Neuroinflammation and Central Sensitization in Chronic and Widespread Pain

Ru-Rong Ji, Ph.D.; Andrea Nackley, Ph.D.; Yul Huh, B.S., M.S.; Niccolò Terrando, Ph.D.; William Maixner, D.D.S., Ph.D.


Anesthesiology. 2018;129(2):343-366. 

In This Article

Concluding Remarks and Future Directions

Neuroinflammation resulting from neuroglial and neuroimmune interactions not only serves as a driving force for chronic pain but is also implicated in other neurologic and psychiatric diseases such as Alzheimer disease, Parkinson disease, multiple sclerosis, autism, major depression, and schizophrenia.[39] Chronic pain is commonly associated with depression, anxiety, and sleep disorders, and the prevalence of chronic pain is especially high in the rapidly growing populations of aged people and females with overlapping chronic pain conditions. Thus, targeting excessive neuroinflammation will help to alleviate chronic pain and control the progression of neurologic and psychiatric diseases in aged as well as younger populations. Mechanistically, neuroinflammation drives widespread chronic pain via central sensitization, which can be induced and maintained by cytokines, chemokines, and other glia-produced mediators circulated in the cerebrospinal fluid. Therefore, increasing the precision with which drugs can target neuroinflammation in the CNS, namely by increasing access to the spinal cord and brain, and developing the ability to accurately measure evolving neuroinflammatory changes in the CNS particularly in the cerebrospinal fluid will be of great importance. By developing specific neuroinflammatory profiles, their creation may also reveal novel biomarkers and means to identify chronic pain states. For instance, a recent study utilizing functional imaging of patients with chronic low-back pain revealed glial activation in the brain.[118] In line with the use of an analgesic marker of glial activation, translocator protein,[291] the development of additional novel radioligands to characterize different activation states of glial cells in the brain, as well as in spinal cord, dorsal root ganglia, and peripheral nerves, is of pressing need. Specialized proresolution mediators including resolvins and protectins, as well as bone marrow stem cells and neuromodulation, can serve as alternative approaches to providing effective control of neuroinflammation with perhaps less side effects than more directly targeted neuroinflammation treatments including cytokine, chemokine, and mitogen-activated protein kinase inhibitors. With the high incidence of postoperative pain after trauma and nerve injury resulting from surgeries[265] and the worsening opioid crisis in the United States,[292] the development of effective nonopioid treatments for the prevention and resolution of neuroinflammation and postoperative pain is of the utmost importance for clinical practice and health care. The benefits of developing novel treatments may extend further toward improving cognitive function in postoperative patients, a topic that will be addressed by the authors in future reviews.