New Genetic Discovery Offers Hope for Chronic Pain Treatment

Chronic pain is a widespread and life-altering condition, ranking among the leading causes of disability globally. It significantly impacts daily life for millions and adds a substantial personal and economic burden. Although scientists have long studied the molecular mechanisms behind chronic pain, pinpointing the exact processes involved has remained challenging—until now.

In a groundbreaking collaborative effort, researchers led by Professor David Bennett from the Neuron Defense and Control Network (NDCN) and Professor Simon Newstead at the University of Oxford have uncovered a new genetic link related to pain perception. They successfully determined the structure of a molecular transporter encoded by this gene and established its role in modulating pain signals.

Published in the journal Nature, the study introduces promising avenues for developing targeted drugs against chronic pain. The research centers around the gene SLC45A4, which was found to be associated with higher pain levels in individuals. Genetic analysis from large databases, such as the UK Biobank and FinnGen, revealed that variants of SLC45A4 are more prevalent in people reporting increased pain.

Further investigations identified SLC45A4 as a neuronal polyamine transporter—an essential component in nerve function and pain regulation. Polyamines are natural chemicals within the body responsible for various cellular processes. Overaccumulation of these compounds is believed to sensitize nerve cells, causing them to send exaggerated pain signals. This excess activity may lead to long-term nerve damage, underpinning chronic pain conditions.

Until now, the lack of a specific molecular target has hindered effective treatment of chronic pain, often leading to reliance on opioids, which carry significant risks of addiction and adverse effects. Professor Bennett emphasized the importance of understanding the underlying mechanisms: "We need new therapeutic targets to treat chronic pain safely and effectively."

Using genetic data, the team discovered that individuals with certain variants of SLC45A4 are more likely to experience higher pain levels. Connecting these findings to biological function, the researchers revealed that SLC45A4 encodes a transporter responsible for moving polyamines across nerve cell membranes—in particular, within the dorsal root ganglion, a key area involved in pain sensation.

Employing cryo-electron microscopy, the team visualized the structure of this transporter in human neurons for the first time, confirming its critical role in regulating nerve excitability. Experiments with mice lacking the SLC45A4 gene demonstrated reduced responses to pain stimuli, indicating the gene's significant role in pain perception.

Professor Newstead remarked, "Understanding how membrane transporters influence nerve signaling deepens our knowledge of pain mechanisms and opens up new possibilities for treatment." The discovery suggests that targeting the SLC45A4 transporter could lead to novel, more precise pain medications, potentially reducing reliance on opioids.

Looking ahead, further research aims to develop drugs that modulate this transporter’s activity, offering safer and more effective options for managing chronic pain worldwide. Professor Bennett summarized, "We have identified a new pain gene, unraveled its structure, and linked its function directly to nerve excitability. This is a promising step toward better pain therapies."

Source: https://medicalxpress.com/news/2025-08-genetic-link-pain-drug.html