Overview: The absence of the NCX3 gene amplifies pain signals in the spinal cord, a new mouse study reveals. Increasing levels of NCX3 in the spinal cord helped reduce symptoms associated with chronic pain.
Source: University of Oxford
Oxford researchers have discovered a gene that regulates pain sensitization by amplifying pain signals in the spinal cord, helping them understand an important mechanism underlying chronic pain in humans, and providing a new treatment target.
Chronic pain is a common problem that affects millions of people around the world, but why some people are more prone to it and what factors lead to chronic pain is not fully understood.
It is known that repeated stimulation, such as with a sharp pinprick, can lead to an increased sensitivity to pain. This process is called “pain arousal” and contributes to clinical pain disorders.
In a two-part study, researchers at Oxford’s Nuffield Department of Clinical Neurosciences first compared genetic variation in samples from more than 1,000 participants from Colombia, looking for clues as to whether there were genetic variants that were more common in people who were in more pain. -upwards. They noticed a significant difference in variants of one specific gene (the protein Sodium Calcium exchanger type-3, NCX3).
The researchers then conducted a series of experiments in mice to understand how NCX3 regulates the arousal of pain and whether it could be a treatment target. NCX3 was expressed in the neurons of the mouse spinal cord that process and transmit pain signals to the brain.
NCX3 was needed for these neurons to export the excess calcium that builds up after activity. In the absence of NCX3, the spinal cord neurons showed more activity in response to injury signals from the periphery and pain arousal increased.
Conversely, increasing levels of NCX3 in the spinal cord could reduce pain in the mouse.
David Bennett, professor of neurology and neurobiology in the Nuffield Department of Clinical Neuroscience, said: “This is the first time we’ve been able to study pain in humans and then directly demonstrate the mechanism behind it in mice, providing us with a very broad understanding. of the factors involved and how we can start developing new treatments for them.”
Professor Bennett added: “Chronic pain is a global problem and can be extremely debilitating. We conducted the study in Colombia because of the mixed ancestry of the population there, which includes indigenous Indian, African and European populations, which gave us a wide range of genetic diversity to look at. This is what makes these findings so exciting because of their potential international applications.
“The findings imply that any drugs that can increase NCX3 activity are expected to decrease pain sensitization in humans.”
About this news about genetics and pain research
Author: press office
Source: University of Oxford
Contact: Press Office – University of Oxford
Image: The image is in the public domain
Original research: Open access.
†Sodium-calcium exchanger-3 regulates pain “wind-up”: from human psychophysics to spinal mechanismsby Teodora Trendafilova et al. neuron
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Abstract
Sodium-calcium exchanger-3 regulates pain “wind-up”: from human psychophysics to spinal mechanisms
Highlights
- Significant genetic association between human pain arousal and the NCX3 locus
- NCX3 null mice exhibit hypersensitivity in inflammatory and neuropathic pain models
- NCX3 null dorsal horn spinal neurons show increased wind-up and intracellular Ca2+
- Virally mediated spinal overexpression of NCX3 reduces pain-related behavior in mice
Overview
Repeated application of harmful stimuli leads to a progressively increased pain perception; this temporal summation is enhanced and predictive of clinical pain disorders. The electrophysiological correlate is “wind-up”, with spinal cord neurons of the dorsal horn increasing their response to repeated nociceptor stimulation.
To understand the genetic basis of temporal summation, we performed a wind-up GWAS in healthy human volunteers and found a significant association with SLC8A3 coding sodium-calcium exchanger type 3 (NCX3† NCX3 was expressed in mouse dorsal horn neurons, and mice were missing NCX3 showed normal, acute pain but hypersensitivity to the second stage of the formalin test and chronic constriction injury.
Dorsal horn neurons are missing NCX3 showed increased intracellular calcium after repeated stimulation, delayed calcium clearance and increased wind-up. In addition, virally mediated spinal expression of NCX3 reduced central sensitization.
Our study highlights Ca2+ efflux as an underlying pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.