Chronic Pain Causes Brain Inflammation. Why Should You Care?

Research Findings: Pain is a multidimensional experience, and how much the pain is 'bothersome' significantly impacts the quality of life of the sufferer. In fact, the emotional component of pain has been argued to be a great metric in measurements of quality of life. There is extensive interaction between systems involved in pain processing and brain regions responsible for mood. Notably, chronic pain co-exists with depression, which is thought to involve imbalance in a brain system that uses the neurochemical dopamine. Dr. Cahill recently published a paper in Journal of Neuroscience (available as a free open access article on their website at The Journal of Neuroscience ) that neuro-inflammation,   as the result of ongoing pain caused by nerve damage (neuropathic pain), occurs in brain regions important for reward and mood. Reward circuitry is important for how we feel (mood), our motivation, and our ability to feel pleasure. Her research team identified that non-neuronal brain cells, called microglia, alter brain activity important for producing reward. This research identifies a pathway from microglia to neurons that causes suppression of the neurochemical dopamine and thus likely contributes to many of the devastating sequelae of chronic pain, including the poor response many pain patients have to their opioid prescription medications, debilitating affective disorders, and substance abuse (Figure 1). Her research is supported by the recent clinical trial that reported minocycline, a microglial inhibitor, did not alter pain intensity, but diminished how bothersome pain is in patients with neuropathic pain. This publication was recently picked up by multiple media sites including the OC Register (Wednesday, June 17th) as well as various websites including: MD magazine, Free Press Joumal, Medical News Today, Neurology Advisor and Psychiatry Advisor.

Why is this research important? Approximately, 20-25% of Americans suffer from chronic pain making it the most common form of chronic illness under the age of 60. The Institute of Medicine estimates that it costs our society $635 billion spent per year. Treating non-cancer chronic pain is a challenge for physicians because many patients do not respond to typical analgesics, such as ibuprofen-like drugs or opioids such as morphine. Additionally, treating patients with opioids long term has been come controversial because of the high incidence of addiction to pain medications, and there are studies questioning the effectiveness of opioids for treating certain types of chronic pain, especially those of nerve injury origin. Dr. Cahill's study imposes a paradigm shift in the field of chronic pain because it identifies that chronic pain can cause neuro-inflammation in brain regions important for reward experiences. The work identifies novel signaling and biophysical mechanisms by which microglia alter neuron activity in reward circuits, important for mood, motivation, and pleasure. The impact of our research is not restricted to the problem of pain, but is broadly relevant to mood disorders such as depression and substance abuse. Both of these medical conditions are associated with disruption of reward circuitry. Chronic pain patients are more than twice as likely to suffer anxiety and depression, and co-existence of pain with mood disorders is reported to be 30-100% depending on the causes of chronic pain. Importantly, chronic pain is second only to bipolar disorder as the major cause of suicide among all medical illnesses. Dr. Cahill's study suggests that treatments that target neuroinflammation will be an important novel therapy to alleviate many of the troubling emotional sequelae of chronic pain. Our study also has implications for why some chronic pain patients become addicted to their opioid analgesics used for managing chronic pain.

Next steps: There are many directions for this research. First, we would like to establish that the circuitry changes account for affective-like behaviors. We have a novel compound from Dr. Yves De Koninck that has the potential to restore function and normalize reward-like behavior. Once these compounds get approval for clinical trials, we will test whether restoring reward function is therapeutic in a chronic pain population. We would also like to follow this up with clinical research pursuing imaging studies to identify whether chronic pain patients also show the same disruption in reward circuitry.

Take home message: Chronic pain is a devastating disease that negatively affects a person's quality of life. Not only do patients have to live with pain everyday; they also commonly suffer from depression. Our studies show that chronic pain changes your brain in areas important for mood. Importantly, we provide proof that the prevalence of depression in chronic pain patients is likely an organic disease and is not psychological. The work indicates that changes in the brain caused by pain likely cause this mood disorder; depression is not simply a consequence of their state of mind from having to live with pain. We have identified multiple proteins thet can be targeted for translational medicine to determine their effectiveness in improving quality of life for those suffering from chronic pain, as well as potentially for Major Depressive Disorders. Our research identifies a pathway that likely contributes to many of the devastating sequelae of chronic pain, which include the poor therapeutic response of oploid analgesics in a subset of chronic pain patients, debilitating affective disorders and substance abuse.