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Review
. 2021 Feb 3;41(5):855-865.
doi: 10.1523/JNEUROSCI.1650-20.2020. Epub 2020 Nov 25.

The Neuroimmunology of Chronic Pain: From Rodents to Humans

Peter M Grace  1 , Vivianne L Tawfik  2 , Camilla I Svensson  3 , Michael D Burton  4 , Marco L Loggia  5 , Mark R Hutchinson  6
Affiliations
Review

The Neuroimmunology of Chronic Pain: From Rodents to Humans

Peter M Grace et al. J Neurosci. .

Abstract

Chronic pain, encompassing conditions, such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders, is highly prevalent but remains poorly treated. The vast majority of therapeutics are directed solely at neurons, despite the fact that signaling between immune cells, glia, and neurons is now recognized as indispensable for the initiation and maintenance of chronic pain. This review highlights recent advances in understanding fundamental neuroimmune signaling mechanisms and novel therapeutic targets in rodent models of chronic pain. We further discuss new technological developments to study, diagnose, and quantify neuroimmune contributions to chronic pain in patient populations.

Keywords: Fc gamma receptors; Nrf2; TSPO; biomarkers; cannabinoids; sex differences.

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Figures

Figure 1.
Figure 1.
Annual publications on pain and pain neuroimmunology (2000-2019). Total numbers of publications related to pain (pain OR hyperalgesia OR allodynic OR allodynia OR hypernociception OR hypernociceptive OR nociception OR neuropathic) and pain neuroimmunology ((pain OR hyperalgesia OR allodynic OR allodynia OR hypernociception OR hypernociceptive OR nociception OR neuropathic) AND (astrocyte OR astrocytic OR astroglia OR microglia OR oligodendrocyte OR neuroimmune OR neuroimmunology OR neuroinflammation)), between 2000 and 2019, were tabulated from Dimensions using a PubMed limited filter. The pain neuroimmunology publications are expressed as a percentage of the total number of publications related to pain.
Figure 2.
Figure 2.
Nrf2 activation alleviates nitro-oxidative stress and neuroinflammation. Pharmacological agents, such as dimethyl fumarate and sulforaphane, can induce nuclear translocation of Nrf2 by disrupting its cytosolic complex with Kelch-like ECH-associated protein 1 (Keap1). Nrf2 binds to DNA, aided by small musculoaponeurotic fibrosarcoma (sMAF) proteins, increasing expression of a suite of antioxidant genes, for example, those encoding heme oxygenase-1 (HO-1), superoxide dismutase (SOD) 1 and 2, catalase (CAT), and others. Antioxidants scavenge ROS/RNS that otherwise facilitate IκBα phosphorylation, inducing NFκB-dependent proinflammatory gene expression. NFκB p65 subunit-DNA binding is further prevented through competition with Nrf2 for CREB-binding protein (CBP). Antioxidants also scavenge ROS/RNS generated by dysfunctional mitochondria. Although not depicted, antioxidants further reduce neuroinflammation by scavenging ROS/RNS that otherwise activate mitogen activated protein kinases.
Figure 3.
Figure 3.
TSPO ([11C]PBR28) signal increases in chronic pain patients. A, Brain TSPO signal elevation in chronic low back pain (cLBP) patients (median images and group comparison). B, Individual data showing consistently higher thalamic [11C]PBR28 signal in patients, compared with sex-, age-, and binding affinity-matched controls (Loggia et al., 2015). C, [11C]PBR28 signal elevations in the lower spinal cord segments in patients with radicular LBP (“Pain target”) compared with reference region (“Pain reference”) and healthy controls (“Control”) (Albrecht et al., 2018). D, [11C]PBR28 signal elevation in patients with fibromyalgia (Albrecht et al., 2019a).
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