Researchers at the Max Delbrück Center, led by Oscar Sánchez-Carranza in Professor Gary Lewin’s lab, discovered that the PIEZO2 protein plays a role in chronic pain hypersensitivity. This finding introduces a potential new target for pain relief medications, addressing why drugs targeting sodium channels have not met expectations.
Lewin explains, “Chronic pain often involves heightened sensitivity of pain receptors, called nociceptors, in humans. This study shows that the PIEZO2 channel is crucial in transmitting sensory signals that sustain chronic pain.”
The PIEZO2 protein acts as an ion channel in human sensory receptors. Previous research indicated its role in transmitting touch sensations to the brain. Individuals with “loss-of-function” mutations in the PIEZO2 gene may have reduced sensitivity to gentle touch or vibration.
Conversely, those with “gain-of-function mutations” often experience complex developmental disorders. However, until now, it was unclear whether gain-of-function mutations contribute to mechanical hypersensitivity.
To study the sensitivity of their touch receptors, sánchez-Carranza created mice with “gain-of-function” mutations in the PIEZO2 gene. His team found that these mutations significantly increased the ion channel’s activity, making touch and pain receptors more sensitive to mechanical stimuli.
Image of Piezo2 gene expression (shown in magenta) in lumbar dorsal root ganglion sections from mice.
Credit: Lewin Lab
Typically, pain receptors require firm pressure to activate, but in these mice, even light touches triggered them. This sensitivity persisted even after the stimulus was removed, a surprising finding that links PIEZO2 mutations directly to changes in pain receptor function for the first time.
PIEZO2 might play a role in pain conditions like fibromyalgia. Studies show that in conditions such as fibromyalgia and small fiber neuropathies, pain-initiating sensory receptors called C-fiber nociceptors are overly active, even without stimulation.
Researchers found that altering just one amino acid in PIEZO2 can mimic this hyperactivity in chronic pain. This suggests that PIEZO2 could be involved in these human conditions, potentially influencing new treatments.
Chronic pain affects up to 20% of adults and is often poorly managed with current medications. By targeting specific aspects of how PIEZO2 channels open, new pain medications could provide better relief by addressing the root cause of nociceptor sensitivity, unlike current treatments focusing on sodium channels, which have had limited success.
Journal reference:
Oscar Sánchez Carranza, Sampurna Chakrabarti, et al., Piezo2 voltage-block regulates mechanical pain sensitivity. Brain. DOI: 10.1101/2022.10.04.510762.
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