(Boston)—Chronic pain can continue long after an initial injury. When a nerve outside the brain and spinal cord (a peripheral nerve) is damaged and does not heal properly, it keeps sending constant pain signals. Over time, this non-stop bombardment of pain signals changes how your spinal cord and brain process information through sensory and emotion-associated circuits becoming hyper-reactive, turning up the volume on pain.
Current pain treatments do not work well for everyone and can cause significant side effects. Painkillers like morphine just hide the pain, but researchers at Boston University Chobanian & Avedisian School of Medicine have identified the underlying problem. They found that when they blocked a protein called RGS4 in the dorsal root ganglia innervating the lumbar spinal cord, in an experimental model, the nervous system returned to a calm, normal state.
“Our findings suggest that one reason pain may become chronic is that sensory nerves themselves undergo molecular changes that keep them unusually sensitive. By reducing RGS4 activity, our models were allowed to recover from abnormal pain sensitivity, while increasing RGS4 could make otherwise uninjured models more sensitive to pain. Importantly, the main players that control the maintenance of chronic pain in experimental models are expressed in human nerve tissue as well, suggesting that RGS4 could work the same way in people,” explains corresponding author Venetia Zachariou, PhD, Edward Avedisian Professor and chair of pharmacology, physiology & biophysics department at the school.
The team used several groups of experimental models in which they could either remove RGS4, reduce it specifically in sensory nerve cells, or, increase its levels. They then tested the functional consequences of chronic pain conditions, including peripheral nerve injury, postoperative pain, inflammatory pain and chemotherapy-induced nerve damage.
According to the researchers, the long-term clinical implication is that it may be possible to develop treatments that interrupt the biological processes that cause pain to persist, rather than simply reducing pain signals after chronic pain has already developed. Because the pathway they identified can be manipulated in sensory nerve cells outside the brain and spinal cord, it may also provide opportunities to develop more targeted treatments while potentially limiting effects elsewhere in the nervous system.
The researchers believe understanding the detailed mechanisms that controls transition from acute to chronic pain, and the maintenance of chronic (pathological) pain would be essential to guide the development of effective and safer medications. “Rather than simply masking pain after it becomes chronic, we hope this work contributes to therapies that interrupt the biological processes that cause pain to persist in the first place,” says Zachariou.
These findings appear online in the journal Science Signaling.
Funding for this research was provided by R01NS135775 to V.Z. and M.G.-M., R01NS117101 to M.G.-M., F31NS115318 to A.L. and T32GM159592 to NP.
Science Signaling
Experimental study
Animals
G subunit–interacting protein RGS4 in the dorsal root ganglia mediates molecular and behavioral maladaptations in murine pain models
6-Oct-2026