Genetic mutation causes low sensitivity to pain

A UCL-led research team has identified a rare mutation that causes one family to have unusually low sensitivity to pain. They studied an Italian family, the Marsilis, which includes six people who have a distinctive pain response that has not been identified in any other people. "The members of this family can burn themselves or experience pain-free bone fractures without feeling any pain. But they have a normal intraepidermal nerve fibre density, which means their nerves are all there, they're just not working how they should be. We're working to gain a better understanding of exactly why they don't feel much pain, to see if that could help us find new pain relief treatments," said the study's lead author, Dr James Cox (UCL Wolfson Institute for Biomedical Research).

One in ten people experience moderately to severely disabling chronic pain, but treatments beyond common painkillers remain elusive. Understanding the causes of congenital analgesia, a rare inherited condition that reduces the capacity to feel physical pain, is one of the main areas of research that could lead to new pain relief therapies. Two other mutations causing congenital analgesia are being actively explored by researchers alongside pharmaceutical firms, but have yet to yield any breakthrough drugs.

The research team added to previous work with the Italian family to clarify the nature of their phenotype (the observable characteristics caused by their genetics) - named the Marsili syndrome after their surname - finding that they're hyposensitive to noxious heat, hyposensitive to capsaicin (in chilli peppers) and have experienced pain-free bone fractures. Using DNA from blood samples, the researchers conducted a whole exome sequencing - mapping out the protein-coding genes in the genome of each family member.

 They identified a novel point mutation in the ZFHX2 gene. The mutation alters a part of the gene's protein sequence that is normally consistent across species as variable as mice and frogs. The researchers then conducted two animal studies to understand how the gene affects pain sensations in mice. They initially used mice that had been bred with the ZFHX2 gene entirely absent, and found them to have altered pain thresholds. They then bred a new line of mice that had the relevant mutation, and those mice were notably insensitive to high temperatures.

Further analysis of the mice bearing the mutation clarified that the gene regulates a number of other genes that have previously-established connections to pain signalling. By identifying this mutation and clarifying that it contributes to the family's pain insensitivity, we have opened up a whole new route to drug discovery for pain relief. With more research to understand exactly how the mutation impacts pain sensitivity, and to see what other genes might be involved.
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Sound-sleep can relief chronic pain

Pain physiologist Alban Latremoliere, PhD, of Boston Children's and sleep physiologist Chloe Alexandre, PhD, of BIDMC precisely measured the effects of chronic sleep loss on sleepiness and sensitivity to painful and non-painful stimuli.

 They tested standard pain medications, like ibuprofen and morphine, as well as wakefulness-promoting agents like caffeine and modafinil. Their findings reveal an unexpected role for alertness in setting pain sensitivity.

The team measured normal sleep cycles with tiny headsets that took electroencephalography (EEG) and electromyography (EMG) readings. "For each mouse, we have exact baseline data on how much they sleep and what their sensory sensitivity is," says Latremoliere, who works in the lab of Clifford Woolf, PhD, in the F.M. Kirby Neurobiology Center at Boston Children's.

To keep the mice awake, researchers provided custom-made toys as interest flagged while being careful not to overstimulate them. "Mice love nesting, so when they started to get sleepy (as seen by their EEG/EMG pattern) we would give them nesting materials like a wipe or cotton ball," says Latremoliere.

"Rodents like chewing, so we introduced a lot of activities based around chewing, for example, having to chew through something to get to a cotton ball." In this way they kept
groups of six to 12 mice awake for as long as 12 hours in one session, or six hours for five consecutive days, monitoring sleepiness and stress hormones (to make sure they weren't stressed) and testing for pain.

Pain sensitivity was measured in a blinded fashion by exposing mice to controlled amounts of heat, cold, pressure or capsaicin and then measuring how long it took the animal to move away or lick away the discomfort caused by capsaicin.

Researchers also tested responses to non-painful stimuli, such as jumping when startled by a sudden loud sound.
"We found that five consecutive days of moderate sleep deprivation can significantly exacerbate pain sensitivity over time in healthy mice," says Alexandre.

"The response was specific to pain, and was not due to a state of general hyperexcitability to any stimuli.
Surprisingly, common analgesics like ibuprofen did not block sleep-loss-induced pain hypersensitivity. Even morphine lost most of its efficacy in sleep-deprived mice.

These observations suggest that patients using these drugs for pain relief might have to increase their dose to compensate for lost efficacy due to sleep loss, thereby increasing their risk for side effects. In contrast, caffeine
and modafinil, drugs used to promote wakefulness, successfully blocked the pain hypersensitivity caused by both acute and chronic sleep loss.

Interestingly, in non-sleep-deprived mice, these compounds had no analgesic properties. Researchers conclude that rather than just taking painkillers, patients with chronic pain might benefit from better sleep habits or sleep-promoting medications at night.