|
1
|
Clark DN, Brown SV, Xu L, Lee RL, Ragusa JV, Xu Z, Milner JD, Filiano AJ. Prolonged STAT1 signaling in neurons causes hyperactive behavior. Brain Behav Immun 2025; 124:1-8. [PMID: 39542073 PMCID: PMC11745914 DOI: 10.1016/j.bbi.2024.11.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/29/2024] [Accepted: 11/09/2024] [Indexed: 11/17/2024] Open
Abstract
The interferon (IFN)-induced STAT1 signaling pathway is a canonical immune pathway that has also been implicated in regulating neuronal activity. The pathway is enriched in brains of individuals with autism spectrum disorder (ASD) and schizophrenia (SZ). Over-activation of the STAT1 pathway causes pathological transcriptional responses, however it is unclear how these responses might translate into behavioral phenotypes. We hypothesized that prolonged STAT1 signaling in neurons would be sufficient to cause behavioral deficits associated with neurodevelopmental disorders. In this study, we developed a novel mouse model with the clinical STAT1 gain-of-function mutation, T385M, in neurons. These mice were hyperactive and displayed neural hypoactivity with less neuron counts in the caudate putamen. Driving the STAT1 gain-of-function mutation exclusively in dopaminergic neurons, which project to the caudate putamen of the dorsal striatum, mimicked some hyperactive behaviors without a reduction of neurons. Moreover, we demonstrated that this phenotype is neuron specific, as mice with prolonged STAT1 signaling in all excitatory or inhibitory neurons or in microglia were not hyperactive. Overall, these findings suggest that STAT1 signaling in neurons is a crucial player in regulating striatal neuron activity and aspects of motor behavior.
Collapse
Affiliation(s)
- Danielle N Clark
- Department of Integrative Immunobiology, Duke University, Durham, NC, USA; Marcus Center for Cellular Cures, Duke University, Durham, NC, USA
| | - Shelby V Brown
- Marcus Center for Cellular Cures, Duke University, Durham, NC, USA
| | - Li Xu
- Marcus Center for Cellular Cures, Duke University, Durham, NC, USA
| | - Rae-Ling Lee
- Marcus Center for Cellular Cures, Duke University, Durham, NC, USA
| | - Joey V Ragusa
- Department of Pathology, Duke University, Durham, NC, USA
| | - Zhenghao Xu
- Marcus Center for Cellular Cures, Duke University, Durham, NC, USA
| | - Joshua D Milner
- Department of Pediatrics, Columbia University, New York, NY, USA
| | - Anthony J Filiano
- Department of Integrative Immunobiology, Duke University, Durham, NC, USA; Marcus Center for Cellular Cures, Duke University, Durham, NC, USA; Department of Pathology, Duke University, Durham, NC, USA; Department of Neurosurgery, Duke University, Durham, NC, USA.
| |
Collapse
|
|
2
|
Smith PA. BDNF in Neuropathic Pain; the Culprit that Cannot be Apprehended. Neuroscience 2024; 543:49-64. [PMID: 38417539 DOI: 10.1016/j.neuroscience.2024.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 02/20/2024] [Indexed: 03/01/2024]
Abstract
In males but not in females, brain derived neurotrophic factor (BDNF) plays an obligatory role in the onset and maintenance of neuropathic pain. Afferent terminals of injured peripheral nerves release colony stimulating factor (CSF-1) and other mediators into the dorsal horn. These transform the phenotype of dorsal horn microglia such that they express P2X4 purinoceptors. Activation of these receptors by neuron-derived ATP promotes BDNF release. This microglial-derived BDNF increases synaptic activation of excitatory dorsal horn neurons and decreases that of inhibitory neurons. It also alters the neuronal chloride gradient such the normal inhibitory effect of GABA is converted to excitation. By as yet undefined processes, this attenuated inhibition increases NMDA receptor function. BDNF also promotes the release of pro-inflammatory cytokines from astrocytes. All of these actions culminate in the increase dorsal horn excitability that underlies many forms of neuropathic pain. Peripheral nerve injury also alters excitability of structures in the thalamus, cortex and mesolimbic system that are responsible for pain perception and for the generation of co-morbidities such as anxiety and depression. The weight of evidence from male rodents suggests that this preferential modulation of excitably of supra-spinal pain processing structures also involves the action of microglial-derived BDNF. Possible mechanisms promoting the preferential release of BDNF in pain signaling structures are discussed. In females, invading T-lymphocytes increase dorsal horn excitability but it remains to be determined whether similar processes operate in supra-spinal structures. Despite its ubiquitous role in pain aetiology neither BDNF nor TrkB receptors represent potential therapeutic targets.
Collapse
Affiliation(s)
- Peter A Smith
- Neuroscience and Mental Health Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada.
| |
Collapse
|
|
3
|
Whitaker EE, Mecum NE, Cott RC, Goode DJ. Expression of MHC II in DRG neurons attenuates paclitaxel-induced cold hypersensitivity in male and female mice. PLoS One 2024; 19:e0298396. [PMID: 38330029 PMCID: PMC10852343 DOI: 10.1371/journal.pone.0298396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 01/23/2024] [Indexed: 02/10/2024] Open
Abstract
Chemotherapy is often a life-saving treatment, but the development of intractable pain caused by chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity that restricts cancer survival rates. Recent reports demonstrate that paclitaxel (PTX) robustly increases anti-inflammatory CD4+ T cells in the dorsal root ganglion (DRG), and that T cells and anti-inflammatory cytokines are protective against CIPN. However, the mechanism by which CD4+ T cells are activated, and the extent cytokines released by CD4+ T cells target DRG neurons are unknown. Here, we are the first to detect major histocompatibility complex II (MHCII) protein in mouse DRG neurons and to find CD4+ T cells breaching the satellite glial cell barrier to be in close proximity to neurons, together suggesting CD4+ T cell activation and targeted cytokine release. MHCII protein is primarily expressed in small nociceptive neurons in male and female mouse DRG but increased after PTX in small nociceptive neurons in only female DRG. Reducing one copy of MHCII in small nociceptive neurons decreased anti-inflammatory IL-10 and IL-4 producing CD4+ T cells in naïve male DRG and increased their hypersensitivity to cold. Administration of PTX to male and female mice that lacked one copy of MHCII in nociceptive neurons decreased anti-inflammatory CD4+ T cells in the DRG and increased the severity of PTX-induced cold hypersensitivity. Collectively, our results demonstrate expression of MHCII protein in mouse DRG neurons, which modulates cytokine producing CD4+ T cells in the DRG and attenuates cold hypersensitivity during homeostasis and after PTX treatment.
Collapse
Affiliation(s)
- Emily E. Whitaker
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine, United States of America
| | - Neal E. Mecum
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine, United States of America
| | - Riley C. Cott
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine, United States of America
| | - Diana J. Goode
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine, United States of America
| |
Collapse
|
|
4
|
Smith PA. Neuropathic pain; what we know and what we should do about it. FRONTIERS IN PAIN RESEARCH 2023; 4:1220034. [PMID: 37810432 PMCID: PMC10559888 DOI: 10.3389/fpain.2023.1220034] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 09/05/2023] [Indexed: 10/10/2023] Open
Abstract
Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve injury promotes Schwann cell activation and invasion of immunocompetent cells into the site of injury, spinal cord and higher sensory structures such as thalamus and cingulate and sensory cortices. Various cytokines, chemokines, growth factors, monoamines and neuropeptides effect two-way signalling between neurons, glia and immune cells. This promotes sustained hyperexcitability and spontaneous activity in primary afferents that is crucial for onset and persistence of pain as well as misprocessing of sensory information in the spinal cord and supraspinal structures. Much of the current understanding of pain aetiology and identification of drug targets derives from studies of the consequences of peripheral nerve injury in rodent models. Although a vast amount of information has been forthcoming, the translation of this information into the clinical arena has been minimal. Few, if any, major therapeutic approaches have appeared since the mid 1990's. This may reflect failure to recognise differences in pain processing in males vs. females, differences in cellular responses to different types of injury and differences in pain processing in humans vs. animals. Basic science and clinical approaches which seek to bridge this knowledge gap include better assessment of pain in animal models, use of pain models which better emulate human disease, and stratification of human pain phenotypes according to quantitative assessment of signs and symptoms of disease. This can lead to more personalized and effective treatments for individual patients. Significance statement: There is an urgent need to find new treatments for neuropathic pain. Although classical animal models have revealed essential features of pain aetiology such as peripheral and central sensitization and some of the molecular and cellular mechanisms involved, they do not adequately model the multiplicity of disease states or injuries that may bring forth neuropathic pain in the clinic. This review seeks to integrate information from the multiplicity of disciplines that seek to understand neuropathic pain; including immunology, cell biology, electrophysiology and biophysics, anatomy, cell biology, neurology, molecular biology, pharmacology and behavioral science. Beyond this, it underlines ongoing refinements in basic science and clinical practice that will engender improved approaches to pain management.
Collapse
Affiliation(s)
- Peter A. Smith
- Neuroscience and Mental Health Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
5
|
Whitaker EE, Mecum NE, Cott RC, Goode DJ. Novel expression of major histocompatibility complex II in dorsal root ganglion neurons attenuates paclitaxel-induced cold hypersensitivity in male and female mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.31.535136. [PMID: 37066176 PMCID: PMC10103942 DOI: 10.1101/2023.03.31.535136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Chemotherapy is often a life-saving treatment, but the development of intractable pain caused by chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity that restricts survival rates. Recent reports demonstrate that paclitaxel (PTX) robustly increases anti-inflammatory CD4+ T cells in the dorsal root ganglion (DRG), and that T cells and anti-inflammatory cytokines are protective against CIPN. However, the mechanism by which CD4+ T cells are activated, and the extent cytokines released by CD4+ T cells target DRG neurons are unknown. Here, we found novel expression of functional major histocompatibility complex II (MHCII) protein in DRG neurons, and CD4+ T cells in close proximity to DRG neurons, together suggesting CD4+ T cell activation and targeted cytokine release. MHCII protein is primarily expressed in small nociceptive neurons in male mouse DRG regardless of PTX, while MHCII is induced in small nociceptive neurons in female DRG after PTX. Accordingly, reducing MHCII in small nociceptive neurons increased hypersensitivity to cold only in naive male mice, but increased severity of PTX-induced cold hypersensitivity in both sexes. Collectively, our results demonstrate expression of MHCII on DRG neurons and a functional role during homeostasis and inflammation.
Collapse
|
|
6
|
Clark DN, O'Neil SM, Xu L, Steppe JT, Savage JT, Raghunathan K, Filiano AJ. Prolonged STAT1 activation in neurons drives a pathological transcriptional response. J Neuroimmunol 2023; 382:578168. [PMID: 37556887 PMCID: PMC10527980 DOI: 10.1016/j.jneuroim.2023.578168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/21/2023] [Accepted: 07/31/2023] [Indexed: 08/11/2023]
Abstract
Neurons require physiological IFN-γ signaling to maintain central nervous system (CNS) homeostasis, however, pathological IFN-γ signaling can cause CNS pathologies. The downstream signaling mechanisms that cause these drastically different outcomes in neurons has not been well studied. We hypothesized that different levels of IFN-γ signaling in neurons results in differential activation of its downstream transcription factor, signal transducer and activator of transduction 1 (STAT1), causing varying outcomes. Using primary cortical neurons, we showed that physiological IFN-γ elicited brief and transient STAT1 activation, whereas pathological IFN-γ induced prolonged STAT1 activation, which primed the pathway to be more responsive to a subsequent IFN-γ challenge. This is an IFN-γ specific response, as other IFNs and cytokines did not elicit such STAT1 activation nor priming in neurons. Additionally, we did not see the same effect in microglia or astrocytes, suggesting this non-canonical IFN-γ/STAT1 signaling is unique to neurons. Prolonged STAT1 activation was facilitated by continuous janus kinase (JAK) activity, even in the absence of IFN-γ. Finally, although IFN-γ initially induced a canonical IFN-γ transcriptional response in neurons, pathological levels of IFN-γ caused long-term changes in synaptic pathway transcripts. Overall, these findings suggest that IFN-γ signaling occurs via non-canonical mechanisms in neurons, and differential STAT1 activation may explain how neurons have both homeostatic and pathological responses to IFN-γ signaling.
Collapse
Affiliation(s)
- Danielle N Clark
- Department of Integrative Immunobiology, Duke University, Durham, NC 27705, USA; Marcus Center for Cellular Cures, Duke University, Durham, NC 27705, USA
| | - Shane M O'Neil
- Marcus Center for Cellular Cures, Duke University, Durham, NC 27705, USA
| | - Li Xu
- Marcus Center for Cellular Cures, Duke University, Durham, NC 27705, USA
| | - Justin T Steppe
- Department of Pathology, Duke University, Durham, NC 27705, USA
| | - Justin T Savage
- Department of Neurobiology, Duke University, Durham, NC 27705, USA
| | | | - Anthony J Filiano
- Department of Integrative Immunobiology, Duke University, Durham, NC 27705, USA; Department of Pathology, Duke University, Durham, NC 27705, USA; Department of Neurosurgery, Duke University, Durham, NC 27705, USA; Marcus Center for Cellular Cures, Duke University, Durham, NC 27705, USA.
| |
Collapse
|
|
7
|
Kann O, Almouhanna F, Chausse B. Interferon γ: a master cytokine in microglia-mediated neural network dysfunction and neurodegeneration. Trends Neurosci 2022; 45:913-927. [PMID: 36283867 DOI: 10.1016/j.tins.2022.10.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/30/2022] [Accepted: 10/06/2022] [Indexed: 11/06/2022]
Abstract
Traditionally, lymphocytic interferon γ (IFN-γ) was considered to be a simple 'booster' of proinflammatory responses by microglia (brain-resident macrophages) during bacterial or viral infection. Recent slice culture (in situ) and in vivo studies suggest, however, that IFN-γ has a unique role in microglial activation. Priming by IFN-γ results in proliferation (microgliosis), enhanced synapse elimination, and moderate nitric oxide release sufficient to impair synaptic transmission, gamma rhythm activity, and cognitive functions. Moreover, IFN-γ is pivotal for driving Toll-like receptor (TLR)-activated microglia into neurotoxic phenotypes that induce energetic and oxidative stress, severe network dysfunction, and neuronal death. Pharmacological targeting of activated microglia could be beneficial during elevated IFN-γ levels, blood-brain barrier leakage, and parenchymal T lymphocyte infiltration associated with, for instance, encephalitis, multiple sclerosis, and Alzheimer's disease.
Collapse
Affiliation(s)
- Oliver Kann
- Institute of Physiology and Pathophysiology, University of Heidelberg, D-69120 Heidelberg, Germany; Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, D-69120 Heidelberg, Germany.
| | - Fadi Almouhanna
- Institute of Physiology and Pathophysiology, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Bruno Chausse
- Institute of Physiology and Pathophysiology, University of Heidelberg, D-69120 Heidelberg, Germany
| |
Collapse
|
|
8
|
Clark DN, Begg LR, Filiano AJ. Unique aspects of IFN-γ/STAT1 signaling in neurons. Immunol Rev 2022; 311:187-204. [PMID: 35656941 PMCID: PMC10120860 DOI: 10.1111/imr.13092] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/01/2022] [Accepted: 05/12/2022] [Indexed: 01/05/2023]
Abstract
The IFN-γ/STAT1 immune signaling pathway impacts many homeostatic and pathological aspects of neurons, beyond its canonical role in controlling intracellular pathogens. Well known for its potent pro-inflammatory and anti-viral functions in the periphery, the IFN-γ/STAT1 pathway is rapidly activated then deactivated to prevent excessive inflammation; however, neurons utilize unique IFN-γ/STAT1 activation patterns, which may contribute to the non-canonical neuron-specific downstream effects. Though it is now well-established that the immune system interacts and supports the CNS in health and disease, many aspects regarding IFN-γ production in the CNS and how neurons respond to IFN-γ are unclear. Additionally, it is not well understood how the diversity of the IFN-γ/STAT1 pathway is regulated in neurons to control homeostatic functions, support immune surveillance, and prevent pathologies. In this review, we discuss the neuron-specific mechanisms and kinetics of IFN-γ/STAT1 activation, the potential sources and entry sites of IFN-γ in the CNS, and the diverse set of homeostatic and pathological effects IFN-γ/STAT1 signaling in neurons has on CNS health and disease. We will also highlight the different contexts and conditions under which IFN-γ-induced STAT1 activation has been studied in neurons, and how various factors might contribute to the vast array of downstream effects observed.
Collapse
Affiliation(s)
- Danielle N. Clark
- Department of Immunology, Duke University, Durham, North Carolina, USA
- Marcus Center for Cellular Cures, Duke University, Durham, North Carolina, USA
| | - Lauren R. Begg
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Anthony J. Filiano
- Department of Immunology, Duke University, Durham, North Carolina, USA
- Marcus Center for Cellular Cures, Duke University, Durham, North Carolina, USA
- Department of Pathology, Duke University, Durham, North Carolina, USA
- Department of Neurosurgery, Duke University, Durham, North Carolina, USA
| |
Collapse
|
|
9
|
Goode DJ, Whitaker EE, Mecum NE. Ovariectomy increases paclitaxel-induced mechanical hypersensitivity and reduces anti-inflammatory CD4+ T cells in the dorsal root ganglion of female mice. J Neuroimmunol 2022; 367:577878. [DOI: 10.1016/j.jneuroim.2022.577878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/01/2022] [Accepted: 04/19/2022] [Indexed: 12/28/2022]
|
|
10
|
Tan PH, Ji J, Yeh CC, Ji RR. Interferons in Pain and Infections: Emerging Roles in Neuro-Immune and Neuro-Glial Interactions. Front Immunol 2021; 12:783725. [PMID: 34804074 PMCID: PMC8602180 DOI: 10.3389/fimmu.2021.783725] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 10/19/2021] [Indexed: 12/24/2022] Open
Abstract
Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-β are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-β can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections.
Collapse
Affiliation(s)
- Ping-Heng Tan
- Department of Anesthesiology, Chi Mei Medical Center, Tainan City, Taiwan
| | - Jasmine Ji
- Neuroscience Department, Wellesley College, Wellesley, Massachusetts, MA, United States
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
| | - Chun-Chang Yeh
- Department of Anesthesiology of Tri-Service General Hospital & National Defense Medical Center, Taipei City, Taiwan
| | - Ru-Rong Ji
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
- Department of Neurobiology, Duke University Medical Center, Durham, NC, United States
- Department of Cell Biology, Duke University Medical Center, Durham, NC, United States
| |
Collapse
|
|
11
|
Boakye PA, Tang SJ, Smith PA. Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1β. FRONTIERS IN PAIN RESEARCH 2021; 2:698157. [PMID: 35295524 PMCID: PMC8915739 DOI: 10.3389/fpain.2021.698157] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/14/2021] [Indexed: 01/04/2023] Open
Abstract
Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells are activated leading to the generation of an "inflammatory soup" containing cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins, and alter ion channel function in primary afferent neurons. This leads to increased excitability and spontaneous activity and the generation of secondary mediators including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, and Wnt5a. Release of these mediators from primary afferent neurons alters the properties of spinal microglial cells causing them to release tertiary mediators, in many situations via ATP-dependent mechanisms. Tertiary mediators such as BDNF, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and other Wnt ligands facilitate the generation and transmission of nociceptive information by increasing excitatory glutamatergic transmission and attenuating inhibitory GABA and glycinergic transmission in the spinal dorsal horn. This review focusses on activation of microglia by secondary mediators, release of tertiary mediators from microglia and a description of their actions in the spinal dorsal horn. Attention is drawn to the substantial differences in the precise roles of various mediators in males compared to females. At least 25 different mediators have been identified but the similarity of their actions at sensory nerve endings, in the dorsal root ganglia and in the spinal cord means there is considerable redundancy in the available mechanisms. Despite this, behavioral studies show that interruption of the actions of any single mediator can relieve signs of pain in experimental animals. We draw attention this paradox. It is difficult to explain how inactivation of one mediator can relieve pain when so many parallel pathways are available.
Collapse
Affiliation(s)
- Paul A. Boakye
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Shao-Jun Tang
- Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Peter A. Smith
- Neuroscience and Mental Health Institute and Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
12
|
Peng J, Yi MH, Jeong H, McEwan PP, Zheng J, Wu G, Ganatra S, Ren Y, Richardson JR, Oh SB, Wu LJ. The voltage-gated proton channel Hv1 promotes microglia-astrocyte communication and neuropathic pain after peripheral nerve injury. Mol Brain 2021; 14:99. [PMID: 34183051 PMCID: PMC8240390 DOI: 10.1186/s13041-021-00812-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/18/2021] [Indexed: 12/30/2022] Open
Abstract
Activation of spinal cord microglia contributes to the development of peripheral nerve injury-induced neuropathic pain. However, the molecular mechanisms underlying microglial function in neuropathic pain are not fully understood. We identified that the voltage-gated proton channel Hv1, which is functionally expressed in spinal microglia, was significantly increased after spinal nerve transection (SNT). Hv1 mediated voltage-gated proton currents in spinal microglia and mice lacking Hv1 (Hv1 KO) display attenuated pain hypersensitivities after SNT compared with wildtype (WT) mice. In addition, microglial production of reactive oxygen species (ROS) and subsequent astrocyte activation in the spinal cord was reduced in Hv1 KO mice after SNT. Cytokine screening and immunostaining further revealed that IFN-γ expression was compromised in spinal astrocytes in Hv1 KO mice. These results demonstrate that Hv1 proton channel contributes to microglial ROS production, astrocyte activation, IFN-γ upregulation, and subsequent pain hypersensitivities after SNT. This study suggests Hv1-dependent microglia-astrocyte communication in pain hypersensitivities and identifies Hv1 as a novel therapeutic target for alleviating neuropathic pain.
Collapse
Affiliation(s)
- Jiyun Peng
- Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08854, USA.
- Institute of Life Science, Nanchang University, Nanchang, 330031, China.
| | - Min-Hee Yi
- Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Heejin Jeong
- Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, 03080, Republic of Korea
| | | | - Jiaying Zheng
- Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Gongxiong Wu
- One Harvard Street Institute of Health, Brookline, MA, 02446, USA
| | - Shashank Ganatra
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08854, USA
| | - Yi Ren
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08854, USA
- Department of Biomedical Sciences, Florida State University, Tallahassee, FL, 32306, USA
| | - Jason R Richardson
- Departments of Environmental Health Sciences, Florida International University, Miami, FL, 33199, USA
| | - Seog Bae Oh
- Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, 03080, Republic of Korea.
| | - Long-Jun Wu
- Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08854, USA.
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
- Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA.
| |
Collapse
|
|
13
|
Reischer G, Heinke B, Sandkühler J. Interferon-γ facilitates the synaptic transmission between primary afferent C-fibres and lamina I neurons in the rat spinal dorsal horn via microglia activation. Mol Pain 2021; 16:1744806920917249. [PMID: 32264753 PMCID: PMC7144669 DOI: 10.1177/1744806920917249] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Recent studies have demonstrated an important role of the pro-inflammatory cytokine interferon-γ in neuropathic pain. Interferon-γ is upregulated in the lumbar spinal cord of nerve-injured rodents and intrathecal injection of interferon-γ has been shown to induce neuropathic pain-like behaviours in naive rodents. A potential mechanism in the pathogenesis of neuropathic pain is a long-lasting amplification of nociceptive synaptic transmission in lamina I of the spinal dorsal horn. Here, we tested the effects of interferon-γ on the properties of the first synapse in nociceptive pathways in the superficial spinal dorsal horn. We performed whole-cell patch-clamp recordings in lamina I neurons in a spinal cord slice preparation with dorsal roots attached from young rats. We determined the effects of acute (at least 25 min) or longer lasting (4–8 h) treatment of the transversal slices with recombinant rat interferon-γ on spontaneous excitatory postsynaptic currents or on monosynaptic Aδ- and C-fibre-evoked excitatory postsynaptic currents, respectively. Prolonged treatment with interferon-γ facilitated monosynaptic C-fibre-evoked excitatory postsynaptic currents and this effect could be blocked by co-application of minocycline an inhibitor of microglial activation. In contrast, Aδ-fibre-evoked excitatory postsynaptic currents were not affected by the prolonged interferon-γ treatment. Acute interferon-γ application in the bathing solution did not change strength of monosynaptic Aδ- or C-fibre synapses in lamina I. However, the rate, but not the amplitude, of spontaneous excitatory postsynaptic currents recorded in lamina I neurons was decreased. This effect could not be blocked by the application of minocycline. Long-lasting treatment of rat spinal cord slices with interferon-γ induced an input specific facilitation of synaptic strength in spinal nociceptive pathways. Enhanced transmission between C-fibres and spinal lamina I neurons was mediated by the activation of microglial cells. We showed that the pro-inflammatory cytokine interferon-γ modifies the processing of information at the first synaptic relay station in nociceptive pathways.
Collapse
Affiliation(s)
- Gerda Reischer
- Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Bernhard Heinke
- Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Jürgen Sandkühler
- Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
14
|
Hendrix J, Nijs J, Ickmans K, Godderis L, Ghosh M, Polli A. The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms. Antioxidants (Basel) 2020; 9:E1166. [PMID: 33238564 PMCID: PMC7700330 DOI: 10.3390/antiox9111166] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/20/2020] [Accepted: 11/21/2020] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress can be induced by various stimuli and altered in certain conditions, including exercise and pain. Although many studies have investigated oxidative stress in relation to either exercise or pain, the literature presents conflicting results. Therefore, this review critically discusses existing literature about this topic, aiming to provide a clear overview of known interactions between oxidative stress, exercise, and pain in healthy people as well as in people with chronic pain, and to highlight possible confounding factors to keep in mind when reflecting on these interactions. In addition, autonomic regulation and epigenetic mechanisms are proposed as potential mechanisms of action underlying the interplay between oxidative stress, exercise, and pain. This review highlights that the relation between oxidative stress, exercise, and pain is poorly understood and not straightforward, as it is dependent on the characteristics of exercise, but also on which population is investigated. To be able to compare studies on this topic, strict guidelines should be developed to limit the effect of several confounding factors. This way, the true interplay between oxidative stress, exercise, and pain, and the underlying mechanisms of action can be revealed and validated via independent studies.
Collapse
Affiliation(s)
- Jolien Hendrix
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (J.H.); (J.N.); (K.I.)
- Centre for Environment and Health, Department of Public Health and Primary Care, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (L.G.); (M.G.)
| | - Jo Nijs
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (J.H.); (J.N.); (K.I.)
- Department of Physical Medicine and Physiotherapy, University Hospital Brussels, 1090 Brussels, Belgium
- Unit of Physiotherapy, Department of Health and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
- University of Gothenburg Center for Person-Centred Care (GPCC), Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
| | - Kelly Ickmans
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (J.H.); (J.N.); (K.I.)
- Department of Physical Medicine and Physiotherapy, University Hospital Brussels, 1090 Brussels, Belgium
- Research Foundation—Flanders (FWO), 1050 Brussels, Belgium
| | - Lode Godderis
- Centre for Environment and Health, Department of Public Health and Primary Care, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (L.G.); (M.G.)
- External Service for Prevention and Protection at Work (IDEWE), 3001 Heverlee, Belgium
| | - Manosij Ghosh
- Centre for Environment and Health, Department of Public Health and Primary Care, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (L.G.); (M.G.)
- Research Foundation—Flanders (FWO), 1050 Brussels, Belgium
| | - Andrea Polli
- Pain in Motion Research Group (PAIN), Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (J.H.); (J.N.); (K.I.)
- Centre for Environment and Health, Department of Public Health and Primary Care, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; (L.G.); (M.G.)
- Research Foundation—Flanders (FWO), 1050 Brussels, Belgium
| |
Collapse
|
|
15
|
IFN- γ Correlations with Pain Assessment, Radiological Findings, and Clinical Intercourse in Patient after Lumbar Microdiscectomy: Preliminary Study. DISEASE MARKERS 2020; 2020:1318930. [PMID: 33110454 PMCID: PMC7578716 DOI: 10.1155/2020/1318930] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 05/05/2020] [Accepted: 09/14/2020] [Indexed: 01/23/2023]
Abstract
Objectives We investigated the influence of pain decrease after lumbar microdiscectomy on the interferon gamma (IFN-γ) serum level in patients with lumbar disc herniations. The study challenges the mechanism of sciatica pain and the role of IFN-γ in radicular pain development. Material and Methods. We performed clinical and immunoenzymatic assessment in a group of 27 patients with lumbar radicular pain due to disc herniations before and 3 months after surgery. Clinical status was assessed with the use of the Numeric Rating Scale (NRS), the Pain Rating Index and Pain Intensity Index of McGill Pain Questionnaire (SF-MPQ), the Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI). The plasma concentrations of IFN-γ were ascertained by an immunoenzymatic method. Results We observe significant correlations between the results of the pain in the back region assessment NRS back scale after the surgery with the level of IFN-γ before the procedure (rs = 0.528; p = 0.008) and after the procedure (rs = 0.455; p = 0.025). These are moderate and positive correlations—the decrease in pain is correlated with the lower IFN-γ level. Additionally, there are significant correlations between the results of the PRI scale and the IFN-γ level. The PRI score before surgery correlates positively with IFN-γ after surgery (rs = 0.462; p = 0.023), and the PRI score after surgery correlates positively with IFN before surgery (rs = 0.529; p = 0.005) and after surgery (rs = 0.549; p = 0.003). All correlations are moderate in severity—severe pain before surgery correlates with a higher level of IFN-γ after surgery and also higher IFN-γ before surgery. There were significant differences in the IFN-γ level before (Z = −2.733; p = 0.006) and after (Z = −2.391; p = 0.017) surgery in the groups of patients with and without nerve compression. In the group of patients with nerve compression, the level of IFN-γ before and after surgery was lower. Conclusions Less pain ratio after operation correlates with the level of IFN-γ. In the group of patients without significant nerve compression confirmed by MRI scans, the level of IFN-γ before and after surgery was higher than that in the group with nerve root compression.
Collapse
|
|
16
|
Smith PA. K + Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain. Front Cell Neurosci 2020; 14:566418. [PMID: 33093824 PMCID: PMC7528628 DOI: 10.3389/fncel.2020.566418] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 08/21/2020] [Indexed: 12/12/2022] Open
Abstract
Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally induced neuropathic pain. Some of this activity results from modulation, increased activity and /or expression of voltage-gated Na+ channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. K+ channels expressed in dorsal root ganglia (DRG) include delayed rectifiers (Kv1.1, 1.2), A-channels (Kv1.4, 3.3, 3.4, 4.1, 4.2, and 4.3), KCNQ or M-channels (Kv7.2, 7.3, 7.4, and 7.5), ATP-sensitive channels (KIR6.2), Ca2+-activated K+ channels (KCa1.1, 2.1, 2.2, 2.3, and 3.1), Na+-activated K+ channels (KCa4.1 and 4.2) and two pore domain leak channels (K2p; TWIK related channels). Function of all K+ channel types is reduced via a multiplicity of processes leading to altered expression and/or post-translational modification. This also increases excitability of DRG cell bodies and nociceptive free nerve endings, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. Correlation of these cellular changes with behavioral studies provides almost indisputable evidence for K+ channel dysfunction in the onset and maintenance of neuropathic pain. This idea is underlined by the observation that selective impairment of just one subtype of DRG K+ channel can produce signs of pain in vivo. Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1β (IL-1β) in control of K+ channel function. Despite the current state of knowledge, attempts to target K+ channels for therapeutic pain management have met with limited success. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K+ channel activators.
Collapse
Affiliation(s)
- Peter A. Smith
- Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
17
|
Wilke BU, Kummer KK, Leitner MG, Kress M. Chloride - The Underrated Ion in Nociceptors. Front Neurosci 2020; 14:287. [PMID: 32322187 PMCID: PMC7158864 DOI: 10.3389/fnins.2020.00287] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 03/12/2020] [Indexed: 01/06/2023] Open
Abstract
In contrast to pain processing neurons in the spinal cord, where the importance of chloride conductances is already well established, chloride homeostasis in primary afferent neurons has received less attention. Sensory neurons maintain high intracellular chloride concentrations through balanced activity of Na+-K+-2Cl- cotransporter 1 (NKCC1) and K+-Cl- cotransporter 2 (KCC2). Whereas in other cell types activation of chloride conductances causes hyperpolarization, activation of the same conductances in primary afferent neurons may lead to inhibitory or excitatory depolarization depending on the actual chloride reversal potential and the total amount of chloride efflux during channel or transporter activation. Dorsal root ganglion (DRG) neurons express a multitude of chloride channel types belonging to different channel families, such as ligand-gated, ionotropic γ-aminobutyric acid (GABA) or glycine receptors, Ca2+-activated chloride channels of the anoctamin/TMEM16, bestrophin or tweety-homolog family, CLC chloride channels and transporters, cystic fibrosis transmembrane conductance regulator (CFTR) as well as volume-regulated anion channels (VRACs). Specific chloride conductances are involved in signal transduction and amplification at the peripheral nerve terminal, contribute to excitability and action potential generation of sensory neurons, or crucially shape synaptic transmission in the spinal dorsal horn. In addition, chloride channels can be modified by a plethora of inflammatory mediators affecting them directly, via protein-protein interaction, or through signaling cascades. Since chloride channels as well as mediators that modulate chloride fluxes are regulated in pain disorders and contribute to nociceptor excitation and sensitization it is timely and important to emphasize their critical role in nociceptive primary afferents in this review.
Collapse
Affiliation(s)
| | | | | | - Michaela Kress
- Institute of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
18
|
Immunopotentiator thymosin alpha-1 attenuates inflammatory pain by modulating the Wnt3a/β-catenin pathway in spinal cord. Neuroreport 2020; 31:69-75. [PMID: 31764244 DOI: 10.1097/wnr.0000000000001370] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The mechanism of inflammatory pain involves the central nervous system (CNS) and the immune system. It is reported that immunopotentiator thymosin alpha-1 (Tα1) can reduce inflammation, protect neurons and strengthen the immune function. However, the roles of Tα1 in inflammatory pain still remain unclear. In this study, we found Tα1 can attenuate the complete Freund's adjuvant (CFA)-induced mechanical allodynia and heat hyperalgesia. Meanwhile, it reduced the upregulation of CFA-induced inflammatory mediators (interferon (IFN)-γ, tumor necrosis factor-α and brain-derived neurotrophic factor). In addition, we found the Wnt3a/β-catenin pathway was activated in spinal cord after the injection of CFA, paralleling with pain hypersensitivity. However, Tα1 reversed this status. In summary, Tα1 could attenuate inflammatory pain by modulating the Wnt3a/β-catenin pathway. It might be related to the downregulation of inflammatory mediators.
Collapse
|
|
19
|
Liu S, Karaganis S, Mo RF, Li XX, Wen RX, Song XJ. IFNβ Treatment Inhibits Nerve Injury-induced Mechanical Allodynia and MAPK Signaling By Activating ISG15 in Mouse Spinal Cord. THE JOURNAL OF PAIN 2019; 21:836-847. [PMID: 31785403 DOI: 10.1016/j.jpain.2019.11.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 10/15/2019] [Accepted: 11/11/2019] [Indexed: 01/10/2023]
Abstract
Neuropathic pain is difficult to treat and remains a major clinical challenge worldwide. While the mechanisms which underlie the development of neuropathic pain are incompletely understood, interferon signaling by the immune system is known to play a role. Here, we demonstrate a role for interferon β (IFNβ) in attenuating mechanical allodynia induced by the spared nerve injury in mice. The results show that intrathecal administration of IFNβ (dosages up to 5,000 U) produces significant, transient, and dose-dependent attenuation of mechanical allodynia without observable effects on motor activity or feeding behavior, as is common with IFN administration. This analgesic effect is mediated by the ubiquitin-like protein interferon-stimulated gene 15 (ISG15), which is potently induced within the spinal cord following intrathecal delivery of IFNβ. Both free and conjugated ISG15 are elevated following IFNβ treatment, and this effect is increased in UBP43-/- mice lacking a key deconjugating enzyme. The IFNβ-mediated analgesia reduces MAPK signaling activation following nerve injury, and this effect requires induction of ISG15. These findings highlight a new role for IFNβ, ISG15, and MAPK signaling in immunomodulation of neuropathic pain and may lead to new therapeutic possibilities. PERSPECTIVE: Neuropathic pain is frequently intractable in a clinical setting, and new treatment options are needed. Characterizing the antinociceptive potential of IFNβ and the associated downstream signaling pathways in preclinical models may lead to the development of new therapeutic options for debilitating neuropathies.
Collapse
Affiliation(s)
- Su Liu
- SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China; Department of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Stephen Karaganis
- SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China; Department of Life, Earth and Environmental Sciences, West Texas A&M University, Amarillo, Texas
| | - Ru-Fan Mo
- SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Xiao-Xiao Li
- Department of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Ruo-Xin Wen
- SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Xue-Jun Song
- SUSTech Center for Pain Medicine, Medical School, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| |
Collapse
|
|
20
|
The Elevated Serum Level of IFN- γ in Patients with Failed Back Surgery Syndrome Remains Unchanged after Spinal Cord Stimulation. DISEASE MARKERS 2019; 2019:2606808. [PMID: 30755780 PMCID: PMC6348905 DOI: 10.1155/2019/2606808] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/08/2018] [Accepted: 11/25/2018] [Indexed: 01/10/2023]
Abstract
Objectives We investigated the influence of spinal cord stimulation (SCS) on IFN-γ, IL-1β, IL-6, TNF-α, IL-10, and TGF-β serum levels in failed back surgery syndrome (FBSS) patients. The study will try to give new insights into the mechanism of SCS action and the role of IFN-γ and other cytokines in neuropathic pain (NP) development. Materials and Methods Clinical and biochemical assessment was conducted in four groups of patients: group 0 consisted of 24 FBSS patients qualified to SCS therapy, group 1 included 17 patients who were one month after implantation, group 2 featured 12 patients who were 3 months after the implantation, and group C (the control group) with no NP. Clinical status was assessed with the use of Numeric Rating Scale (NRS), the Pain Rating Index of McGill Pain Questionnaire (SF-MPQ), the Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI). The plasma concentrations of IFN-γ were ascertained by an immunoenzymatic method. Results We found a significant difference between the patients before SCS and controls' serum level of IFN-γ. Similarly, a significantly higher level of TNF-α and significantly lower level of IL-10 in FBSS patients than controls were observed. The significant differences were not observed between SCS patients 3 months after the procedure and controls' serum level of IFN-γ and other cytokines. We noticed a positive correlation between IFN-γ concentration with NRS back value before SCS and positive correlation between IFN-γ concentration after SCS with NRS leg value before SCS. Higher IFN-γ concentrations accompanied higher NRS values. Levels of TGF-β and IL-10 may correlate with physical ability and depressive behavior. Conclusions SCS did not influence serum cytokine levels significantly. Serum concentration of IFN-γ may be recognized as an occasional pain factor because of its significantly higher level in FBSS patients versus controls and higher IFN-γ value accompanying higher pain intensity.
Collapse
|
|
21
|
Ebersberger A. The analgesic potential of cytokine neutralization with biologicals. Eur J Pharmacol 2018; 835:19-30. [DOI: 10.1016/j.ejphar.2018.07.040] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/26/2018] [Accepted: 07/19/2018] [Indexed: 12/13/2022]
|
|
22
|
Masocha W, Kristensson K. Human African trypanosomiasis: How do the parasites enter and cause dysfunctions of the nervous system in murine models? Brain Res Bull 2018; 145:18-29. [PMID: 29870779 DOI: 10.1016/j.brainresbull.2018.05.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 05/24/2018] [Accepted: 05/30/2018] [Indexed: 12/27/2022]
Abstract
In this review we describe how Trypanosoma brucei brucei, a rodent pathogenic strain of African trypanosomes, can invade the nervous system, first by localization to the choroid plexus, the circumventricular organs (CVOs) and peripheral ganglia, which have fenestrated vessels, followed by crossing of the blood-brain barrier (BBB) into the white matter, hypothalamus, thalamus and basal ganglia. White blood cells (WBCs) pave the way for the trypanosome neuroinvasion. Experiments with immune deficient mice show that the invasion of WBCs is initiated by the toll-like receptor 9, followed by an augmentation phase that depends on the cytokine IFN-γ and the chemokine CXCL10. Nitric oxide (NO) derived from iNOS then prevents a break-down of the BBB and non-regulated passage of cells. This chain of events is relevant for design of better diagnostic tools to distinguish the different stages of the disease as well as for better understanding of the pathogenesis of the nervous system dysfunctions, which include circadian rhythm changes with sleep pattern disruption, pain syndromes, movement disorders and mental disturbances including dementia.
Collapse
Affiliation(s)
- Willias Masocha
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.
| | | |
Collapse
|
|
23
|
Bidirectional modulation between infiltrating CD3 + T-lymphocytes and astrocytes in the spinal cord drives the development of allodynia in monoarthritic rats. Sci Rep 2018; 8:51. [PMID: 29311654 PMCID: PMC5758647 DOI: 10.1038/s41598-017-18357-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 12/11/2017] [Indexed: 12/30/2022] Open
Abstract
Increasing evidence suggests that T cells and glia participate in the process of neuropathic pain. However, little is known about the involvement of T cells or the interaction between glia and T cells at the molecular level. Here we investigated the phenotype of T cell infiltration into the spinal cord in inflammatory pain and explored potential crosstalk between glia and T cells. The establishment of monoarthritis produced T cell infiltration and astrocyte activation, exhibiting similar kinetics in the spinal cord. T-cell-deficient (Rag1−/−) mice significantly attenuated MA-induced mechanical allodynia and GFAP upregulation. Double immunofluorescence staining showed that CD3 mainly colocalized with interferon-gamma (IFN-γ). Western blot and flow cytometry showed that multiple intrathecal administrations of astrocytic inhibitor fluorocitrate decreased IFN-γ-production without decreasing T cell number in the spinal cord. Spinal IFN-γ blockade reduced MA-induced mechanical allodynia and astroglial activation. In contrast, treatment with rIFN-γ directly elicited persistent mechanical allodynia and upregulation of GFAP and pJNK1/2 in naïve rats. Furthermore, rIFN-γ upregulated the phosphorylation of NF-κB p65 in cultured astrocytes vitro and spinal dorsal horn vivo. The results suggest that Th1 cells and astrocytes maintain inflammatory pain and imply that there may be a positive feedback loop between these cells via IFN-γ.
Collapse
|
|
24
|
Reinbolt RE, Sonis S, Timmers CD, Fernández-Martínez JL, Cernea A, de Andrés-Galiana EJ, Hashemi S, Miller K, Pilarski R, Lustberg MB. Genomic risk prediction of aromatase inhibitor-related arthralgia in patients with breast cancer using a novel machine-learning algorithm. Cancer Med 2017; 7:240-253. [PMID: 29168353 PMCID: PMC5773952 DOI: 10.1002/cam4.1256] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 10/05/2017] [Accepted: 10/13/2017] [Indexed: 02/06/2023] Open
Abstract
Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor‐related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation. Systematic chart review of 700 AI‐treated patients with stage I‐III BC identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. SNP clusters that most closely defined AIA risk were discovered using an NAA that sequentially combined statistical filtering and a machine‐learning algorithm. NCBI PhenGenI and Ensemble databases defined gene attribution of the most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Demographics were similar in cases and controls. A cluster of 70 SNPs, correlating to 57 genes, was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally consistent. Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.
Collapse
Affiliation(s)
- Raquel E Reinbolt
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Stephen Sonis
- Primary Endpoint Solutions, Watertown, Massachusetts.,Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Cynthia D Timmers
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | | | - Ana Cernea
- Primary Endpoint Solutions, Watertown, Massachusetts.,University of Oviedo, Oviedo, Spain
| | | | - Sepehr Hashemi
- Primary Endpoint Solutions, Watertown, Massachusetts.,Harvard School of Dental Medicine, Boston, Massachusetts
| | - Karin Miller
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Robert Pilarski
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Maryam B Lustberg
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| |
Collapse
|
|
25
|
Moen GH, Moen A, Schistad EI, Gjerstad J. Local up-regulation of interferon-γ (IFN-γ) following disc herniation is involved in the inflammatory response underlying acute lumbar radicular pain. Cytokine 2017. [PMID: 28651128 DOI: 10.1016/j.cyto.2017.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Lumbar radicular pain after disc herniation may be associated with release of pro-inflammatory cytokines from nucleus pulposus (NP) tissue. In the present study we examined the role of interferon-γ (IFN-γ) and cluster of differentiation 68 (CD68) in the acute phase of this process. First, in an animal model mimicking the clinical situation after disc herniation, the role of IFN-γ close to the dorsal nerve roots was studied. Next, in patients with lumbar radicular pain due to disc herniation, we examined how two single nucleotide polymorphisms (SNPs; rs2069705 and rs2069718) are important for the IFN-γ expression influenced the pain behavior. The animal data demonstrated a significant increase in the nociceptive activity at the spinal level after local application of NP and IFN-γ onto the dorsal nerve roots. A positive correlation between IFN-γ and CD68 in the NP tissue was also demonstrated. In the patients, a significant increase in Oswestry Disability Index (ODI) score was observed in carriers of the IFN-γ SNPs; rs2069705 A and rs2069718 G alleles. The present data suggest that IFN-γ close to the dorsal nerve roots may contribute to the pathogenesis, the nociceptive activity and the pain behavior following lumbar disc herniation.
Collapse
Affiliation(s)
| | - Aurora Moen
- Department of Biosciences, University of Oslo, Norway; Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Norway.
| | - Elina I Schistad
- Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Norway.
| | - Johannes Gjerstad
- National Institute of Occupational Health, Norway; Department of Biosciences, University of Oslo, Norway; Department of Physical Medicine and Rehabilitation, Oslo University Hospital, Norway.
| |
Collapse
|
|
26
|
Al-Mazidi S, Farhat K, Nedjadi T, Chaudhary A, Zin Al-Abdin O, Rabah D, Al-Zoghaibi M, Djouhri L. Association of Interleukin-6 and Other Cytokines with Self-Reported Pain in Prostate Cancer Patients Receiving Chemotherapy. PAIN MEDICINE 2017; 19:1058-1066. [DOI: 10.1093/pm/pnx145] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Sarah Al-Mazidi
- Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia
- Rehabilitation Department, College of Health and Rehabilitation Sciences, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Karim Farhat
- Cancer Research Chair, Department of Surgery, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia
| | - TaoufiK Nedjadi
- King Abdullah International Medical Research Center (KAIMRC), King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 9515, Jeddah 21423, Saudi Arabia
| | - Adeel Chaudhary
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 9515, Jeddah 21423, Saudi Arabia
| | - Osman Zin Al-Abdin
- Cancer Research Chair, Department of Surgery, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia
| | - Danny Rabah
- Cancer Research Chair, Department of Surgery, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia
| | - Mohammad Al-Zoghaibi
- Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia
| | - Laiche Djouhri
- Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia
| |
Collapse
|
|
27
|
Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions. Sci Rep 2016; 6:34356. [PMID: 27670299 PMCID: PMC5037469 DOI: 10.1038/srep34356] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 09/13/2016] [Indexed: 12/25/2022] Open
Abstract
It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/β receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord.
Collapse
|
|
28
|
Dodds KN, Beckett EAH, Evans SF, Grace PM, Watkins LR, Hutchinson MR. Glial contributions to visceral pain: implications for disease etiology and the female predominance of persistent pain. Transl Psychiatry 2016; 6:e888. [PMID: 27622932 PMCID: PMC5048206 DOI: 10.1038/tp.2016.168] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 07/14/2016] [Accepted: 07/22/2016] [Indexed: 12/27/2022] Open
Abstract
In the central nervous system, bidirectional signaling between glial cells and neurons ('neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions.
Collapse
Affiliation(s)
- K N Dodds
- Discipline of Physiology, School of Medicine, University of Adelaide, Adelaide, SA, Australia
| | - E A H Beckett
- Discipline of Physiology, School of Medicine, University of Adelaide, Adelaide, SA, Australia
| | - S F Evans
- Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, SA, Australia
- Pelvic Pain SA, Norwood, SA, Australia
| | - P M Grace
- Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, SA, Australia
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA
| | - L R Watkins
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA
| | - M R Hutchinson
- Discipline of Physiology, School of Medicine, University of Adelaide, Adelaide, SA, Australia
- ARC Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide, Adelaide, SA, Australia
| |
Collapse
|
|
29
|
Krock E, Rosenzweig DH, Chabot-Doré AJ, Jarzem P, Weber MH, Ouellet JA, Stone LS, Haglund L. Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors. J Cell Mol Med 2014; 18:1213-25. [PMID: 24650225 PMCID: PMC4508160 DOI: 10.1111/jcmm.12268] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 01/29/2014] [Indexed: 01/07/2023] Open
Abstract
Intervertebral disc degeneration (IVD) can result in chronic low back pain, a common cause of morbidity and disability. Inflammation has been associated with IVD degeneration, however the relationship between inflammatory factors and chronic low back pain remains unclear. Furthermore, increased levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are both associated with inflammation and chronic low back pain, but whether degenerating discs release sufficient concentrations of factors that induce nociceptor plasticity remains unclear. Degenerating IVDs from low back pain patients and healthy, painless IVDs from human organ donors were cultured ex vivo. Inflammatory and nociceptive factors released by IVDs into culture media were quantified by enzyme-linked immunosorbent assays and protein arrays. The ability of factors released to induce neurite growth and nociceptive neuropeptide production was investigated. Degenerating discs release increased levels of tumour necrosis factor-α, interleukin-1β, NGF and BDNF. Factors released by degenerating IVDs increased neurite growth and calcitonin gene-related peptide expression, both of which were blocked by anti-NGF treatment. Furthermore, protein arrays found increased levels of 20 inflammatory factors, many of which have nociceptive effects. Our results demonstrate that degenerating and painful human IVDs release increased levels of NGF, inflammatory and nociceptive factors ex vivo that induce neuronal plasticity and may actively diffuse to induce neo-innervation and pain in vivo.
Collapse
Affiliation(s)
- Emerson Krock
- Orthopeadic Research Laboratory, Division of Orthopedic Surgery, McGill University, Montreal, QC, Canada; McGill Scoliosis and Spine Research Group, Montreal, QC, Canada
| | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain 2013; 154 Suppl 1:S10-S28. [PMID: 23792284 PMCID: PMC3858488 DOI: 10.1016/j.pain.2013.06.022] [Citation(s) in RCA: 845] [Impact Index Per Article: 70.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 05/23/2013] [Accepted: 06/12/2013] [Indexed: 12/22/2022]
Abstract
Activation of glial cells and neuro-glial interactions are emerging as key mechanisms underlying chronic pain. Accumulating evidence has implicated 3 types of glial cells in the development and maintenance of chronic pain: microglia and astrocytes of the central nervous system (CNS), and satellite glial cells of the dorsal root and trigeminal ganglia. Painful syndromes are associated with different glial activation states: (1) glial reaction (ie, upregulation of glial markers such as IBA1 and glial fibrillary acidic protein (GFAP) and/or morphological changes, including hypertrophy, proliferation, and modifications of glial networks); (2) phosphorylation of mitogen-activated protein kinase signaling pathways; (3) upregulation of adenosine triphosphate and chemokine receptors and hemichannels and downregulation of glutamate transporters; and (4) synthesis and release of glial mediators (eg, cytokines, chemokines, growth factors, and proteases) to the extracellular space. Although widely detected in chronic pain resulting from nerve trauma, inflammation, cancer, and chemotherapy in rodents, and more recently, human immunodeficiency virus-associated neuropathy in human beings, glial reaction (activation state 1) is not thought to mediate pain sensitivity directly. Instead, activation states 2 to 4 have been demonstrated to enhance pain sensitivity via a number of synergistic neuro-glial interactions. Glial mediators have been shown to powerfully modulate excitatory and inhibitory synaptic transmission at presynaptic, postsynaptic, and extrasynaptic sites. Glial activation also occurs in acute pain conditions, and acute opioid treatment activates peripheral glia to mask opioid analgesia. Thus, chronic pain could be a result of "gliopathy," that is, dysregulation of glial functions in the central and peripheral nervous system. In this review, we provide an update on recent advances and discuss remaining questions.
Collapse
Affiliation(s)
- Ru-Rong Ji
- Department of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC, USA
| | - Temugin Berta
- Department of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC, USA
| | - Maiken Nedergaard
- Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester, Rochester, NY, USA
| |
Collapse
|
|
31
|
Masocha W. Role of chemokines and cytokines in the neuropathogenesis of African trypanosomiasis. World J Clin Infect Dis 2013; 3:79-85. [DOI: 10.5495/wjcid.v3.i4.79] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 09/12/2013] [Accepted: 09/18/2013] [Indexed: 02/06/2023] Open
Abstract
Trypanosoma brucei spp. cause human African trypanosomiasis (HAT) or sleeping sickness in humans and nagana in animals. The early stages of the disease have no specific symptoms; however, the late stage of the disease involves neurological signs of the disease, including disturbance of sleep patterns from which the disease derives the name sleeping sickness. During the late stage of African trypanosomiasis parasites, increased numbers of white blood cells and levels of cytokines and/or chemokines are found in the brain parenchyma and/or cerebrospinal fluid of animal models and HAT patients. In this mini review, contemporary findings on how chemokines and cytokines are thought to play an important role in the central nervous system invasion by the parasites, inflammation and the neuropathology of the disease are discussed. The levels of various cytokines and chemokines, such as interferon-gamma (IFN-γ), interleukin-1 beta (IL-1β), IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), C-C motif chemokine 2 (CCL2), CCL3, C-X-C motif chemokine 8 (CXCL8, IL-8) and CXCL10, in the cerebrospinal fluid (CSF) of HAT patients correlate with the severity or stage of the disease. Thus, these molecules are possible candidates for differentiating between early and late stage HAT. The role of cytokines and chemokines in parasite invasion of the central nervous system is also being elucidated. IFN-γ, TNF-α and CXCL-10 are some of the cytokines and chemokines now known to facilitate parasite penetration of the brain parenchyma. Interestingly, they also constitute some of the candidate molecules with potential to differentiate between stage 1 and 2 of HAT. The increased levels of cytokines, such as IL-1β, IL-6, IFN-γ and TNF-α, as well as prostaglandins, during African trypanosomiasis might contribute to the neurological dysfunctions that occur during HAT.
Collapse
|
|
32
|
Meeus M, Nijs J, Hermans L, Goubert D, Calders P. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? Expert Opin Ther Targets 2013; 17:1081-9. [PMID: 23834645 DOI: 10.1517/14728222.2013.818657] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are characterized by persistent pain and fatigue. It is hypothesized that reactive oxygen species (ROS), caused by oxidative and nitrosative stress, by inhibiting mitochondrial function can be involved in muscle pain and central sensitization as typically seen in these patients. AREAS COVERED The current evidence regarding oxidative and nitrosative stress and mitochondrial dysfunction in CFS and FM is presented in relation to chronic widespread pain. Mitochondrial dysfunction has been shown in leukocytes of CFS patients and in muscle cells of FM patients, which could explain the muscle pain. Additionally, if mitochondrial dysfunction is also present in central neural cells, this could result in lowered ATP pools in neural cells, leading to generalized hypersensitivity and chronic widespread pain. EXPERT OPINION Increased ROS in CFS and FM, resulting in impaired mitochondrial function and reduced ATP in muscle and neural cells, might lead to chronic widespread pain in these patients. Therefore, targeting increased ROS by antioxidants and targeting the mitochondrial biogenesis could offer a solution for the chronic pain in these patients. The role of exercise therapy in restoring mitochondrial dysfunction remains to be explored, and provides important avenues for future research in this area.
Collapse
Affiliation(s)
- Mira Meeus
- University of Antwerp, Faculty of Medicine and Health Sciences, Department of Rehabilitation Sciences and Physiotherapy, Pain in Motion Research Group, Antwerp, Belgium.
| | | | | | | | | |
Collapse
|
|
33
|
Abstract
STUDY DESIGN Animal study. OBJECTIVE Development of an animal model for the study of biochemical changes that occur in the epidural space after intervertebral disc herniation. SUMMARY OF BACKGROUND DATA Although strong evidence for an inflammatory component exists, the biochemical processes underlying pain after disc herniation remain unknown. METHODS Epidural lavage was performed in 48 rats after L5 dorsal root ganglion exposure at baseline and 3, 6, or 24 hours after placement of autologous nucleus pulposus (NP) (N = 15), saline (N = 15), or NP + an interferon-γ antibody (anti-IFN-γ; N = 18) directly onto the dorsal root ganglion. Multiplex assays quantifying interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor α (TNF-α), IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were performed. NP (N = 7) was also analyzed for these cytokines by placing NP into saline and measuring the relative concentration. RESULTS Cytokines measured low at baseline (0-100 pg/mL) in all groups. Compared with saline, NP application caused IL-6 elevation, peaking at T = 3 hours, that was prevented by anti-IFN-γ. NP induced elevation of TNF-α, peaking at T = 24 hours and was prevented by anti-IFN-γ. IFN-γ was elevated after NP at T = 3 hours and T = 24 hours. IL-1α was similar after saline versus NP. The concentrations of IL-1β and IL-10 were elevated at T = 3 hours, 6 hours, and 24 hours in all groups without between-groups difference. The level of IL-4 peaked at T = 3 hours in the NP group and was different than saline and NP + anti-IFN-γ groups, but the time effect was insignificant. There was no change for GM-CSF. The concentration of cytokines measured in normal NP was less than 2 pg/mL for all cytokines except TNF-α. CONCLUSION In this model of acute noncompressive disc herniation, NP caused the elevation of epidural IL-6, TNF-α, and IFN-γ--all attenuated by IFN-γ blockade. IL-1β and IL-10 were both significantly elevated by saline alone and their response was not prevented by IFN-γ blockade. This model may prove useful for the study of the biochemical processes by which NP induces inflammation-induced nerve root irritation and radiculopathic pain.
Collapse
|
|
34
|
Abstract
Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.e., the skin and epithelial cells of the gastrointestinal tract, and between the blood and the brain parenchyma, i.e., the blood-brain barrier (BBB). A description is given on how human pathogenic parasites can reach the CNS via the bloodstream either as free-living or extracellular parasites, by embolization of eggs, or within red or white blood cells when adapted to intracellular life. Molecular mechanisms are discussed by which parasites can interact with or pass across the BBB. The possible targeting of the circumventricular organs by parasites, as well as the parasites' direct entry to the brain from the nasal cavity through the olfactory nerve pathway, is also highlighted. Finally, examples are given which illustrate different mechanisms by which parasites can cause dysfunction or damage in the CNS related to toxic effects of parasite-derived molecules or to immune responses to the infection.
Collapse
|
|
35
|
Nijs J, Meeus M, Van Oosterwijck J, Ickmans K, Moorkens G, Hans G, De Clerck LS. In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome. Eur J Clin Invest 2012; 42:203-12. [PMID: 21793823 DOI: 10.1111/j.1365-2362.2011.02575.x] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Central sensitisation entails several top-down and bottom-up mechanisms, all contributing to the hyperresponsiveness of the central nervous system to a variety of inputs. In the late nineties, it was first hypothesised that chronic fatigue syndrome (CFS) is characterised by hypersensitivity of the central nervous system (i.e. central sensitisation). Since then, several studies have examined central sensitisation in patients with CFS. This study provides an overview of such studies. MATERIALS AND METHODS Narrative review. RESULTS Various studies showed generalised hyperalgesia in CFS for a variety of sensory stimuli, including electrical stimulation, mechanical pressure, heat and histamine. Various tissues are affected by generalised hyperalgesia: the skin, muscle tissue and the lungs. Generalised hyperalgesia in CFS is augmented, rather than decreased, following various types of stressors like exercise and noxious heat pain. Endogenous inhibition is not activated in response to exercise and activation of diffuse noxious inhibitory controls following noxious heat application to the skin is delayed. CONCLUSIONS The observation of central sensitisation in CFS is in line with our current understanding of CFS. The presence of central sensitisation in CFS corroborates with the presence of several psychological influences on the illness, the presence of infectious agents and immune dysfunctions and the dysfunctional hypothalamus-pituitary-adrenal axis as seen in these severely debilitated patients.
Collapse
Affiliation(s)
- Jo Nijs
- Department of Human Physiology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
| | | | | | | | | | | | | |
Collapse
|
|
36
|
Euteneuer F, Schwarz MJ, Hennings A, Riemer S, Stapf T, Selberdinger V, Rief W. Psychobiological aspects of somatization syndromes: contributions of inflammatory cytokines and neopterin. Psychiatry Res 2012; 195:60-5. [PMID: 21864915 DOI: 10.1016/j.psychres.2011.07.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Revised: 06/30/2011] [Accepted: 07/21/2011] [Indexed: 02/09/2023]
Abstract
Previous research suggests a dysregulation of immune-to-brain communication in the pathophysiology of somatization syndromes (multiple somatoform symptoms). We compared blood levels of the inflammatory markers tumor necrosis factor-alpha (TNF-α), interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6) and neopterin between 23 patients with somatization syndromes (Somatoform Symptom Index-8, SSI-8), 23 age- and sex-matched healthy controls and 23 patients with major depression. No group differences were found for IL-1ra and IL-6. While TNF-α was increased in both clinical groups, neopterin was only increased in somatization syndromes. Correlational analyses revealed that neopterin tended to be related to somatoform pain complaints in patients with somatization syndromes. This study is the first to demonstrate increased levels of TNF-α and neopterin in patients with somatization syndromes without a diagnosis of depression, which may support a role of immune alterations in somatization syndromes. Neopterin is a reliable indicator for interferon-γ (IFN-γ) which was identified as the only cytokine that induces significant production of neopterin. Considering recent research indicating that IFN-γ can lead to increased neuronal responsiveness and body perceptions by reducing inhibitory tone in the dorsal horn, the observed association between somatization syndromes and neopterin might support the idea of central sensitization in the pathogenesis of somatoform symptoms.
Collapse
Affiliation(s)
- Frank Euteneuer
- Division of Clinical Psychology and Psychotherapy, Philipps University of Marburg, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Cytokine profiling in acute anterior cruciate ligament injury. Arthroscopy 2010; 26:1296-301. [PMID: 20887928 DOI: 10.1016/j.arthro.2010.02.011] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2009] [Revised: 01/31/2010] [Accepted: 02/10/2010] [Indexed: 02/02/2023]
Abstract
PURPOSE To evaluate the presence and relative concentrations of cytokines, known to be involved in the inflammatory cascade, in acute anterior cruciate ligament (ACL) injury. METHODS We evaluated an extensive cytokine profile in synovial fluid from 12 patients with acute ACL injury undergoing arthroscopy compared with 15 control subjects using a BioPlex assay (Bio-Rad Laboratories, Hercules, CA) to measure the concentration of 17 inflammatory cytokines. RESULTS In patients with acute ACL injury compared with asymptomatic control subjects, the following cytokines were identified at significantly increased concentrations (P < .001, Mann-Whitney U test) compared with control samples: interleukin 6 (105 ± 72 v 0 ± 0 pg/ml), interferon γ (1,544 ± 608 v 9 ± 7.5 pg/ml), macrophage inflammatory protein 1β (16 ± 3.8 v 0.3 ± 0.2 pg/ml), and monocyte chemotactic protein 1 (35 ± 13 v 0.5 ± 0.4 pg/ml). There was no case of a cytokine exhibiting increased levels in asymptomatic compared with symptomatic knee samples. CONCLUSIONS This investigation identified 4 specific cytokines (interleukin 6, interferon γ, monocyte chemotactic protein 1, and macrophage inflammatory protein 1β) out of a panel of 17 inflammatory molecules for which the levels were consistently elevated in the context of ACL injury compared with non-painful, non-acutely injured knees in a volunteer population. LEVEL OF EVIDENCE Level IV, prognostic case series.
Collapse
|
|
38
|
Biggs JE, Lu VB, Stebbing MJ, Balasubramanyan S, Smith PA. Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization? Mol Pain 2010; 6:44. [PMID: 20653959 PMCID: PMC2918544 DOI: 10.1186/1744-8069-6-44] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Accepted: 07/23/2010] [Indexed: 12/12/2022] Open
Abstract
Peripheral nerve injury activates spinal microglia. This leads to enduring changes in the properties of dorsal horn neurons that initiate central sensitization and the onset of neuropathic pain. Although a variety of neuropeptides, cytokines, chemokines and neurotransmitters have been implicated at various points in this process, it is possible that much of the information transfer between activated microglia and neurons, at least in this context, may be explicable in terms of the actions of brain derived neurotrophic factor (BDNF). Microglial-derived BDNF mediates central sensitization in lamina I by attenuating inhibitory synaptic transmission. This involves an alteration in the chloride equilibrium potential as a result of down regulation of the potassium-chloride exporter, KCC2. In lamina II, BDNF duplicates many aspects of the effects of chronic constriction injury (CCI) of the sciatic nerve on excitatory transmission. It mediates an increase in synaptic drive to putative excitatory neurons whilst reducing that to inhibitory neurons. CCI produces a specific pattern of changes in excitatory synaptic transmission to tonic, delay, phasic, transient and irregular neurons. A very similar 'injury footprint' is seen following long-term exposure to BDNF. This review presents new information on the action of BDNF and CCI on lamina II neurons, including the similarity of their actions on the kinetics and distributions of subpopulations of miniature excitatory postsynaptic currents (mEPSC). These findings raise the possibility that BDNF functions as a final common path for a convergence of perturbations that culminate in the generation of neuropathic pain.
Collapse
Affiliation(s)
- James E Biggs
- Department of Pharmacology and Centre for Neuroscience University of Alberta, Edmonton, Alberta, Canada
| | - Van B Lu
- Laboratory of MolecularPhysiology, NIH/NIAAA, Rockville, MD, USA
| | - Martin J Stebbing
- School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia
| | | | - Peter A Smith
- Department of Pharmacology and Centre for Neuroscience University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
39
|
T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci 2009; 29:14415-22. [PMID: 19923276 DOI: 10.1523/jneurosci.4569-09.2009] [Citation(s) in RCA: 331] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Partial peripheral nerve injury in adult rats results in neuropathic pain-like hypersensitivity, while that in neonatal rats does not, a phenomenon also observed in humans. We therefore compared gene expression profiles in the dorsal horn of adult and neonatal rats in response to the spared nerve injury (SNI) model of peripheral neuropathic pain. The 148 differentially regulated genes in adult, but not young, rat spinal cords indicate a greater microglial and T-cell response in adult than in young animals. T-cells show a large infiltration in the adult dorsal horn but not in the neonate after SNI. T-cell-deficient Rag1-null adult mice develop less neuropathic mechanical allodynia than controls, and central expression of cytokines involved in T-cell signaling exhibits large relative differences between young and adult animals after SNI. One such cytokine, interferon-gamma (IFNgamma), is upregulated in the dorsal horn after nerve injury in the adult but not neonate, and we show that IFNgamma signaling is required for full expression of adult neuropathic hypersensitivity. These data reveal that T-cell infiltration and activation in the dorsal horn of the spinal cord following peripheral nerve injury contribute to the evolution of neuropathic pain-like hypersensitivity. The neuroimmune interaction following peripheral nerve injury has therefore a substantial adaptive immune component, which is absent or suppressed in the young CNS.
Collapse
|
|
40
|
Liu CY, Mueller MH, Rogler G, Grundy D, Kreis ME. Differential afferent sensitivity to mucosal lipopolysaccharide from Salmonella typhimurium and Escherichia coli in the rat jejunum. Neurogastroenterol Motil 2009; 21:1335-e129. [PMID: 19614870 DOI: 10.1111/j.1365-2982.2009.01358.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Postinfectious irritable bowel syndrome may develop subsequent to acute bacterial enteritis. We therefore hypothesized that intestinal afferents may develop hypersensitivity upon exposure to luminal lipopolysaccharide (LPS) from pathogens but not from commensal bacteria and that this may be prostaglandin mediated. Extracellular recordings of jejunal afferents were obtained in vivo from male Wistar rats (n = 5 per group; 300-400 g). Lipopolysaccharide from Escherichia coli (E-LPS), Salmonella typhimurium (S-LPS) or vehicle were infused into the intestinal lumen at 5 mg mL(-1). The selective 5-HT(3)-receptor agonist 2-methyl-5-HT (2m5-HT, 15 microgkg(-1), i.v.) was administered at 15-min intervals before and up to 2 h after S-LPS administration. Intraluminal E-LPS had no effect on mesenteric afferent nerve discharge at baseline. By contrast, afferent discharge increased from 21.7 +/- 0.3 impsec(-1) to 28.8 +/- 3.4 impsec(-1) 40 min after S-LPS administration (mean +/- SEM; P < 0.05) and reached 38.8 +/- 4.1 impsec(-1) after 2 h (P < 0.05). The afferent response to 2m5-HT was enhanced 30 min following S-LPS by 30.9 +/- 3.9% (P < 0.05) and remained elevated thereafter. The increase in baseline discharge and sensitivity to 2m5-HT following S-LPS was prevented by pretreatment with naproxen (COX inhibitor, 10 mgkg(-1) i.v.) or AH-6809 (EP1/EP2 receptor antagonist, 1 mg kg(-1)). Intestinal afferents do not alter their discharge rate to LPS from E. coli but to LPS from the pathogenic bacterium S. typhimurium. The latter response entails afferent sensitisation to 2m5-HT that depends on prostanoid release. This acute sensitisation may prime the intestinal afferent innervation for a later development of persistent hypersensitivity.
Collapse
Affiliation(s)
- C Y Liu
- Shandong University, Department of Physiology and Key Lab of Medical Neurobiology, School of Medicine, Shandong, China
| | | | | | | | | |
Collapse
|
|
41
|
Central sensitization: a generator of pain hypersensitivity by central neural plasticity. THE JOURNAL OF PAIN 2009; 10:895-926. [PMID: 19712899 DOI: 10.1016/j.jpain.2009.06.012] [Citation(s) in RCA: 2391] [Impact Index Per Article: 149.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Revised: 06/08/2009] [Accepted: 06/08/2009] [Indexed: 02/08/2023]
Abstract
UNLABELLED Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. The net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification. Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central nervous system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations. PERSPECTIVE In this article, we review the major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.
Collapse
|
|
42
|
Abstract
STUDY DESIGN Prospective observational cohort. OBJECTIVE Correlate epidural inflammatory cytokines with the clinical response to epidural steroid injection in patients with lumbar nerve root irritation. SUMMARY OF BACKGROUND DATA Some back pain syndromes are thought to be associated with activation of inflammatory pathways and others may be associated with primary mechanical derangements. Human studies providing detailed evidence for the primary inflammatory causation, which may be best treated with anti-inflammatory strategies, are lacking. There are currently no accurate diagnostic tests to predict the response to epidural steroid injection or surgical intervention in back pain and sciatica syndromes. METHODS.: Forty-seven consecutive patients with lumbar degenerative changes and low back and/or leg pain were prospectively enrolled. An epidural lavage was performed, followed by injection of marcaine/depo-medrol. Subjects scored their pain before and 3 months after the procedure. The immunoreactivity of an array of cytokines was measured in lavage samples and compared with clinical response to the therapeutic injection. Ten subjects underwent repeat epidural lavage sampling 3 months after the steroid injection. RESULTS Interferon gamma (IFNgamma) was the most consistently detected cytokine. IFNgamma-immunoreactivity also highly correlated with reported reduction of pain 3-months after the epidural steroid injection. In subjects reporting significant pain relief (>50%) from the injection, mean [IFNgamma] was significantly greater compared with patients experiencing no significant relief. The IFNgamma-immunoreactivity in repeat lavage samples decreased to trace residual concentrations in patients who reported pain relief from the steroid injection. CONCLUSION The presence of epidural IFNgamma-immunoreactivity corresponding to >10 pg/mL predicted significant pain relief after epidural steroid injection with >95% accuracy. These results suggest that IFNgamma may be part of a biochemical cascade triggering pain in sciatica; IFNgamma-immunoreactivity may aid as a biomarker for predicting the response to steroid therapy and/or surgical intervention, and may serve as a future therapeutic target.
Collapse
|
|
43
|
Cuellar JM, Scuderi GJ, Cuellar VG, Golish SR, Yeomans DC. Diagnostic utility of cytokine biomarkers in the evaluation of acute knee pain. J Bone Joint Surg Am 2009; 91:2313-20. [PMID: 19797564 DOI: 10.2106/jbjs.h.00835] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND The diagnosis of clinically important meniscal tears of the knee remains challenging, and it is unknown why only some injuries become painful. The role of inflammatory cytokines in generating pain following meniscal injury remains unclear. This study aimed to investigate the cytokine profile in patients with acute knee pain believed to be secondary to meniscal damage. METHODS This prospective cohort study included thirty-two patients without rheumatoid arthritis who had knee pain for less than six months, with either an acute or insidious onset, and elected to have arthroscopic treatment after nonoperative management had failed. Twenty-three of these patients elected to have the contralateral, nonoperatively treated knee lavaged at the time of arthroscopy. Fifteen asymptomatic control subjects also contributed samples of knee joint fluid, for a total of seventy samples from forty-seven subjects. Lavage of the operatively treated, contralateral, and control knees was performed with the patient under regional anesthesia prior to arthroscopy, if applicable, by the infusion of sterile saline solution into the knee followed by the immediate withdrawal into a syringe. The concentrations of seventeen inflammatory cytokines and chemokines were measured with use of a multiplexed immunoassay panel. Preoperative magnetic resonance imaging findings and cytokine assay results were compared with intraoperative findings. RESULTS Multivariate analysis of variance detected significantly greater concentrations of interferon gamma (IFN-gamma); interleukins 2, 4, 6, 10, and 13 (IL-2, IL-4, IL-6, IL-10, and IL-13); monocyte chemotactic protein-1 (MCP-1); and macrophage inflammatory protein-1 beta (MIP-1beta) in fluid samples from painful knees than in samples from nonpainful knees. Correlation analysis demonstrated a significant positive correlation between patient-reported pain scores and concentrations of IL-6 (Spearman rho = 0.7), MCP-1 (rho = 0.8), MIP-1beta (rho = 0.6), and IFN-gamma (rho = 0.6). These four cytokines also demonstrated a positive correlation with each other (rho = 0.5 to 0.7). The presence of IFN-gamma, IL-6, MCP-1, or MIP-1beta performed as well as magnetic resonance imaging in the prediction of intraoperative findings. CONCLUSIONS Intra-articular concentrations of four inflammatory cytokines IFN-gamma, IL-6, MCP-1, and MIP-1beta correlated to pain in patients with symptomatic meniscal tears in the knee but were markedly lower in asymptomatic normal knees and in asymptomatic knees with meniscal tears. These cytokines may be involved in the generation of pain following meniscal injury.
Collapse
Affiliation(s)
- Jason M Cuellar
- Department of Orthopaedic Surgery, NYU-Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10033, USA
| | | | | | | | | |
Collapse
|
|
44
|
Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K. IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci U S A 2009; 106:8032-7. [PMID: 19380717 PMCID: PMC2683100 DOI: 10.1073/pnas.0810420106] [Citation(s) in RCA: 223] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2008] [Indexed: 01/23/2023] Open
Abstract
Neuropathic pain, a highly debilitating pain condition that commonly occurs after nerve damage, is a reflection of the aberrant excitability of dorsal horn neurons. This pathologically altered neurotransmission requires a communication with spinal microglia activated by nerve injury. However, how normal resting microglia become activated remains unknown. Here we show that in naive animals spinal microglia express a receptor for the cytokine IFN-gamma (IFN-gammaR) in a cell-type-specific manner and that stimulating this receptor converts microglia into activated cells and produces a long-lasting pain hypersensitivity evoked by innocuous stimuli (tactile allodynia, a hallmark symptom of neuropathic pain). Conversely, ablating IFN-gammaR severely impairs nerve injury-evoked microglia activation and tactile allodynia without affecting microglia in the contralateral dorsal horn or basal pain sensitivity. We also find that IFN-gamma-stimulated spinal microglia show up-regulation of Lyn tyrosine kinase and purinergic P2X(4) receptor, crucial events for neuropathic pain, and genetic approaches provide evidence linking these events to IFN-gammaR-dependent microglial and behavioral alterations. These results suggest that IFN-gammaR is a key element in the molecular machinery through which resting spinal microglia transform into an activated state that drives neuropathic pain.
Collapse
Affiliation(s)
- Makoto Tsuda
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Takahiro Masuda
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Junko Kitano
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Hiroshi Shimoyama
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Hidetoshi Tozaki-Saitoh
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| | - Kazuhide Inoue
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
| |
Collapse
|
|
45
|
Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain. J Neurosci 2009; 28:12136-45. [PMID: 19005078 DOI: 10.1523/jneurosci.3402-08.2008] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Nerve injuries often lead to neuropathic pain syndrome. The mechanisms contributing to this syndrome involve local inflammatory responses, activation of glia cells, and changes in the plasticity of neuronal nociceptive pathways. Cannabinoid CB(2) receptors contribute to the local containment of neuropathic pain by modulating glial activation in response to nerve injury. Thus, neuropathic pain spreads in mice lacking CB(2) receptors beyond the site of nerve injury. To further investigate the mechanisms leading to the enhanced manifestation of neuropathic pain, we have established expression profiles of spinal cord tissues from wild-type and CB(2)-deficient mice after nerve injury. An enhanced interferon-gamma (IFN-gamma) response was revealed in the absence of CB(2) signaling. Immunofluorescence stainings demonstrated an IFN-gamma production by astrocytes and neurons ispilateral to the nerve injury in wild-type animals. In contrast, CB(2)-deficient mice showed neuronal and astrocytic IFN-gamma immunoreactivity also in the contralateral region, thus matching the pattern of nociceptive hypersensitivity in these animals. Experiments in BV-2 microglia cells revealed that transcriptional changes induced by IFN-gamma in two key elements for neuropathic pain development, iNOS (inducible nitric oxide synthase) and CCR2, are modulated by CB(2) receptor signaling. The most direct support for a functional involvement of IFN-gamma as a mediator of CB(2) signaling was obtained with a double knock-out mouse strain deficient in CB(2) receptors and IFN-gamma. These animals no longer show the enhanced manifestations of neuropathic pain observed in CB(2) knock-outs. These data clearly demonstrate that the CB(2) receptor-mediated control of neuropathic pain is IFN-gamma dependent.
Collapse
|
|
46
|
Inoue K, Koizumi S, Tsuda M. The role of nucleotides in the neuron--glia communication responsible for the brain functions. J Neurochem 2007; 102:1447-1458. [PMID: 17697046 DOI: 10.1111/j.1471-4159.2007.04824.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Accumulating findings indicate that nucleotides play an important role in cell-to-cell communication through P2 purinoceptors, even though ATP is recognized primarily to be a source of free energy and nucleotides are key molecules in cells. P2 purinoceptors are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (7 types; P2X(1)-P2X(7)) contain intrinsic pores that open by binding with ATP. P2Y (8 types; P2Y(1, 2, 4, 6, 11, 12, 13,) and (14)) are activated by nucleotides and couple to intracellular second-messenger systems through heteromeric G-proteins. Nucleotides are released or leaked from non-excitable cells as well as neurons in physiological and pathophysiological conditions. One of the most exciting cells in non-excitable cells is the glia cells, which are classified into astrocytes, oligodendrocytes, and microglia. Astrocytes express many types of P2 purinoceptors and release the 'gliotransmitter' ATP to communicate with neurons, microglia and the vascular walls of capillaries. Microglia also express many types of P2 purinoceptors and are known as resident macrophages in the CNS. ATP and other nucleotides work as 'warning molecules' especially through activating microglia in pathophysiological conditions. Microglia play a key role in neuropathic pain and show phagocytosis through nucleotide-evoked activation of P2X(4) and P2Y(6) receptors, respectively. Such strong molecular, cellular and system-level evidence for extracellular nucleotide signaling places nucleotides in the central stage of cell communications in glia/CNS.
Collapse
Affiliation(s)
- Kazuhide Inoue
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan
| | - Schuichi Koizumi
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan
| | - Makoto Tsuda
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan
| |
Collapse
|
|
47
|
Ohshiro H, Ogawa S, Shinjo K. Visualizing sensory transmission between dorsal root ganglion and dorsal horn neurons in co-culture with calcium imaging. J Neurosci Methods 2007; 165:49-54. [PMID: 17597226 DOI: 10.1016/j.jneumeth.2007.05.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2007] [Revised: 05/14/2007] [Accepted: 05/17/2007] [Indexed: 10/23/2022]
Abstract
Sensory information is conveyed to the central nervous system by primary afferent neurons within dorsal root ganglia (DRG), which synapse onto neurons of the dorsal horn of the spinal cord. This synaptic connection is central to the processing of both sensory and pain stimuli. Here, we describe a model system to monitor synaptic transmission between DRG neurons and dorsal horn neurons that is compatible with high-throughput screening. This co-culture preparation comprises DRG and dorsal horn neurons and utilizes Ca(2+) imaging with the indicator dye Fura-2 to visualize synaptic transmission. Addition of capsaicin to co-cultures stimulated DRG neurons and led to activation of dorsal horn neurons as well as increased intracellular Ca(2+) concentrations. This effect was dose-dependent and absent when DRG neurons were omitted from the culture. NMDA receptors are a critical component of synapses between DRG and dorsal horn neurons as MK-801, a use-dependent non-competitive antagonist, prevented activation of dorsal horn neurons following capsaicin treatment. This model system allows for rapid and efficient analysis of noxious stimulus-evoked Ca(2+) signal transmission and provides a new approach both for investigating synaptic transmission in the spinal cord and for screening potential analgesic compounds.
Collapse
Affiliation(s)
- Hiroyuki Ohshiro
- Discovery Biology Research, Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan
| | | | | |
Collapse
|
|
48
|
Vikman KS, Duggan AW, Siddall PJ. Interferon-gamma induced disruption of GABAergic inhibition in the spinal dorsal horn in vivo. Pain 2007; 133:18-28. [PMID: 17407800 DOI: 10.1016/j.pain.2007.02.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2006] [Revised: 02/01/2007] [Accepted: 02/01/2007] [Indexed: 01/26/2023]
Abstract
The proinflammatory cytokine interferon-gamma (IFN-gamma), which can be present in elevated levels in the central nervous system during pathological conditions, may be involved in the generation of persistent pain states by inducing neuronal hyperexcitability. The aim of the present study was to examine whether loss of dorsal horn GABAergic inhibition may underlie this IFN-gamma-mediated neuronal hyperexcitability. Repetitive intrathecal injections of recombinant rat IFN-gamma (1000 U) or control buffer were administered to rats every second day for eight days. Electrophysiological recordings from lumbar dorsal horn neurons (n=46) were performed under halothane anaesthesia. Cellular responses were recorded before, during and after microiontophoretic application of the GABA antagonist bicuculline. In control animals, all cellular responses studied were significantly enhanced in the presence of bicuculline, including increased spontaneous activity, enhanced responses to innocuous and noxious mechanical stimulation and reduced paired-pulse depression. In contrast, in IFN-gamma-treated animals, bicuculline ejection had little or no facilitating effect on neuronal responses and instead a significant proportion of neurons displayed reduced responses. Seventy-four percent of cells from IFN-gamma treated animals showed a reduction in the response to noxious stimulation and 47% of the cells showed increased rather than reduced paired-pulse depression in the presence of bicuculline, thus suggesting IFN-gamma-induced excitatory actions by GABA. These findings show that the prolonged presence of increased levels of IFN-gamma in the central nervous system may contribute to the generation of central sensitization and persistent pain by reducing inhibitory tone in the dorsal horn. This implies a potential link between disinhibition and cytokine action in the spinal cord.
Collapse
Affiliation(s)
- Kristina S Vikman
- Pain Management Research Institute, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia.
| | | | | |
Collapse
|
|
49
|
Abstract
There is abundant evidence that extracellular ATP and other nucleotides have an important role in pain signaling at both the periphery and in the CNS. The focus of attention now is on the possibility that endogenous ATP and its receptor system might be activated in chronic pathological pain states, particularly in neuropathic and inflammatory pain. Neuropathic pain is often a consequence of nerve injury through surgery, bone compression, diabetes or infection. This type of pain can be so severe that even light touching can be intensely painful; unfortunately, this state is generally resistant to currently available treatments. In this review, we summarize the role of ATP receptors, particularly the P2X4, P2X3 and P2X7 receptors, in neuropathic and inflammatory pain. The expression of P2X4 receptors in the spinal cord is enhanced in spinal microglia after peripheral nerve injury, and blocking pharmacologically and suppressing molecularly P2X4 receptors produce a reduction of the neuropathic pain behaviour. Understanding the key roles of these ATP receptors may lead to new strategies for the management of intractable chronic pain.
Collapse
Affiliation(s)
- Kazuhide Inoue
- Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka, 812-8582, Japan,
| |
Collapse
|
|
50
|
Chong A, Zhang Z, Choi KP, Choudhary V, Djamgoz MBA, Zhang G, Bajic VB. Promoter profiling and coexpression data analysis identifies 24 novel genes that are coregulated with AMPA receptor genes, GRIAs. Genomics 2007; 89:378-84. [PMID: 17208408 DOI: 10.1016/j.ygeno.2006.11.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2006] [Revised: 11/14/2006] [Accepted: 11/24/2006] [Indexed: 11/17/2022]
Abstract
We identified a set of transcriptional elements that are conserved and overrepresented within the promoters of human, mouse, and rat GRIAs by comparing these promoters against a collection of 10,741 gene promoters. Cells regulate functional groups of genes by coordinating the transcriptional and/or posttranscriptional mRNA levels of interacting genes. As such, it is expected that functional groups of genes share the same transcriptional features within their promoters. We found 47 genes whose promoters contain the same combination of transcriptional elements that are overrepresented within the promoters of the GRIA gene family. Coexpressed genes may be transcriptionally coregulated, which in turn suggests that these genes may play complementary roles within a particular functional context. Using microarray expression data, we found 24 (of the 47) genes that share not only a similar promoter profile with GRIAs but also a well-correlated gene expression profile and, thus, we believe these to be coregulated with GRIAs.
Collapse
Affiliation(s)
- Allen Chong
- Molecular Bioinformatics Group, Institute for Infocomm Research, 21 Heng Mui Keng Terrace, Singapore 119613, Singapore.
| | | | | | | | | | | | | |
Collapse
|