Summary: A new study in mice reveals that the absence of the NCX3 gene amplifies pain signals within the spinal cord. Increased levels of NCX3 enzyme in the spinal cord helped reduce symptoms associated with chronic pain.
source: Oxford university
Oxford researchers have discovered a gene that regulates pain sensitivity by amplifying pain signals within the spinal cord, helping them understand an important mechanism underlying chronic pain in humans and providing a new therapeutic target.
Chronic pain is a common problem that affects millions of people worldwide, but why some people are more susceptible to it and what factors lead to chronic pain are not fully understood.
It is known that repeated stimulation, such as acute pin pricks, can lead to increased sensitivity to pain. This process is called “pain termination” and contributes to clinical pain disorders.
In a two-part study, researchers from Oxford’s Nuffield Department of Clinical Neurosciences first compared genetic variation in samples from more than 1,000 participants from Columbia, to look for clues about whether there are any genetic variants more common in people who have experienced severe pain. -above. They observed a significant difference in variants for a specific gene (sodium-calcium exchange protein type 3, NCX3).
The researchers then conducted a series of experiments in mice, to understand how NCX3 regulates pain clearance and whether it could be a therapeutic target. NCX3 was expressed in neurons in the mouse spinal cord that process and transmit pain signals to the brain.
NCX3 was required by these neurons to export the excess calcium that builds the following activity. In the absence of NCX3, spinal cord neurons showed more activity in response to injury signals from the periphery and pain increased.
Conversely, increased levels of NCX3 within the spinal cord could reduce pain in the mouse.
David Bennett, Professor of Neurology and Neuroscience 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 show the mechanism behind it in mice, which provides us with a really broad understanding of the factors involved and how we can begin to developing new treatments for it.”
Professor Bennett added: “Chronic pain is a global problem and can be very debilitating. We conducted the study in Colombia because of the mixed origins of the populations there, including indigenous Indians, Africans and Europeans, which gave us a wide range of genetic diversity to consider. This makes these findings very exciting. Because of its potential international applications.
“The results indicate that any drugs that can increase NCX3 activity would be expected to decrease pain sensitivity in humans.”
About this genetics and pain news
original search: open access.
“The sodium-calcium exchanger-3 regulates pain: from human psychology to spinal mechanismsWritten by Teodora Trendavilova et al. neuron
The sodium-calcium exchanger-3 regulates pain: from human psychology to spinal mechanisms
- Significant genetic association between human pain closure and the NCX3 locus
- NCX3 null mice show hypersensitivity in models of inflammatory pain and neuropathy
- Neurons in NCX3 dorsal horn null spines show increased wind and intracellular Ca2+
- Spinal overexpression mediated by a virus NCX3 Reduces pain-related behavior in mice
The repeated application of noxious stimuli gradually increases the perception of pain; This temporal clustering and prediction of clinical pain disorders are enhanced. Its electrophysiological link is related to ‘filtering’, in which neurons in the spinal column of the dorsal horn increase their response to repeated pain receptor stimulation.
To understand the genetic basis of temporal aggregation, we performed a GWAS to eliminate healthy human volunteers and found a significant association with SLC8A3 Coding of a sodium-calcium type 3 exchanger (NCX3). NCX3 It was expressed in neurons of the dorsal horn of the mouse, and mice lack NCX3 Show normal and acute pain but hypersensitivity to stage II formalin testing and chronic constriction injury.
Lack of neurons in the dorsal horn NCX3 showed increased intracellular calcium after repeated stimulation, slowed calcium clearance, and increased clearance. Furthermore, viral-mediated spinal-enhanced expression NCX3 Decreased central sensitivity.
Our study highlights Ca2+ Flow as a primary pathway for temporal aggregation and persistent pain, which may be amenable to therapeutic targeting.