Pathological pain and the neuroimmune interface

Grace, Peter M.; Hutchinson, Mark R.; Maier, Steven F.; Watkins, Linda R.

doi:10.1038/nri3621

Cited by 754 publications

(820 citation statements)

References 175 publications

(244 reference statements)

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“…Glial and neuroimmune mechanisms have been extensively characterized in the context of pathological pain (Grace et al, 2014a), while researchers attempting to decode the complex etiology of neurodegenerative disorders such as Alzheimer's disease have also argued for a more holistic framework, where the interactions and compensatory responses between neurons, glia, and vascular cells all contribute to the progression of the disease (De Strooper and Karran, 2016). Given their role in immune surveillance and debris clearance, it is perhaps unsurprising that microglial activation in particular has been implicated in neurodegenerative diseases beyond Alzheimer's disease, including multiple sclerosis and Parkinson's disease (Chung et al, 2015b;Heneka et al, 2015;Hong et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

223

170

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Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

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Section: Resultsmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

223

170

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“…Emerging evidence suggests that the peripheral and central neuroinflammation associated with the chemokine-cytokine network following nerve damage plays pivotal roles in the pathogenesis of neuropathic pain [2,3]. Thus, further investigation of the functions of the chemokinecytokine network-mediated regulation of neuroinflammation might lead to novel therapeutic strategies [4].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

Bai

Wang

et al. 2016

Neurosci. Bull.

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Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mechanism. Here, we determined that spared nerve injury (SNI) increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia (DRG) neurons and satellite glial cells. SNI also induced longlasting upregulation of CXCL12 and CXCR4 in the ipsilateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNIinduced a sustained increase in TNF-a expression in the DRG and spinal cord. Intraperitoneal injection (i.p.) of the TNF-a synthesis inhibitor thalidomide reduced the SNI-induced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection (i.t.) of the CXCR4 antagonist AMD3100, both 30 min before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. administration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the activation of ERK in the spinal cord. The mechanical hypersensitivity induced in naïve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-a might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL12/CXCR4 signaling via ERK activation contributes to the development and maintenance of neuropathic pain.

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“…Factors that sensitize nociceptors include those secreted by infiltrating/activated leukocytes, such as cytokines/ chemokines, growth factors, and lipids, and those released from damaged cells, such as ATP, H + , and reactive compounds like hydroxynonenals (4)(5)(6)(7). Despite the common assumption that immune cells are the major drivers of inflammatory pain, the exact cell types involved and their roles in different types of tissue inflammation have not yet been elucidated.…”

mentioning

confidence: 99%

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

Ghasemlou

Chiu

Julien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

156

135

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Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund's adjuvant (CFA) as a model of adjuvant-and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G + CD11b + neutrophils and T-cell receptor (TCR) β + T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b + Ly6G − myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2 + Ly6C hi ) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b + Ly6G − myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation.pain | inflammation | cytokines | monocytes | macrophages

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Pathological pain and the neuroimmune interface

Cited by 754 publications

References 175 publications

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity

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Pathological pain and the neuroimmune interface

Cited by 754 publications

References 175 publications

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

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CD11b⁺Ly6G⁻myeloid cells mediate mechanical inflammatory pain hypersensitivity