Microglia in Pain: Detrimental and Protective Roles in Pathogenesis and Resolution of Pain
2018; Cell Press; Volume: 100; Issue: 6 Linguagem: Inglês
10.1016/j.neuron.2018.11.009
ISSN1097-4199
AutoresGang Chen, Yu‐Qiu Zhang, Yawar J. Qadri, Charles N. Serhan, Ru‐Rong Ji,
Tópico(s)Neuropeptides and Animal Physiology
ResumoThe previous decade has seen a rapid increase in microglial studies on pain, with a unique focus on microgliosis in the spinal cord after nerve injury and neuropathic pain. Numerous signaling molecules are altered in microglia and contribute to the pathogenesis of pain. Here, we discuss how microglial signaling regulates spinal cord synaptic plasticity in acute and chronic pain conditions with different degrees and variations of microgliosis. We highlight that microglial mediators such as pro- and anti-inflammatory cytokines are powerful neuromodulators that regulate synaptic transmission and pain via neuron-glial interactions. We also reveal an emerging role of microglia in the resolution of pain, in part via specialized pro-resolving mediators including resolvins, protectins, and maresins. We also discuss a possible role of microglia in chronic itch. The previous decade has seen a rapid increase in microglial studies on pain, with a unique focus on microgliosis in the spinal cord after nerve injury and neuropathic pain. Numerous signaling molecules are altered in microglia and contribute to the pathogenesis of pain. Here, we discuss how microglial signaling regulates spinal cord synaptic plasticity in acute and chronic pain conditions with different degrees and variations of microgliosis. We highlight that microglial mediators such as pro- and anti-inflammatory cytokines are powerful neuromodulators that regulate synaptic transmission and pain via neuron-glial interactions. We also reveal an emerging role of microglia in the resolution of pain, in part via specialized pro-resolving mediators including resolvins, protectins, and maresins. We also discuss a possible role of microglia in chronic itch. Microglia are macrophage-like cells in the CNS that regulate homeostasis in the brain and spinal cord. During development, microglia originate from erythro-myeloid progenitors in the yolk sac and develop in the forming CNS (Crotti and Ransohoff, 2016Crotti A. Ransohoff R.M. Microglial physiology and pathophysiology: Insights from genome-wide transcriptional profiling.Immunity. 2016; 44: 505-515Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Increasing evidence suggests that microglia are a heterogeneous population throughout the CNS and play an active role in maintaining normal physiological conditions, as they sense the cellular environment with their ramified processes and undergo rapid morphological changes in response to mediators such as ATP (Davalos et al., 2005Davalos D. Grutzendler J. Yang G. Kim J.V. Zuo Y. Jung S. Littman D.R. Dustin M.L. Gan W.B. ATP mediates rapid microglial response to local brain injury in vivo.Nat. Neurosci. 2005; 8: 752-758Crossref PubMed Scopus (1770) Google Scholar, Hanisch and Kettenmann, 2007Hanisch U.K. Kettenmann H. Microglia: Active sensor and versatile effector cells in the normal and pathologic brain.Nat. Neurosci. 2007; 10: 1387-1394Crossref PubMed Scopus (1935) Google Scholar). During development microglia dynamically interact with synapses to modify their structures and functions in the healthy brain. For example, microglial processes engulf synapses and induce synaptic pruning during critical developmental stages, which involves the activation of the classic complement cascade (e.g., neuronal C1q and microglial C3 receptors) (Stevens et al., 2007Stevens B. Allen N.J. Vazquez L.E. Howell G.R. Christopherson K.S. Nouri N. Micheva K.D. Mehalow A.K. Huberman A.D. Stafford B. et al.The classical complement cascade mediates CNS synapse elimination.Cell. 2007; 131: 1164-1178Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar). Microglia are long-lived cells, with a median lifetime of well over 15 months, and half of all microglia survive for the entirety of a mouse’s lifespan (Füger et al., 2017Füger P. Hefendehl J.K. Veeraraghavalu K. Wendeln A.C. Schlosser C. Obermüller U. Wegenast-Braun B.M. Neher J.J. Martus P. Kohsaka S. et al.Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging.Nat. Neurosci. 2017; 20: 1371-1376Crossref PubMed Scopus (20) Google Scholar). Microglia are emerging as key regulators of brain diseases. These include neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, stroke, neuropsychiatric diseases, for instance, depression and anxiety, and neurodevelopmental diseases such as autism (Crotti and Ransohoff, 2016Crotti A. Ransohoff R.M. 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Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior.Nat. Neurosci. 2014; 17: 400-406Crossref PubMed Scopus (345) Google Scholar). Microglia contribute to the pathogenesis of brain diseases via regulation of neuroinflammation, a localized inflammation in the peripheral nervous system and central nervous system (CNS) (Heppner et al., 2015Heppner F.L. Ransohoff R.M. Becher B. Immune attack: The role of inflammation in Alzheimer disease.Nat. Rev. Neurosci. 2015; 16: 358-372Crossref PubMed Scopus (536) Google Scholar, Ji et al., 2014Ji R.R. Xu Z.Z. Gao Y.J. Emerging targets in neuroinflammation-driven chronic pain.Nat. Rev. Drug Discov. 2014; 13: 533-548Crossref PubMed Scopus (222) Google Scholar, Ransohoff, 2016Ransohoff R.M. How neuroinflammation contributes to neurodegeneration.Science. 2016; 353: 777-783Crossref PubMed Google Scholar). A PubMed query reveals hundreds to thousands of publications demonstrating the role of microglia in each of these diseases (Figure 1A). Notably, there are over sixteen hundred publications on microglia and pain, showing a rapid increase in the last 10 years (Figure 1B). While the majority of studies on microglia and brain diseases focus on how microglia effect synaptic pruning and neurodegeneration, pain researchers searched for neuromodulators produced by microglia that can rapidly modulate synaptic plasticity, a driving force for the pathogenesis of pain after tissue and nerve injury (Luo et al., 2014Luo C. Kuner T. Kuner R. Synaptic plasticity in pathological pain.Trends Neurosci. 2014; 37: 343-355Abstract Full Text Full Text PDF PubMed Google Scholar, Woolf and Salter, 2000Woolf C.J. Salter M.W. Neuronal plasticity: Increasing the gain in pain.Science. 2000; 288: 1765-1769Crossref PubMed Scopus (2521) Google Scholar). The injury-induced synaptic plasticity in the spinal cord and brain pain circuits is also termed central sensitization, which sustains chronic pain and causes widespread pain beyond the initial injury site (Ji et al., 2018Ji R.R. Nackley A. Huh Y. Terrando N. Maixner W. Neuroinflammation and central sensitization in chronic pain.Anesthesiology. 2018; 129: 343-366Crossref PubMed Google Scholar, Woolf, 1983Woolf C.J. Evidence for a central component of post-injury pain hypersensitivity.Nature. 1983; 306: 686-688Crossref PubMed Google Scholar). Another striking difference between pain and other neurological diseases is the rapid onset of pain: microglia regulate neuronal and synaptic activities to change pain behavior within minutes to tens of minutes following treatment with microglial activators and inhibitors (Berta et al., 2014Berta T. Park C.K. Xu Z.Z. Xie R.G. Liu T. Lü N. Liu Y.C. Ji R.R. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion.J. 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This was first reported in 1975 when Gilmore showed proliferation of non-neuronal cells (also called “neuro-glia”) in spinal cords of irradiated, immature rats following transection of the sciatic nerve (Gilmore, 1975Gilmore S.A. Proliferation of non-neuronal cells in spinal cords of irradiated, immature rats following transection of the sciatic nerve.Anat. Rec. 1975; 181: 799-811Crossref PubMed Scopus (8) Google Scholar). Gilmore and Skinner further reported that sciatic nerve injury in adult rats also resulted in a proliferation of non-neuronal cells in the spinal cord using Nissl and H&E staining (Gilmore and Skinner, 1979Gilmore S.A. Skinner R.D. Intraspinal non-neuronal cellular responses to peripheral nerve injury.Anat. Rec. 1979; 194: 369-387Crossref PubMed Google Scholar). In 1993, Eriksson and his coworkers demonstrated remarkable microgliosis in the pain-modulating spinal cord and brain stem regions after nerve injury using immunostaining of OX-42, an antibody that recognizes complement receptor CR3 (CD11b) (Eriksson et al., 1993Eriksson N.P. Persson J.K. Svensson M. Arvidsson J. Molander C. Aldskogius H. A quantitative analysis of the microglial cell reaction in central primary sensory projection territories following peripheral nerve injury in the adult rat.Exp. Brain Res. 1993; 96: 19-27Crossref PubMed Scopus (124) Google Scholar), with others reproducing a profound microglial proliferation, evident within 2 days after nerve injury (Beggs and Salter, 2007Beggs S. Salter M.W. Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury.Brain Behav. Immun. 2007; 21: 624-633Crossref PubMed Scopus (88) Google Scholar, Echeverry et al., 2008Echeverry S. Shi X.Q. Zhang J. Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain.Pain. 2008; 135: 37-47Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Suter et al., 2007Suter M.R. Wen Y.R. Decosterd I. Ji R.R. Do glial cells control pain?.Neuron Glia Biol. 2007; 3: 255-268Crossref PubMed Scopus (0) Google Scholar). Insights into the specific role of microglia in pain were revealed in 2003 when three separate groups showed microglial involvement in neuropathic pain after peripheral nerve injury (Jin et al., 2003Jin S.X. Zhuang Z.Y. Woolf C.J. Ji R.R. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain.J. Neurosci. 2003; 23: 4017-4022Crossref PubMed Google Scholar, Raghavendra et al., 2003Raghavendra V. Tanga F. DeLeo J.A. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy.J. Pharmacol. Exp. Ther. 2003; 306: 624-630Crossref PubMed Scopus (570) Google Scholar, Tsuda et al., 2003Tsuda M. Shigemoto-Mogami Y. Koizumi S. Mizokoshi A. Kohsaka S. Salter M.W. Inoue K. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury.Nature. 2003; 424: 778-783Crossref PubMed Scopus (970) Google Scholar). Jin et al. reported that spinal nerve ligation evokes phosphorylation of p38 MAP kinase (P-p38, an active form of p38) only in CD11b (OX-42)-expressing spinal microglia but not in GFAP-expressing astrocytes or NeuN-expressing neurons, and, furthermore, intrathecal injection of a p38 inhibitor reduced mechanical allodynia, a cardinal feature of neuropathic pain after nerve injury (Jin et al., 2003Jin S.X. Zhuang Z.Y. Woolf C.J. Ji R.R. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain.J. Neurosci. 2003; 23: 4017-4022Crossref PubMed Google Scholar). Raghavendra et al. showed that spinal injection of minocycline, a non-specific microglial inhibitor, inhibited mechanical hyperalgesia and allodynia in the early phase but not the late phase after spinal nerve transection. This inhibition in the early phase of nerve injury was associated with inhibition of microglial activation in the spinal cord (Raghavendra et al., 2003Raghavendra V. Tanga F. DeLeo J.A. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy.J. Pharmacol. Exp. Ther. 2003; 306: 624-630Crossref PubMed Scopus (570) Google Scholar). Tsuda et al. demonstrated that spinal injection of ATP-activated microglia was sufficient to evoke rapid mechanical allodynia within 1 hr of treatment. Furthermore, they found (1) nerve injury results in upregulation of the ATP receptor subtype P2X4 exclusively in spinal cord microglia and (2) spinal inhibition of P2X4 attenuated mechanical allodynia (Tsuda et al., 2003Tsuda M. Shigemoto-Mogami Y. Koizumi S. Mizokoshi A. Kohsaka S. Salter M.W. Inoue K. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury.Nature. 2003; 424: 778-783Crossref PubMed Scopus (970) Google Scholar). In 2004, Tsuda et al. also confirmed the role of p38 in spinal microglia for the development of mechanical allodynia after nerve injury (Tsuda et al., 2004Tsuda M. Mizokoshi A. Shigemoto-Mogami Y. Koizumi S. Inoue K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury.Glia. 2004; 45: 89-95Crossref PubMed Scopus (365) Google Scholar). In 2005, Coull et al. demonstrated that spinal microglia produce the brain-derived neurotrophic factor (BDNF) to drive neuropathic pain (Coull et al., 2005Coull J.A. Beggs S. Boudreau D. Boivin D. Tsuda M. Inoue K. Gravel C. Salter M.W. De Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain.Nature. 2005; 438: 1017-1021Crossref PubMed Scopus (1088) Google Scholar). A major issue in microglia research is the lack of selective pharmacological tools. Grace and collaborators developed Gq- and Gi-coupled DREADDs (designer receptor exclusively activated by a designer drug) for selective activation or inhibition of microglia. DREADDs under a CD68 promoter were intrathecally transfected via an AAV9 vector to target microglia or macrophages. Activation of microglia with Gq (stimulatory) DREADD, which is stimulated by its clozapine-N-oxide (CNO) ligand, is sufficient to induce mechanical allodynia via interleukin-1 (IL-1) secretion, as this allodynia can be abolished by intrathecal IL-1 receptor antagonist. In contrast, nerve-injury-induced allodynia is attenuated by intrathecal activation of Gi (inhibitory) DREADD (Grace et al., 2016Grace P.M. Strand K.A. Galer E.L. Urban D.J. Wang X. Baratta M.V. Fabisiak T.J. Anderson N.D. Cheng K. Greene L.I. et al.Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.Proc. Natl. Acad. Sci. USA. 2016; 113: E3441-E3450Crossref PubMed Scopus (226) Google Scholar, Grace et al., 2018Grace P.M. Wang X. Strand K.A. Baratta M.V. Zhang Y. Galer E.L. Yin H. Maier S.F. Watkins L.R. DREADDed microglia in pain: Implications for spinal inflammatory signaling in male rats.Exp. Neurol. 2018; 304: 125-131Crossref PubMed Scopus (2) Google Scholar). This chemogenetic approach further supports a critical role of spinal microglia in establishing mechanical allodynia. There are a number of excellent reviews that focus on the role of microglia in neuropathic pain (Clark and Malcangio, 2012Clark A.K. Malcangio M. Microglial signalling mechanisms: Cathepsin S and Fractalkine.Exp. Neurol. 2012; 234: 283-292Crossref PubMed Scopus (0) Google Scholar, Inoue and Tsuda, 2018Inoue K. Tsuda M. Microglia in neuropathic pain: Cellular and molecular mechanisms and therapeutic potential.Nat. Rev. Neurosci. 2018; 19: 138-152Crossref PubMed Scopus (8) Google Scholar, McMahon and Malcangio, 2009McMahon S.B. Malcangio M. Current challenges in glia-pain biology.Neuron. 2009; 64: 46-54Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, Salter and Stevens, 2017Salter M.W. 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Microglia in the spinal cord horn are strongly activated after peripheral nerve injury (Guan et al., 2016Guan Z. Kuhn J.A. Wang X. Colquitt B. Solorzano C. Vaman S. Guan A.K. Evans-Reinsch Z. Braz J. Devor M. et al.Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain.Nat. Neurosci. 2016; 19: 94-101Crossref PubMed Scopus (96) Google Scholar, Tsuda et al., 2005Tsuda M. Inoue K. Salter M.W. Neuropathic pain and spinal microglia: A big problem from molecules in “small” glia.Trends Neurosci. 2005; 28: 101-107Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar). Spinal microglial activation after nerve injury requires neuronal activity (Wen et al., 2007Wen Y.R. Suter M.R. Kawasaki Y. Huang J. Pertin M. Kohno T. Berde C.B. Decosterd I. Ji R.R. Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve injury model.Anesthesiology. 2007; 107: 312-321Crossref PubMed Scopus (0) Google Scholar, Xie et al., 2009Xie W. Strong J.A. Zhang J.M. Early blockade of injured primary sensory afferents reduces glial cell activation in two rat neuropathic pain models.Neuroscience. 2009; 160: 847-857Crossref PubMed Scopus (0) Google Scholar). While C-fiber activation is sufficient to elicit spinal microglial activation (Gruber-Schoffnegger et al., 2013Gruber-Schoffnegger D. Drdla-Schutting R. Hönigsperger C. Wunderbaldinger G. Gassner M. Sandkühler J. Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-α and IL-1β is mediated by glial cells.J. Neurosci. 2013; 33: 6540-6551Crossref PubMed Scopus (0) Google Scholar, Hathway et al., 2009Hathway G.J. Vega-Avelaira D. Moss A. 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Guan et al. show that peripheral nerve injury induces a rapid increase in the expression of colony stimulating factor 1 (CSF1) in injured DRG neurons (Guan et al., 2016Guan Z. Kuhn J.A. Wang X. Colquitt B. Solorzano C. Vaman S. Guan A.K. Evans-Reinsch Z. Braz J. Devor M. et al.Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain.Nat. Neurosci. 2016; 19: 94-101Crossref PubMed Scopus (96) Google Scholar, Okubo et al., 2016Okubo M. Yamanaka H. Kobayashi K. Dai Y. Kanda H. Yagi H. Noguchi K. Macrophage-colony stimulating factor derived from injured primary afferent induces proliferation of spinal microglia and neuropathic pain in rats.PLoS ONE. 2016; 11: e0153375Crossref PubMed Scopus (21) Google Scholar). The CSF1 released from damaged primary afferents acts on spinal microglia to induce microgliosis and pain behaviors. Spinal injection of CSF1 inhibitor (Okubo et al., 2016Okubo M. Yamanaka H. Kobayashi K. Dai Y. Kanda H. Yagi H. Noguchi K. Macrophage-colony stimulating factor derived from injured primary afferent induces proliferation of spinal microglia and neuropathic pain in rats.PLoS ONE. 2016; 11: e0153375Crossref PubMed Scopus (21) Google Scholar) or Cre-mediated deletion of Csf1 in DRG neurons (Guan et al., 2016Guan Z. Kuhn J.A. Wang X. Colquitt B. Solorzano C. Vaman S. Guan A.K. Evans-Reinsch Z. Braz J. Devor M. et al.Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain.Nat. Neurosci. 2016; 19: 94-101Crossref PubMed Scopus (96) Google Scholar) both attenuate nerve-injury-induced microgliosis and mechanical allodynia. Furthermore, intrathecal injection of CSF1 in naive mice induced mechanical hypersensitivity and microgliosis (Guan et al., 2016Guan Z. Kuhn J.A. Wang X. Colquitt B. Solorzano C. Vaman S. Guan A.K. Evans-Reinsch Z. Braz J. Devor M. et al.Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain.Nat. Neurosci. 2016; 19: 94-101Crossref PubMed Scopus (96) Google Scholar). Sensory neurons also release several chemokines after nerve injury to activate microglia. CCL2 is strongly upregulated in DRG neurons by nerve injury and contributes to neuropathic pain via CCR2 receptor (White et al., 2005White F.A. Sun J. Waters S.M. Ma C. Ren D. Ripsch M. Steflik J. Cortright D.N. Lamotte R.H. Miller R.J. Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion.Proc. Natl. Acad. Sci. USA. 2005; 102: 14092-14097Crossref PubMed Scopus (0) Google Scholar). Although CCR2 was implicated in microglial activation in neuropathic pain (Abbadie et al., 2003Abbadie C. Lindia J.A. Cumiskey A.M. Peterson L.B. Mudgett J.S. Bayne E.K. DeMartino J.A. MacIntyre D.E. Forrest M.J. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2.Proc. Natl. Acad. Sci. 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JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain.J. Neurosci. 2009; 29: 4096-4108Crossref PubMed Scopus (319) Google Scholar, White et al., 2005White F.A. Sun J. Waters S.M. Ma C. Ren D. Ripsch M. Steflik J. Cortright D.N. Lamotte R.H. Miller R.J. Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion.Proc. Natl. Acad. Sci. USA. 2005; 102: 14092-14097Crossref PubMed Scopus (0) Google Scholar). It is well documented that CXCL1, released from DRG neurons, induces microgliosis and mechanical allodynia via CX3CR1 (Clark and Malcangio, 2012Clark A.K. Malcangio M. Microglial signalling mechanisms: Cathepsin S and Fractalkine.Exp. Neurol. 2012; 234: 283-292Crossref PubMed Scopus (0) Google Scholar). Furthermore, liberation of CXCL1 from the DRG cell surface requires cathepsin S (Clark et al., 2009Clark A.K. Yip P.K. Malcangio M. The liberation of fractalkine in the dorsal horn requires microglial cathepsin S.J. Neurosci. 2009; 29: 6945-6954Crossref PubMed Scopus (108) Google Scholar). Additionally, CCL21 is rapidly induced in a small population of DRG neurons and enhances microglial activation and neuropathic pain via CCR7 receptor (Biber et al., 2011Biber K. Tsuda M. Tozaki-Saitoh H. Tsukamoto K. Toyomitsu E. Masuda T. Boddeke H. Inoue K. Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development.EMBO J. 2011; 30: 1864-1873Crossref PubMed Scopus (89) Google Scholar). Neuronal proteases also play an important role in microglia activation. Nerve injury induces a rapid and transient upregulation of metalloproteinase-9 (MMP-9) expression in injured DRG neurons, which contributes to the induction but not maintenance of neuropathic pain (Ji et al., 2009Ji R.R. Xu Z.Z. Wang X. Lo E.H. Matrix metalloprotease regulation of neuropathic pain.Trends Pharmacol. Sci. 2009; 30: 336-340Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Intrathecal MMP-9 administration produces neuropathic pain symptoms and microgliosis through IL-1β cleavage. Conversely, MMP-9 inhibition or knockdown reduces microgliosis and mechanical allodynia (Kawasaki et al., 2008aKawasaki Y. Xu Z.Z. Wang X. Park J.Y. Zhuang Z.Y. Tan P.H. Gao Y.J. Roy K. Corfas G. Lo E.H. Ji R.R. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain.Nat. Med. 2008; 14: 331-336Crossref PubMed Scopus (392) Google Scholar). Caspase 6, a cysteine-aspartic acid protease, is specifically expressed by axonal terminals in the spinal cord and released to the cerebrospinal fluid by neuronal activation (Berta et al., 2014Berta T. Park C.K. Xu Z.Z. Xie R.G. Liu T. Lü N. Liu Y.C. Ji R.R. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion.J. Clin. Invest. 2014; 124: 1173-1186Crossref PubMed Scopus (65) Google Scholar). Nerve injury causes a profound upregulation of caspase-6 mRNA in injured DRG neurons, which contributes to microglial activation and neuropathic pain (Berta et al., 2016Berta T. Qadri Y.J. Chen G. Ji R.R. Microglial signaling in chronic pain with a special focus on caspase 6, p38 MAP kinase, and sex dependence.J. Dent. Res. 2016; 95: 1124-1131Crossref PubMed Scopus (15) Google Scholar, Berta et al., 2017Berta T. Perrin F.E. Pertin M. Tonello R. Liu Y.C. Chamessian A. Kato A.C. Ji R.R. Decosterd I. Gene Expression Profiling of Cutaneous Injured and Non-Injured Nociceptors in SNI Animal Model of Neuropathic Pain.Sci. Rep. 2017; 7: 9367Crossref PubMed Scopus (4) Google Scholar). Extracellular application of caspase-6 triggers a substance tumor necrosis factor (TNF) release from microglia, leading to TNF-dependent pain following intrathecal injection (Berta et al., 2014Berta T. Park C.K. Xu Z.Z. Xie R.G. Liu T. Lü N. Liu Y.C. Ji R.R. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion.J. Clin. Invest. 2014; 124: 1173-1186Crossref PubMed Scopus (65) Google Scholar). Following peripheral nerve injury, Neuregulin-1 is also released from primary afferents to activate ErbB receptors on spinal microglia. Intrathecal injection of neuregulin-1 induced microgliosis and development of pain hypersensitivity via phosphorylation of ERK1/2 (extracellular signal-related kinase 1/2) and Akt in microglia (Calvo et al., 2010Calvo M. Zhu N. Tsantoulas C. Ma Z. Grist J. Loeb J.A. Bennett D.L. Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury.J. Neurosci. 2010; 30: 5437-5450Crossref PubMed Scopus (92) Google Scholar). Once microglia are activated by the activators released after nerve injury, various microglial signaling molecules are upregulated in the spinal cord dorsal horn, including cell-surface receptors, as well as intracellular and secreted signaling molecules (Table 1).Table 1Microglial Signal Molecules that Are Upregulated after Peripheral Nerve Injury and Positively Contribute to Promoting Neuropathic Pain (Mechanical Allodynia)Upregulation of Signaling MoleculesNerve Injury ModelsContribution to Mechanical AllodyniaReferencesPurine
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