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Microglia Transmit Pain to the Brain During Stress

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Chronic pain is a multifaceted disorder that causes profound disability worldwide, affecting more than 1.5 billion people. It has long been known that psychological stress contributes to adverse chronic pain outcomes in patients, but it is unclear how this is initiated or amplified by stress. Now, researchers from Ohio State University have published results showing that activation of microglia in the mouse spinal cord is responsible for increased pain sensitivity in response to stress. This is one of the first research articles to demonstrate a role for microglia, the innate immune cells of the central nervous system, in promoting pain behavior during stress in the absence of injury. 

“A lot of physiological overlap exists between stress and pain, with both processes affecting the body’s normal homeostatic levels. Therefore, it’s critical for emerging research to understand the distinguishing features between both stress and pain in order to better understand the neurobiology underlying these processes,” said the paper’s first author, Caroline Sawicki. “The persistence of either pain or stress can lead to long-term dysregulation of normal physiology and behavior, potentially leading to dire consequences.”

The research team used an established mouse model of psychosocial stress known as repeated social defeat to identify a heightened inflammatory environment in the spinal cord of stressed mice that was accompanied by lower pain thresholds. Notably, microglia were activated in the spinal cords of these mice exclusively in regions involved in pain processing. Corresponding to microglial activation, stress increased the expression of inflammatory and pro-nociceptive (pain-processing) genes in the spinal cord. To mechanistically test the role of microglia in the development of pain by stress, researh used a microglia-specific pharmacologic inhibitor to deplete microglia throughout the central nervous system. Elimination of microglia from the brain and spinal cord prevented the development of stress-induced pain sensitivity, which corresponded with reduced inflammation in the spinal cord.

These findings demonstrate that disruptions in microglial functioning likely influence the neurocircuitry that underlies the development of pain by stress. The results here indicate that microglia facilitate the transmission of pain to the brain during stress through an inflammatory-driven mechanism. Therefore, microglia may serve as a therapeutic cellular target in the alleviation of pain symptoms associated with stress. Understanding the mechanisms by which stress affects the development and progression of pain may lead to novel interventions for treating human chronic pain states that are poorly controlled by currently available therapies.

Sawicki commented on the significance on the study: “These findings demonstrate a key role for microglial cells in mediating the development of pain conditions by stress. Microglia are predominantly known for their role in immune surveillance and maintenance of neurological homeostasis. This study sheds a new light on the idea that microglia can be targeted as a therapeutic cellular target in the alleviation of pain associated with stress.”

Chronic pain, despite its vast worldwide epidemiology, has not yet been countered by effective therapies. Pain relief medications such as opioids have proved to be their own public health concern. Around 10 million US citizens were prescribed long-term opioid therapy in 2014 alone.

This new study, despite being in an animal model rather than in human patients, highlights the complexity of long-term pain pathology, and shows once again that research cannot ignore the brain in treating chronic pain. Sawicki concluded, “Although chronic pain symptoms may be managed by medications, these fail to sufficiently address the underlying stress in the exacerbation of pain. New therapies should aim to address not only the source of physical pain, but also the neural components which impact the brain’s ability to inhibit pain signals.”

Reference: Sawicki, C. M., Kim, J. K., Weber, M. D., Faw, T. D., McKim, D. B., Madalena, K. M., … Sheridan, J. F. (2018). Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord During Repeated Social Defeat Stress. Journal of Neuroscience, 2785–18. https://doi.org/10.1523/JNEUROSCI.2785-18.2018