Chronic pain is one of the worst convictions of modern medicine. Affects one in five peopleis the main cause of world dependence And to top it off, Current treatments They are insufficient or come with devastating side effects such as Opioid addiction as fentanyl. But now, A great investigation Posted in the prestigious magazine Nature It has opened a door that could change everything.
A gene as responsible for chronic pain. An international team of scientists has identified a gene, the SLC45A4as a key actor in the perception of pain by the human. And it is not another gene on the list. They are the necessary instructions to manufacture a protein that acts as a “guardian” of the membrane of Our sensory neuronscontrolling the passage of mysterious molecules called polyamines.
When manipulating this protein, researchers have reduced the intensity of certain pain without affecting other sensations such as The touch. The finding not only solves an old biological enigma, but also opens the door to a new generation of analgesics for patients with pains that are not controlled with current therapies.
Following the track in the DNA of 130,000 people. Find a small gene Inside the human genome It is not something simple, taking into account the large amount of information that can be found In a sequencing. That is why researchers have resorted to brute force with the processing of a large amount of data.
To do this, they analyzed the genetic information and pain questionnaires of more than 132,000 people from the UK Biobankone of the world’s greatest repositories of medical and genetic information.
Looking for patterns in all data. Using a Complete genome association study (GWAS), which is like crossing thousands of data to find patterns, researchers discovered that certain variants of the SLC45A4 gene were significantly associated with the intensity of chronic pain that people reported. Something that could also explain the different pain thresholds that each person has.
To ensure that it was not a coincidence, they replied the finding in two other gigantic databases such as the Million Veteran Program from the United States and Finngen of Finland. The result in both was similar, so the evidence began to clarify.
But once you have the name of the gene, the question is: what exactly does this gene do to modulate pain?
The guardian of the polyamines: solving a neuronal enigma. This is where history becomes very interesting. It was known that the SLC45A4 manufactured a conveyor protein, a kind of rotating door on the surface of the cells. But nobody knew what he transported. The investigation revealed that its load is the Polyaminessmall molecules that, despite being crucial for almost everything in the cell (From the reading of the DNA to growth), they had a role that was not known in pain.
What was known is that during a pain situation polyamines increased, but the mechanism of action was a mystery. The reason for the mystery is that the effect was different depending on whether they were outside or inside the neuron, but the ‘door’ was not known through which they could enter or leave. Until now. The SLC45A4 protein is that door.
Using advanced verification techniques. Before announcing a discovery like this, it is important to be verified with different techniques. In this case the Electronic Creomicroscopy To obtain a 3D map at the atomic level of the protein. In this way, they saw their structure with an amazing detail.
But seeing it is not just to have a very beautiful photograph hanging in the office, but it could be understood how it was able to recognize polyamines and even a Modulable domain That the protein itself uses to inhibit itself, as an integrated key in its own lock. And this is something that opens many doors to future research related to chronic pain.
Mice with the lowest pain threshold. The fire test came with the experiments in animals. The team created genetically modified mice so that they did not have the SLC45A4 gene. These mice were, in appearance, completely normal. However, when they were subjected to pain proof, the results were amazing.
Specifically, mice were subjected to different tests, such as being on a hot plate or receiving a formalin injection, which is a chemical that Causes pain at high doses. Here it is as they showed a much greater resistance to chronic pain. But when they were given a quick puncture (acute pain) the answer was identical to that of normal mice.
A pain regulator. And this difference is crucial in the investigation. It means that SLC45A4 is not a switch that when we go out ‘we stop feeling any type of pain, but is a fine regulator for persistent and deaf pain, precisely the type that characterizes chronic pain.
Because living completely without pain is not a good idea. The pain in the end is an organism alert system that something is not doing well, for example, that we have appendicitis. If we ‘turn off’ acute pain are many emergency situations that we would literally stop attending until it was too late.
And reason is known. The absence of the protein made a specific type of pain receptors, the so -called Polymodal nociceptors C or fibers C (Those that detect chemical or thermal pain), were much less excitable. That is, it was necessary to expose the receiver to a much stronger stimulus so that the neurons ‘trigger’ an action potential that reached the brain and gave the feeling of pain. Literally, the threshold potential was much lower and, therefore, resisted from great magnitude pain.
A new hope for millions of people. This discovery is more than a simple scientific curiosity. By identifying this protein as the polyamine transporter in neurons related to nociception, a completely new window for drug design opens. And it is that current analgesics act on receptors or block (such as the case of ibuprofen with COX-2).
Now, the drugs designed to modulate the activity of the SLC45A4 would be a radically different approach. It could, in theory, reduce the threshold of pain in chronic patients without affecting the protective responses of acute pain and possibly with less side effects than current medications.
The secret of genetics. Our genetic material It still has many mysterious ‘corners’. There are proteins that They still don’t know each other And that they arise from new investigations or we know that there is a part of our DNA that a priori did not have a real function, but Then some use was discovered. This means that within this field they emerge new techniques such as Crisprwhich are really important advances for the combat of very serious diseases.
Images | Warren Umoh Sasun Boughdayan
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