those women in the UK manages normal delivery without asking for Entonox or epidurals,” said Michael Lee, one of four lead authors on the paper. Entonox is an inhaled gas used for pain relief, and an epidural provides analgesia through an injection of medication into the space around the spinal cord.
The researchers managed to identify 189 participants for the genetic study. The group also examined whether experimental pain thresholds – when a person first reports pain in response to a stimulus such as heat or pressure – were increased in these women.
“We focused on somatic [body] pain thresholds because we didn’t have a visceral pain stimulus that mimics labor. I know colleagues who would happily put balloons up orifices to stimulate the viscera in animal models, but it is not something I wish to do in humans,” Lee said humorously. Visceral pain refers to pain coming from the body’s internal organs.
Strikingly, the results showed that women who did not require pain relievers during labor had elevated heat, cold and mechanical pain thresholds, meaning that it took more of each stimulus before the women reported pain. This suggests that these women had high thresholds to pain in general.
“It’s important that these women are healthy and performed the same as controls on cognitive and psychometric testing. The genetic mutation discovered seems to have analgesic effects only,” Lee added.
A genetic “hit” in KCNG4
The results raised the obvious question: Why did these women experience less pain? Was it psychological hardiness, or were there underlying genetic reasons?
Because of their expertise in genetics, the authors focused on possible genetic causes. They analyzed DNA sequences from the 189 participants who did not require analgesia during labor in the hope of identifying novel genes involved in pain. This led them to the mutation in the KCNG4 gene, in four individuals.
KCNG4 makes Kv6.4, which is a specialized protein known as a potassium channel that is present on the surface of neurons and boosts their electrical excitability (in general, increased excitability is thought to contribute to chronic pain). It turned out that the KCNG4 mutation found in the four patients caused Kv6.4 to lose its function.
This led the researchers to suspect that the mutation reduced electrical excitability. Laboratory work with a commonly used experimental line of human cells would show that the mutation did indeed dampen the excitability of these cells. Additional experiments would show that the mutant Kv6.4 remained stuck inside the cells, unable to make it to the cell surface.
To the mouse!
The researchers then thought that if the mutation decreased the electrical excitability of an experimental cell line, maybe it did the same in neurons that play a role in the pain system (in this case, cells called nociceptors) in animals; moving their research from so-called “cells in a (laboratory) dish” into live behaving animals would be necessary to support the idea.
So, the collaboration grew to include Ewan St. John Smith, who first asked whether Kv6.4 was present in nociceptors from the uterus of a mouse. The answer was yes.
The next question was to see what happened to the excitability of the nociceptors if they were genetically engineered to contain the mutated form of Kv6.4 the researchers had identified in their earlier experiments. As predicted, such cells from mice were indeed less electrically excitable than those with normal Kv6.4.
Together, the work from cells and animals provided an explanation for how the mutation in KCNG4 found in the four individuals caused reduced pain during labor, as Smith explained:
“The KCNG4 gene variant we identified produces a version of the Kv6.4 protein that remains stuck inside nociceptors, being unable to reach the nerve’s surface where it is required to function.”
“As a result,” Smith continued, “nociceptors are harder to switch on, which means that you need a greater stimulus to activate the nerve and produce a nociceptive signal. This is demonstrated by the fact that women with this gene variant, who requested no pain relief during childbirth, also had a higher threshold for pressure pain, that is, more pressure was needed to make them go, ‘ouch!’” Smith said.
Overall, Smith stressed that the findings from the new study could be a starting point to investigate and treat visceral pain.
“There wasn’t anything out there on how Kv6.4 might modulate pain sensation, let alone visceral pain. So maybe we could target Kv6.4 for other types of pain, particularly visceral pain, which is poorly treated compared to other types of pain. It’s another body of work to be done, but the starting point looks interesting,” Smith said.
Khanna agreed, further saying, “It would be interesting to see if these women [with the KCNG4 mutation] suffer as much from other visceral pain conditions like irritable bowel syndrome, and especially whether this is more present in women than men.”
If so, perhaps the luck of genetics would provide pain relief even well beyond the delivery room…
Fred Schwaller, PhD, is a freelance science writer based in Germany.
This story first appeared on the IASP Pain Research Forum and has been edited for RELIEF.