Nature’s epidural: Genetic variant may explain why some women don’t need pain relief during childbirth

cjb250 — Tue, 21 Jul 2020 15:00:21 +0000

Childbirth is widely recognised as a painful experience. However, every woman’s experience of labour and birth is unique, and the level of discomfort and pain experienced during labour varies substantially between women.

A collaboration between clinicians and scientists based at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH), and the ̽��ֱ�� of Cambridge sought to investigate why some mothers report less pain during labour.

A group of women was recruited and characterised by the team led by Dr Michael Lee from the ̽��ֱ��’s Division of Anaesthesia. All the women had carried their first-born to full term and did not request any pain relief during an uncomplicated vaginal delivery. Dr Lee and colleagues carried out a number of tests on the women, including applying heat and pressure to their arms and getting them to plunge their hands into icy water.

Compared to a control group of women that experienced similar births, but were given pain relief, the test group showed higher pain thresholds for heat, cold and mechanical pressure, consistent with them not requesting pain relief during childbirth. ̽��ֱ��researchers found no differences in the emotional and cognitive abilities of either group, suggesting an intrinsic difference in their ability to detect pain.

“It is unusual for women to not request gas and air, or epidural for pain relief during labour, particularly when delivering for the first time,” said Dr Lee, joint first author. “When we tested these women, it was clear their pain threshold was generally much higher than it was for other women.”

Next, senior co-author, Professor Geoff Woods, and his colleagues at the Cambridge Institute for Medical Research sequenced the genetic code of both groups of women and found that those in the test group had a higher-than-expected prevalence of a rare variant of the gene KCNG4. It’s estimated that one approximately 1 in 100 women carry this variant.

KCNG4 provides the code for the production of a protein that forms part of a ‘gate’, controlling the electric signal that flows along our nerve cells. As the joint first author Dr Van Lu showed, sensitivity of this gatekeeper to electric signals that had the ability to open the gate and turn nerves on was reduced by the rare variant.

This was confirmed in a study involving mice led by Dr Ewan St. John Smith from the Department of Pharmacology, who showed that the threshold at which the ‘defective’ gates open, and hence the nerve cell switches ‘on’, is higher – which may explain why women with this rare gene variant experience less pain during childbirth.

Dr St. John Smith, senior co-author, explained: “ ̽��ֱ��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 labour – to switch it on. This makes it less likely that pain signals can reach the brain.”

“Not only have we identified a genetic variant in a new player underlying different pain sensitivities,” added senior co-author Professor Frank Reimann, “but we hope this can open avenues to the development of new drugs to manage pain.”

“This approach of studying individuals who show unexpected extremes of pain experience also may find wider application in other contexts, helping us understand how we experience pain and develop new drugs to treat it,” said Professor David Menon, senior co-author.

̽��ֱ��research was support by the Addenbrooke’s Charitable Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome, Rosetrees Trust and the BBSRC.

Reference
Lee, M.C. et al (2020). Human labour pain is influenced by the voltage-gated potassium channel Kv6.4 subunit. Cell Reports; 21 July 2020; DOI: 10.1016/j.celrep.2020.107941

Women who do not need pain relief during childbirth may be carriers of a key genetic variant that acts a natural epidural, say scientists at the ̽��ֱ�� of Cambridge. In a study published today in the journal Cell Reports, the researchers explain how the variant limits the ability of nerve cells to send pain signals to the brain.

This [variant] acts like a natural epidural. It means it takes a much greater signal – in other words, stronger contractions during labour – to switch it on. This makes it less likely that pain signals can reach the brain

Ewan St. John Smith

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Mother and newborn baby

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‘Pain sensing’ gene discovery could help in development of new methods of pain relief

cjb250 — Mon, 25 May 2015 15:00:29 +0000

Pain perception is an evolutionarily-conserved warning mechanism that alerts us to dangers in the environment and to potential tissue damage. However, rare individuals – around one in a million people in the UK – are born unable to feel pain. These people accumulate numerous self-inflicted injuries, often leading to reduced lifespan.

Using detailed genome mapping, two teams of researchers collaborated to analyse the genetic make-up of 11 families across Europe and Asia affected by an inherited condition known as congenital insensitivity to pain (CIP). This enabled them to pinpoint the cause of the condition to variants of the gene PRDM12. Family members affected by CIP carried two copies of the variant; however, if they had only inherited one copy from their parents, they were unaffected.

̽��ֱ��team looked at nerve biopsies taken from the patients to see what had gone wrong and found that particular pain-sensing neurons were absent. From these clinical features of the disease, the team predicted that there would be a block to the production of pain-sensing neurons during the development of the embryo – they confirmed this using a combination of studies in mouse and frog models, and in human induced pluripotent stem cells (skin cells that had been reset to their ‘master state’, which enables them to develop into almost any type of cell in the body).

PRDM12 had previously been implicated in the modification of chromatin, a small molecule that attaches to our DNA and acts like a switch to turn genes on and off (an effect known as epigenetics). ̽��ֱ��researchers showed that all the genetic variants of PRDM12 in the CIP patients blocked the gene's function. As chromatin is particularly important during formation of particular specialised cell types such as neurons, this provides a possible explanation for why pain-sensing neurons do not form properly in the CIP patients.

" ̽��ֱ��ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception," says Professor Geoff Woods from the Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge, who co-led the study. "Both are equally important to the development of new pain treatments – if we know the mechanisms that underlie pain sensation, we can then potentially control and reduce unnecessary pain."

PRDM12 is only the fifth gene related to lack of pain perception to have been identified to date. However, two of the previously-discovered genes have already led to the development of new pain killers that are currently been tested in clinical trials.

"We are very hopeful that this new gene could be an excellent candidate for drug development, particularly given recent successes with drugs targeting chromatin regulators in human disease," adds Dr Ya-Chun Chen from the ̽��ֱ�� of Cambridge, the study’s first author. "This could potentially benefit those who are at danger from lack of pain perception and help in the development of new treatments for pain relief."

Reference
Chen, Y-C et al. Transcriptional regulator PRDM12 is essential for human pain perception. Nature Genetics; 25 May 2015.

A gene essential to the production of pain-sensing neurons in humans has been identified by an international team of researchers co-led by the ̽��ֱ�� of Cambridge. ̽��ֱ��discovery, reported today in the journal Nature Genetics, could have implications for the development of new methods of pain relief.

̽��ֱ��ability to sense pain is essential to our self-preservation, yet we understand far more about excessive pain than we do about lack of pain perception

Geoff Woods

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̽��ֱ��Gift of Pain (cropped and distorted)

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̽��ֱ�� of Cambridge - Geoff Woods

Nature’s epidural: Genetic variant may explain why some women don’t need pain relief during childbirth

‘Pain sensing’ gene discovery could help in development of new methods of pain relief