In a recent study published in The Journal of Neuroscience, scientists from Mount Sinai Hospital have discovered that a specific protein called RGS4 (Regulator of G protein signaling 4) may play an important role in maintaining the body’s long-term chronic pain state, which may serve as a novel potential target to help develop new therapies for human chronic pain and other diseases.
The study findings or can help clinicians effectively block the progression of acute pain to chronic pain in patients. In chronic pain conditions, patients not only feel pain, but also experience a series of symptoms that make their body weaker, such as lack of sensation, depression and reduced exercise capacity. The transition from acute to chronic pain (pathological) is often accompanied by adaptive changes in the body’s immune cells, glial cells and neuronal cells, many of which are still unclear to researchers. Current therapies for neuropathic or chronic inflammatory pain tend to be limited in effectiveness and cause serious side effects for patients; commonly used opioids can temporarily relieve some of the pain symptoms of patients, but long-term treatment puts patients at serious risk such as addiction, therefore, there is an urgent need for researchers to develop a novel therapy or drug for chronic pain rather than simply reducing the pain symptoms of patients.
Professor Venetia Zachariou said that this study revealed that RGS4 may promote the transition from acute and subacute pain to pathological pain and maintain the pain state; since chronic pain states affect multiple neurochemical processes in the body, and a single targeted drug is unlikely to work; however, to the excitement of the researchers, they found a multifunctional protein that may act as a special target to interfere with the maintenance of pain state in patients.
RGS4 is a multifunctional protein that is widely expressed in brain circuits that respond to pathological pain, emotion, and motivation. Based on this study, the researchers found that RGS4 plays a very critical role in maintaining the body’s pain state (which is not related to nerve damage or inflammation). Using a genetic mouse model to eliminate the gene that expresses RGS4, the researchers found that inhibiting the activity of RGS4 or can interfere with the maintenance of chronic pain state in mice.
In particular, the researchers used genetically modified mice to elucidate the key role of RGS4 in the induction, extent, and maintenance of chronic pain symptoms. They found that when RGS4 was genetically inactivated, it did not affect the induction of acute pain or chronic pain, but rather RGS4 inactivation promoted the recovery of hyperesthesia symptoms in preclinical models of peripheral nerve injury, chemotherapy-induced neuropathy, and peripheral inflammation. Mice lacking RGS4 develop all of the expected symptoms of nerve damage, but they recover within 3 weeks, and inhibition of RGS4 activity is also directly associated with an increase in body movement-related behavior.
The researchers also used genetic tools to reduce the expression of RGS4 in the ventral posterolateral nucleus of the thalamus, a pain-processing center that receives input from the spinal cord and relays relevant information to several cerebral cortical areas. The researchers found that inhibiting RGS4 in brain regions triggered the recovery of mechanical and cold pain. In addition, they also used next-generation sequencing technology to gain insight into the genes and intracellular pathways affected by RGS4. The researchers then further studied the role of RGS4 in the spinal cord and brain emotion regulation regions to better understand the mechanism of this protein affecting the body’s sensory and affective pain symptoms.
Finally, researcher Zachariou said, “we are currently trying to explore the role of RGS4 in the spinal cord and brain emotion regulation regions, we hope to better understand the molecular mechanism of this protein affecting sensory and affective pain symptoms, and we also hope to perform more studies to test the therapeutic potential of RGS4 inhibitors.”
Reference
Kleopatra Avrampou, Kerri D. Pryce, Aarthi Ramakrishnan, et al., RGS4 maintains chronic pain symptoms in rodent models, The Journal of Neuroscience (2019). DOI: 10.1523/JNEUROSCI.3154-18.2019