Alleviating Epigenetically-Regulated Chronic Pain

Pain is a natural symptom of damage to the body, either done by disease or injury. Usually, it subsides upon healing. But when pain persists beyond healing, or occurs for no apparent reason for a prolonged period of time, it is more than just a symptom. It is a chronic condition in its own right that needs attention.

However, chronic pain is difficult to treat, even diagnose properly, because it is poorly understood in many cases. Plus, conventional therapies are not always effective, and more potent medications, like prescription opioids, risk addiction. Hence, there is an unmet need to find more effective ways to treat persistent pain. To do this, scientists must uncover the underlying molecular and cellular mechanisms involved in the process so that they can serve as novel targets for more adequate therapeutic interventions.

Recently a new study out of Germany identified two particular mechanisms that appear to influence pain processing and sensitivity. One is an epigenetic factor, and the other is an organic anion transporter (OAT1) whose function in the nervous system was previously unknown.

The discovery was made by a team of researchers at the Interdisciplinary Center for Neurosciences (ICN) at Heidelberg University. They found that HDAC4, an epigenetic regulator, affects the gene expression of neural cells associated with pain processing, and OAT1, a renal transporter, regulates pain in the spinal cord.  

“Normal, acute physiological pain prevents tissue damage and, in the case of injury, resolves with healing. Chronic pathological pain, however, persists after the injury has mended and can manifest even in the absence of a cause,” said Dr. Daniela Mauceri, who led the research group.

The progression from acute to chronic pain caused by adverse changes in gene expression, or how the information in a gene is read to produce proteins and RNA molecules. Persistent pain occurs when these types of changes take place in neurons of the spinal dorsal horn, which is the region of the spinal cord where the pain is processed. 

HDAC4 is a major player in changes to gene expression. In mouse experiments, long-lasting pain was shown to be triggered by the inactivation of HDAC4 in the neurons of the spinal dorsal horn. Generally, HDAC4 is confined to the cytosol, or the liquid region found outside the nucleus of a cell.

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In tests, preventing HDAC4 from reaching the cytosol in spinal cord neurons of mice caused a lesser chronic pain response. In addition, administration of an OAT1 blocker causes pain hypersensitivity in mice to decrease. Interestingly, the OAT1 blocker used in the test, Probenecid, also provided relief for already present chronic pain.

“OAT1 inhibitors like Probenecid, which can be administered directly into the spinal cord using pain pumps, might be interesting to test as a treatment option in chronic pain patients,” said Dr. Mauceri.

Taken together, HDAC4 and OAT1 make exciting targets for the treatment of chronic pain. Therapies that can modulate HDAC4 as well as OAT1 to prevent the establishment of epigenetically-regulated inflammatory pain states could possibly provide a more comprehensive and effective therapy for chronic pain management.

Source: C. Litke, et al. Organic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in miceNature Communications, 2022; 13 (1).

Reference: How chronic pain arises: Researchers identify molecular mechanisms that influence pain processing and sensitivity.  Heidelberg University, March 8, 2022.

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