summary: Researchers have identified a novel role for the PIEZO2 protein in mediating chronic pain hypersensitivity, suggesting a new target for pain relief. The study shows that mutations in PIEZO2 make pain receptors, or pain receptors, hypersensitive to mechanical stimuli, causing persistent pain. This discovery may lead to new analgesics that effectively combat chronic pain by targeting PIEZO2 channels.
Key Facts:
- Chronic Pain Links: Mutations in the PIEZO2 protein cause hypersensitivity of pain receptors.
- Pain receptor sensitivity: The mutation causes pain receptors to react as painful to light touch.
- New drug targets: Targeting PIEZO2 channels may improve the treatment of chronic pain.
sauce: Helmholtz
A research team led by Oscar Sánchez Carranza from the laboratory of Professor Gary Lewin at the Max Delbrück Center has identified a novel function for the PIEZO2 protein in mediating chronic pain hypersensitivity.
This work suggests a new target for painkillers and may explain why painkillers that target voltage-gated sodium channels have proven disappointing as clinical targets.
The study was published in the journal braina leading neurology journal.
“There is a good correlation between chronic pain and sensitization of pain receptors in humans,” Lewin says. “This study suggests that PIEZO2 channels are important mediators of sensory signals that maintain chronic pain.”
The PIEZO2 protein forms ion channels in human sensory receptors. Previous studies have shown that ion channels are involved in transmitting the sense of touch to the brain. People with “loss-of-function” mutations in the PIEZO2 gene are less sensitive to light touch and vibration.
In contrast, patients with “gain-of-function” mutations in PIEZO are often diagnosed with complex developmental disorders, but whether gain-of-function mutations are responsible for mechanical hypersensitivity has not previously been demonstrated.
Mutation dramatically sensitizes pain receptors
To study this association, Sánchez-Carranza created two strains of so-called “gain-of-function” mice, each carrying a different version of the mutated PIEZO2 gene.
He expected to find that the touch receptors in these mice were highly sensitive. In cell biology experiments, his team found that the PIEZO2 mutation had a powerful effect on the activity of ion channels.
For example, one mutation causes the channel to open with 10 times less force than a normal, non-mutated channel.
Sánchez-Carranza and his colleagues used electrophysiological techniques developed in the Lewin lab to measure electrical activity in sensory neurons isolated from the transgenic mice.
In addition to sensitizing touch receptors, as expected, the researchers found that the mutation also dramatically increased the sensitivity of nociceptors, neurons that detect painful mechanical stimuli, to mechanical stimulation.
Furthermore, the researchers discovered that pain receptors are also activated by mechanical stimuli, which are normally felt as light touch.
“To activate the pain receptors, you need to apply pressure to the skin,” explains Sánchez Carranza.
But the pain receptors in the genetically modified mice were stimulated by levels of mechanical force that would normally be detected as touch. The receptors were incredibly sensitive.”
What was particularly surprising, Lewin says, was that a single mutation in PIEZO2 was enough to shift the physiology of pain receptors from one type of neuron to another — and, more importantly, the neurons continued to fire even when the stimulus was removed.
This is the first study to reveal an association between gain-of-function mutations in the PIEZO2 gene and pain receptors.
PIEZO2 may be involved in pain syndromes such as fibromyalgia
Clinical studies have shown that patients with chronic pain syndromes such as fibromyalgia and small fiber neuropathy have overactivity of C-fiber nociceptors, the sensory receptors that trigger pain.
When researchers recorded the activity of pain receptors in such people, they found that the pain receptors were active even in the absence of mechanical stimulation, but the mechanism behind this was unclear.
“We found that by changing just one amino acid in PIEZO2, we could actually mimic a lot of what happens in chronic C-fiber pain,” Lewin says.
In humans, “PIEZO2 may be involved in many of these pathologies.” Nociceptive neurons are the largest population of sensory neurons innervating the skin: human skin has four times more pain receptors than touch receptors.
According to a 2023 study from the National Institutes of Health, up to 20% of the adult population suffers from chronic pain that is not adequately treated with existing medications. The same NIH study found that two-thirds of people who reported chronic pain in 2019 were still suffering a year later.
The findings suggest that certain aspects of the PIEZO2 channel opening mechanism may be targets for new painkillers. Many efforts to develop new painkillers have focused on voltage-gated sodium channels, with limited success, Lewin said.
“By addressing the underlying cause of pain receptor sensitization, new drugs may provide better relief for people suffering from chronic pain.”
About this pain research news
author: Vera Glasser
sauce: Helmholtz
contact: Vera Glasser – Helmholtz
image: Image courtesy of Neuroscience News
Original Research: Open access.
“Piezo2 voltage block modulates mechanical pain sensitivity” Gary Lewin et al. brain
Abstract
Piezo2 voltage block modulates mechanical pain sensitivity
PIEZO2 is a trimeric, mechanically gated ion channel expressed in most sensory neurons in the spinal dorsal root ganglion. Mechanosensitive PIEZO2 channels are genetically required for normal touch sensation in both mice and humans.
We previously showed that PIEZO2 channels are also strongly modulated by membrane voltage: specifically, all channels can be opened by mechanical force only in the presence of highly positive voltages.
Conversely, most PIEZO2 channels are blocked at normal negative resting membrane potentials, but the physiological function of this unusual biophysical property of PIEZO2 channels has remained unknown.
