Microglial Modulation as a Target for Chronic Pain: From the Bench to the Bedside and Back

Abstract

With a widespread opioid epidemic and profound biopsychosocial implications, chronic pain is a multifaceted public health issue requiring urgent attention. The treatment of chronic pain is particularly important to anesthesiologists given our unique role as perioperative physicians and pain medicine specialists. The present review details the recent shift from a neuronal theory of chronic pain to one that includes complex neuron-glia interactions. In particular, we highlight microglia, the myeloid-lineage cells of the central nervous system, as initiators of a postinjury neuroimmune response that contributes to the acute to chronic pain transition. We discuss ever-advancing preclinical studies, wherein significant success has been made through pharmacologic and genetic modulation of microglia, and we emphasize where these approaches have made the transition to the clinical realm. Furthermore, we highlight the most current, novel efforts to visualize glial activation in vivo using positron emission tomography and improve the diagnosis of chronic pain through radiotracer binding of specific targets, like the 18 kDa translocator protein in microglia and myeloid-lineage cells. Our rapidly advancing knowledge about microglia and their involvement in pain suggests that the era of glial-targeted therapeutics is just beginning so long as we refocus our attention on optimizing preclinical studies using a clinically informed approach, before translation.

Figure 1.

Exponential increase in the number of published papers on glia and pain since the 1990s. PubMed search hits for “glia and pain” were tabulated from 1990 through 2018 to track growing interest in glial biology as it pertains to pain. Major milestones from this research are also noted, including the need to use the newest knowledge on glia to improve glial-targeted treatments.

Figure 2.

Microglia and astrocytes comprise the majority of glial cells in the CNS. Microglia are labeled with CD11b (yellow), a marker of microglial activation, and astrocytes are labeled with the astrocytic marker GFAP (pink) in the dorsal horn of the spinal cord of mice that underwent tibial fracture and casting as a model of complex regional pain syndrome.

Figure 3.

Glial modulation of dorsal horn circuits is key to homeostasis and response to injury. Either direct or indirect injury to a primary afferent (presynaptic) neuron activates microglia in the dorsal horn of the spinal cord. The release of neuronal algesic mediators such as ATP and HMGB1, act on microglial P2XRs and TLR4, respectively, to activate downstream signaling through p38 MAPK and ultimately enhance local cytokine release that is the hallmark of neuroinflammation. These proinflammatory cytokines such as IL-1β and TNF-α can then act on their synaptically expressed receptors to enhance excitatory neurotransmission and produce pain. DRG, dorsal root ganglion.