Neuroimmune modulation of pain and regenerative pain medicine

Buchheit, Thomas Edward; Huh, Yul; Maixner, William; Cheng, Jianguo; Ji, Ru-Rong

doi:10.1172/jci134439

Cited by 31 publications

(20 citation statements)

References 196 publications

(213 reference statements)

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“…Several of these potential targets have already been the target of considerable research and development efforts, resulting in inhibitors and antagonists in various stages of clinical trials for human disease, which may facilitate their application to testing their efficacy in chronic pain conditions in humans. The list of targets covered in this review is in no way all-inclusive, and many other therapeutic strategies have been discussed elsewhere, including neuromodulation [143], intrathecal cell therapy [144], glial modulators (e.g., ibudilast) [145], TLR4 antagonists, IL-10 gene therapy [146,147], and β-blockers, each of which represents an exciting prospective strategy to treat pain through modulation of central glia and neuronal function.…”

Section: Discussionmentioning

confidence: 99%

Central Nervous System Targets: Glial Cell Mechanisms in Chronic Pain

et al. 2020

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Interactions between central glial cells and neurons in the pain circuitry are critical contributors to the pathogenesis of chronic pain. In the central nervous system (CNS), two major glial cell types predominate: astrocytes and microglia. Injuries or pathological conditions which evoke pain are concurrently associated with the presence of a reactive microglia or astrocyte state, which is characterized by a variety of changes in the morphological, molecular, and functional properties of these cells. In this review, we highlight the changes that reactive microglia and astrocytes undergo following painful injuries and insults and discuss the critical and interactive role these two cell types play in the initiation and maintenance of chronic pain. Additionally, we focus on several crucial mechanisms by which microglia and astrocytes contribute to chronic pain and provide commentary on the therapeutic promise of targeting these pathways. In particular, we discuss how the inflammasome in activated microglia drives maturation and release of key pro-inflammatory cytokines, which drive pain through neuronal-and glial regulations. Moreover, we highlight several potentially-druggable hemichannels and proteases produced by reactive microglia and astrocytes in pain states and discuss how these pathways regulate distinct phases during pain pathogenesis. We also review two emerging areas in chronic pain research: 1) sexually dimorphic glial cell signaling and 2) the role of oligodendrocytes. Finally, we highlight important considerations for potential pain therapeutics targeting glial cell mediators as well as questions that remain in our conceptual understanding of glial cell activation in pain states.

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Section: Discussionmentioning

confidence: 99%

Central Nervous System Targets: Glial Cell Mechanisms in Chronic Pain

et al. 2020

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“…Inflammation produces inflammatory mediators, such as prostaglandins, ATP, and bradykinin, which evoke spontaneous pain and produce nociceptor sensitization (peripheral sensitization) that can trigger pain hypersensitivity via TRP channels, such as TRPV1, TRPA1, and TRPV4, and sodium channels, such as Nav1.7 and Nav1.8 (2,8). It is emerging as a hot topic to investigate interactions between immune cells, such as macrophages, neutrophils, dendritic cells, stem cells, and T cells and nociceptors in the context of inflammation and pain (9)(10)(11)(12). Studies suggest that immune cell-derived pro-inflammatory cytokines (e.g., TNF-a, IL-1b, IL-17) and pro-inflammatory chemokines (e.g., CCL2 and CXCL1) can act directly on nociceptors to elicit peripheral sensitization and pain (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice

Luo

et al. 2021

Front. Immunol.

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The incidence of chronic pain is especially high in women, but the underlying mechanisms remain poorly understood. Interleukin-23 (IL-23) is a pro-inflammatory cytokine and contributes to inflammatory diseases (e.g., arthritis and psoriasis) through dendritic/T cell signaling. Here we examined the IL-23 involvement in sexual dimorphism of pain, using an optogenetic approach in transgenic mice expressing channelrhodopsin-2 (ChR2) in TRPV1-positive nociceptive neurons. In situ hybridization revealed that compared to males, females had a significantly larger portion of small-sized (100-200 μm2) Trpv1+ neurons in dorsal root ganglion (DRG). Blue light stimulation of a hindpaw of transgenic mice induced intensity-dependent spontaneous pain. At the highest intensity, females showed more intense spontaneous pain than males. Intraplantar injection of IL-23 (100 ng) induced mechanical allodynia in females only but had no effects on paw edema. Furthermore, intraplantar IL-23 only potentiated blue light-induced pain in females, and intrathecal injection of IL-23 also potentiated low-dose capsaicin (500 ng) induced spontaneous pain in females but not males. IL-23 expresses in DRG macrophages of both sexes. Intrathecal injection of IL-23 induced significantly greater p38 phosphorylation (p-p38), a marker of nociceptor activation, in DRGs of female mice than male mice. In THP-1 human macrophages estrogen and chemotherapy co-application increased IL-23 secretion, and furthermore, estrogen and IL-23 co-application, but not estrogen and IL-23 alone, significantly increased IL-17A release. These findings suggest a novel role of IL-23 in macrophage signaling and female-dominant pain, including C-fiber-mediated spontaneous pain. Our study has also provided new insight into cytokine-mediated macrophage-nociceptor interactions, in a sex-dependent manner.

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“…This topic was eloquently reviewed recently. 370 Clinical data examining physical function and pain severity support the use of blood- and cell-derived pain therapies (such as platelet-rich plasma, autologous conditioned serum, mesenchymal stromal cells) in osteoarthritis of knees and hips, tendinopathy, and degenerative spine disease. Although there is some evidence to support tissue regeneration, the results are not consistent.…”

Section: Clinical Pain Therapies Targeting the Neuroimmune Interfacementioning

confidence: 99%

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice

Su¹,

Zhang²,

He³

et al. 2022

JPR

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Chronic pain remains a public health problem and contributes to the ongoing opioid epidemic. Current pain management therapies still leave many patients with poorly controlled pain, thus new or improved treatments are desperately needed. One major challenge in pain research is the translation of preclinical findings into effective clinical practice. The local neuroimmune interface plays an important role in the initiation and maintenance of chronic pain and is therefore a promising target for novel therapeutic development. Neurons interface with immune and immunocompetent cells in many distinct microenvironments along the nociceptive circuitry. The local neuroimmune interface can modulate the activity and property of the neurons to affect peripheral and central sensitization. In this review, we highlight a specific subset of many neuroimmune interfaces. In the central nervous system, we examine the interface between neurons and microglia, astrocytes, and T lymphocytes. In the periphery, we profile the interface between neurons in the dorsal root ganglion with T lymphocytes, satellite glial cells, and macrophages. To bridge the gap between preclinical research and clinical practice, we review the preclinical studies of each neuroimmune interface, discuss current clinical treatments in pain medicine that may exert its action at the neuroimmune interface, and highlight opportunities for future clinical research efforts.

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Neuroimmune modulation of pain and regenerative pain medicine

Cited by 31 publications

References 196 publications

Central Nervous System Targets: Glial Cell Mechanisms in Chronic Pain

Central Nervous System Targets: Glial Cell Mechanisms in Chronic Pain

IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice

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