Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).
Todd, A. J. Neuronal circuitry for pain processing in the dorsal horn. Nat. Rev. Neurosci. 11, 823–836 (2010).
Braz, J., Solorzano, C., Wang, X. & Basbaum, A. I. Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 82, 522–536 (2014).
Peirs, C. & Seal, R. P. Neural circuits for pain: recent advances and current views. Science 354, 578–584 (2016).
Bushnell, M. C., Ceko, M. & Low, L. A. Cognitive and emotional control of pain and its disruption in chronic pain. Nat. Rev. Neurosci. 14, 502–511 (2013).
Bliss, T. V., Collingridge, G. L., Kaang, B. K. & Zhuo, M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat. Rev. Neurosci. 17, 485–496 (2016).
Melzack, R. & Wall, P. D. Pain mechanisms: a new theory. Science 150, 971–979 (1965).
Colloca, L. et al. Neuropathic pain. Nat. Rev. Dis. Primers 3, 17002 (2017).
Kuner, R. & Flor, H. Structural plasticity and reorganisation in chronic pain. Nat. Rev. Neurosci. 18, 20–30 (2016).
Woolf, C. J. & Salter, M. W. Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1769 (2000).
Lu, Y. et al. A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia. J. Clin. Invest. 123, 4050–4062 (2013).
Duan, B. et al. Identification of spinal circuits transmitting and gating mechanical pain. Cell 159, 1417–1432 (2014).
Petitjean, H. et al. Dorsal horn parvalbumin neurons are gate-keepers of touch-evoked pain after nerve injury. Cell Rep. 13, 1246–1257 (2015).
Peirs, C. et al. Dorsal horn circuits for persistent mechanical pain. Neuron 87, 797–812 (2015).
Foster, E. et al. Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch. Neuron 85, 1289–1304 (2015).
Cheng, L. et al. Identification of spinal circuits involved in touch-evoked dynamic mechanical pain. Nat. Neurosci. 20, 804–814 (2017).
Ji, R. R., Xu, Z. Z. & Gao, Y. J. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13, 533–548 (2014).
Gilmore, S. A. Proliferation of non-neuronal cells in spinal cords of irradiated, immature rats following transection of the sciatic nerve. Anat. Rec. 181, 799–811 (1975).
Gilmore, S. A. & Skinner, R. D. Intraspinal non-neuronal cellular responses to peripheral nerve injury. Anat. Rec. 194, 369–387 (1979).
Bennett, G. J. & Xie, Y. K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87–107 (1988).
Seltzer, Z., Dubner, R. & Shir, Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 43, 205–218 (1990).
Kim, S. H. & Chung, J. M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355–363 (1992).
Decosterd, I. & Woolf, C. J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 (2000).
Raghavendra, 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. 306, 624–630 (2003).
Colburn, R. W. et al. Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J. Neuroimmunol. 79, 163–175 (1997).
Inoue, K. & Tsuda, M. Microglia and neuropathic pain. Glia 57, 1469–1479 (2009).
Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003).
This study shows a causal role of spinal microglia expressing P2X4 in a rodent model of neuropathic pain.
Jin, 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. 23, 4017–4022 (2003).
This study shows that spinal microglia contribute to pain hypersensitivity after PNI via activation of p38 MAPKs.
Milligan, E. D. et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur. J. Neurosci. 20, 2294–2302 (2004).
Clark, A. K. et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl Acad. Sci. USA 104, 10655–10660 (2007).
Zhuang, Z. Y. et al. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav. Immun. 21, 642–651 (2007).
Tsuda, M. et al. IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc. Natl Acad. Sci. USA 106, 8032–8037 (2009).
Guan, Z. et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94–101 (2016).
This study demonstrates that CSF1 expression is induced in injured DRG neurons and that this triggers microglial proliferation and neuropathic pain.
Kobayashi, M., Konishi, H., Sayo, A., Takai, T. & Kiyama, H. TREM2/DAP12 signal elicits proinflammatory response in microglia and exacerbates neuropathic pain. J. Neurosci. 36, 11138–11150 (2016).
Sawada, A. et al. Suppression of bone marrow-derived microglia in the amygdala improves anxiety-like behavior induced by chronic partial sciatic nerve ligation in mice. Pain 155, 1762–1772 (2014).
Taylor, A. M. et al. Microglia disrupt mesolimbic reward circuitry in chronic pain. J. Neurosci. 35, 8442–8450 (2015).
Liu, Y. et al. TNF-alpha differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. J. Neurosci. 37, 871–881 (2017).
Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).
Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).
Wake, H., Moorhouse, A. J., Miyamoto, A. & Nabekura, J. Microglia: actively surveying and shaping neuronal circuit structure and function. Trends Neurosci. 36, 209–217 (2013).
Gu, N. et al. Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain. Brain Behav. Immun. 55, 82–92 (2016).
Batti, L. et al. TMEM16F regulates spinal microglial function in neuropathic pain states. Cell Rep. 15, 2608–2615 (2016).
Tozaki-Saitoh, H. et al. P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J. Neurosci. 28, 4949–4956 (2008).
Gehrmann, J. & Banati, R. B. Microglial turnover in the injured CNS: activated microglia undergo delayed DNA fragmentation following peripheral nerve injury. J. Neuropathol. Exp. Neurol. 54, 680–688 (1995).
Tsuda, M. et al. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain 134, 1127–1139 (2011).
Gu, N. et al. Spinal microgliosis due to resident microglial proliferation is required for pain hypersensitivity after peripheral nerve injury. Cell Rep. 16, 605–614 (2016).
Zhang, J. et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J. Neurosci. 27, 12396–12406 (2007).
Tashima, R. et al. Bone marrow-derived cells in the population of spinal microglia after peripheral nerve injury. Sci. Rep. 6, 23701 (2016).
This study shows little contribution of circulating bone-marrow-derived cells to the population of spinal microglia after PNI.
Larochelle, A., Bellavance, M. A., Michaud, J. P. & Rivest, S. Bone marrow-derived macrophages and the CNS: an update on the use of experimental chimeric mouse models and bone marrow transplantation in neurological disorders. Biochim. Biophys. Acta 1862, 310–322 (2015).
Denk, F., Crow, M., Didangelos, A., Lopes, D. M. & McMahon, S. B. Persistent alterations in microglial enhancers in a model of chronic pain. Cell Rep. 15, 1771–1781 (2016).
Lim, H., Lee, H., Noh, K. & Lee, S. J. IKK/NF-kappaB-dependent satellite glia activation induces spinal cord microglia activation and neuropathic pain after nerve injury. Pain 158, 1666–1677 (2017).
Svendsen, K. B., Jensen, T. S., Hansen, H. J. & Bach, F. W. Sensory function and quality of life in patients with multiple sclerosis and pain. Pain 114, 473–481 (2005).
Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).
Honore, P. et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 98, 585–598 (2000).
Okubo, M. et al. Macrophage-colony stimulating factor derived from injured primary afferent induces proliferation of spinal microglia and neuropathic pain in rats. PLoS ONE 11, e0153375 (2016).
McVicar, D. W. & Trinchieri, G. CSF-1R, DAP12 and beta-catenin: a menage a trois. Nat. Immunol. 10, 681–683 (2009).
Polgar, E., Hughes, D. I., Arham, A. Z. & Todd, A. J. Loss of neurons from laminas I-III of the spinal dorsal horn is not required for development of tactile allodynia in the spared nerve injury model of neuropathic pain. J. Neurosci. 25, 6658–6666 (2005).
Tay, T. L. et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20, 793–803 (2017).
Moss, A. et al. Spinal microglia and neuropathic pain in young rats. Pain 128, 215–224 (2007).
McKelvey, R., Berta, T., Old, E., Ji, R. R. & Fitzgerald, M. Neuropathic pain is constitutively suppressed in early life by anti-inflammatory neuroimmune regulation. J. Neurosci. 35, 457–466 (2015).
Griffin, R. S. et al. Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity. J. Neurosci. 27, 8699–8708 (2007).
Jeong, H. et al. High-resolution transcriptome analysis reveals neuropathic pain gene-expression signatures in spinal microglia after nerve injury. Pain 157, 964–976 (2016).
Tamura, T., Yanai, H., Savitsky, D. & Taniguchi, T. The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 26, 535–584 (2008).
Masuda, T. et al. IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Rep. 1, 334–340 (2012).
Masuda, T. et al. Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. Nat. Commun. 5, 3771 (2014).
This study provides evidence that the IRF8–IRF5 transcriptional cascade is necessary for producing P2X4-expressing microglia after PNI and in neuropathic pain.
Masuda, T. et al. Transcription factor IRF1 is responsible for IRF8-mediated IL-1beta expression in reactive microglia. J. Pharmacol. Sci. 128, 216–220 (2015).
Holtman, I. R., Skola, D. & Glass, C. K. Transcriptional control of microglia phenotypes in health and disease. J. Clin. Invest. 127, 3220–3229 (2017).
Coull, J. A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).
This study identifies a mechanism of signalling from activated microglia to SDH neurons that is causally associated with neuropathic pain.
Ulmann, L. et al. Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. J. Neurosci. 28, 11263–11268 (2008).
Tsuda, M. et al. Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays. Mol. Pain 5, 28 (2009).
Biber, K. et al. Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J. 30, 1864–1873 (2011).
Tsuda, M., Masuda, T., Tozaki-Saitoh, H. & Inoue, K. P2X4 receptors and neuropathic pain. Front. Cell Neurosci. 7, 191 (2013).
Nakatsuka, T. & Gu, J. G. ATP P2X receptor-mediated enhancement of glutamate release and evoked EPSCs in dorsal horn neurons of the rat spinal cord. J. Neurosci. 21, 6522–6531 (2001).
Fam, S. R., Gallagher, C. J. & Salter, M. W. P2Y1 purinoceptor-mediated Ca2+ signaling and Ca2+ wave propagation in dorsal spinal cord astrocytes. J. Neurosci. 20, 2800–2808 (2000).
Imura, Y. et al. Microglia release ATP by exocytosis. Glia 61, 1320–1330 (2013).
Burma, N. E. et al. Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents. Nat. Med. 23, 355–360 (2017).
Jo, Y. H. & Schlichter, R. Synaptic corelease of ATP and GABA in cultured spinal neurons. Nat. Neurosci. 2, 241–245 (1999).
Masuda, T. et al. Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain. Nat. Commun. 7, 12529 (2016).
This study reports that SDH neurons are the principal source of extracellular ATP in the spinal cord that causes PNI-induced pain hypersensitivity.
Sawada, K. et al. Identification of a vesicular nucleotide transporter. Proc. Natl Acad. Sci. USA 105, 5683–5686 (2008).
Trang, T., Beggs, S., Wan, X. & Salter, M. W. P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J. Neurosci. 29, 3518–3528 (2009).
Hildebrand, M. E. et al. Potentiation of synaptic GluN2B NMDAR currents by fyn kinase is gated through BDNF-mediated disinhibition in spinal pain processing. Cell Rep. 17, 2753–2765 (2016).
Keller, A. F., Beggs, S., Salter, M. W. & De Koninck, Y. Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain. Mol. Pain 3, 27 (2007).
Sorge, R. E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18, 1081–1083 (2015).
Lever, I., Cunningham, J., Grist, J., Yip, P. K. & Malcangio, M. Release of BDNF and GABA in the dorsal horn of neuropathic rats. Eur. J. Neurosci. 18, 1169–1174 (2003).
Zhao, J. et al. Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Mol. Cell Neurosci. 31, 539–548 (2006).
Inoue, K. The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol. Ther. 109, 210–226 (2006).
Chessell, I. P. et al. Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114, 386–396 (2005).
Kobayashi, K., Takahashi, E., Miyagawa, Y., Yamanaka, H. & Noguchi, K. Induction of the P2X7 receptor in spinal microglia in a neuropathic pain model. Neurosci. Lett. 504, 57–61 (2011).
Tanga, F. Y., Nutile-McMenemy, N. & DeLeo, J. A. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc. Natl Acad. Sci. USA 102, 5856–5861 (2005).
Kim, D. et al. A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J. Biol. Chem. 282, 14975–14983 (2007).
Clark, A. K. et al. P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide. J. Neurosci. 30, 573–582 (2010).
Heneka, M. T., Kummer, M. P. & Latz, E. Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14, 463–477 (2014).
Di Virgilio, F., Dal Ben, D., Sarti, A. C., Giuliani, A. L. & Falzoni, S. The P2X7 receptor in infection and inflammation. Immunity 47, 15–31 (2017).
Reeve, A. J., Patel, S., Fox, A., Walker, K. & Urban, L. Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur. J. Pain 4, 247–257 (2000).
Kawasaki, Y., Zhang, L., Cheng, J. K. & Ji, R. R. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J. Neurosci. 28, 5189–5194 (2008).
Clark, A. K. et al. Selective activation of microglia facilitates synaptic strength. J. Neurosci. 35, 4552–4570 (2015).
Viviani, B. et al. Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J. Neurosci. 23, 8692–8700 (2003).
Miyoshi, K., Obata, K., Kondo, T., Okamura, H. & Noguchi, K. Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J. Neurosci. 28, 12775–12787 (2008).
Zhuang, Z. Y. et al. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J. Neurosci. 26, 3551–3560 (2006).
Kohro, Y. et al. A new minimally-invasive method for microinjection into the mouse spinal dorsal horn. Sci. Rep. 5, 14306 (2015).
Kanda, H., Kobayashi, K., Yamanaka, H., Okubo, M. & Noguchi, K. Microglial TNFα induces COX2 and PGI2 synthase expression in spinal endothelial cells during neuropathic pain. eNeuro https://doi.org/10.1523/ENEURO.0064-17.2017 (2017).
Tsuda, 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 45, 89–95 (2004).
Kronschlager, M. T. et al. Gliogenic LTP spreads widely in nociceptive pathways. Science 354, 1144–1148 (2016).
Park, C. K. et al. Resolving TRPV1- and TNF-alpha-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J. Neurosci. 31, 15072–15085 (2011).
Gao, Y. J. et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J. Neurosci. 29, 4096–4108 (2009).
Chen, G. et al. Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice. Brain 137, 2193–2209 (2014).
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
Oida, H. et al. In situ hybridization studies of prostacyclin receptor mRNA expression in various mouse organs. Br. J. Pharmacol. 116, 2828–2837 (1995).
Clark, A. K. & Malcangio, M. Fractalkine/CX3CR1 signaling during neuropathic pain. Front. Cell Neurosci. 8, 121 (2014).
Limatola, C. & Ransohoff, R. M. Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Front. Cell Neurosci. 8, 229 (2014).
Kanda, H., Kobayashi, K., Yamanaka, H. & Noguchi, K. COX-1-dependent prostaglandin D2 in microglia contributes to neuropathic pain via DP2 receptor in spinal neurons. Glia 61, 943–956 (2013).
Shindou, H. et al. Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop. FASEB J. 31, 2973–2980 (2017).
Okubo, M., Yamanaka, H., Kobayashi, K. & Noguchi, K. Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal cord contribute to the generation of neuropathic pain. Glia 58, 599–610 (2010).
Kiyoyuki, Y. et al. Leukotriene enhances NMDA-induced inward currents in dorsal horn neurons of the rat spinal cord after peripheral nerve injury. Mol. Pain 11, 53 (2015).
Hanisch, U. K. & Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387–1394 (2007).
Moore, K. A. et al. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J. Neurosci. 22, 6724–6731 (2002).
Koizumi, S. et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446, 1091–1095 (2007).
Kobayashi, K., Yamanaka, H., Yanamoto, F., Okubo, M. & Noguchi, K. Multiple P2Y subtypes in spinal microglia are involved in neuropathic pain after peripheral nerve injury. Glia 60, 1529–1539 (2012).
Barragan-Iglesias, P. et al. Role of spinal P2Y6 and P2Y11 receptors in neuropathic pain in rats: possible involvement of glial cells. Mol. Pain 10, 29 (2014).
Maeda, M., Tsuda, M., Tozaki-Saitoh, H., Inoue, K. & Kiyama, H. Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn. Glia 58, 1838–1846 (2010).
Ni, H. D. et al. Glial activation in the periaqueductal gray promotes descending facilitation of neuropathic pain through the p38 MAPK signaling pathway. J. Neurosci. Res. 94, 50–61 (2016).
Taylor, A. M., Mehrabani, S., Liu, S., Taylor, A. J. & Cahill, C. M. Topography of microglial activation in sensory- and affect-related brain regions in chronic pain. J. Neurosci. Res. 95, 1330–1335 (2017).
Miyamoto, K., Kume, K. & Ohsawa, M. Role of microglia in mechanical allodynia in the anterior cingulate cortex. J. Pharmacol. Sci. 134, 158–165 (2017).
Ikeda, R., Takahashi, Y., Inoue, K. & Kato, F. NMDA receptor-independent synaptic plasticity in the central amygdala in the rat model of neuropathic pain. Pain 127, 161–172 (2007).
Sorge, R. E. et al. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J. Neurosci. 31, 15450–15454 (2011).
Taves, S. et al. Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: sex-dependent microglial signaling in the spinal cord. Brain Behav. Immun. 55, 70–81 (2016).
Peng, J. et al. Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury. Nat. Commun. 7, 12029 (2016).
Staniland, A. A. et al. Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. J. Neurochem. 114, 1143–1157 (2010).
Mao-Ying, Q. L. et al. Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats. Mol. Brain 5, 16 (2012).
Yang, Y. et al. Delayed activation of spinal microglia contributes to the maintenance of bone cancer pain in female Wistar rats via P2X7 receptor and IL-18. J. Neurosci. 35, 7950–7963 (2015).
Lan, L. S. et al. Down-regulation of Toll-like receptor 4 gene expression by short interfering RNA attenuates bone cancer pain in a rat model. Mol. Pain 6, 2 (2010).
Hu, J. H. et al. Involvement of CX3CR1 in bone cancer pain through the activation of microglia p38 MAPK pathway in the spinal cord. Brain Res. 1465, 1–9 (2012).
Nieto, F. R. et al. Neuron-immune mechanisms contribute to pain in early stages of arthritis. J. Neuroinflamm. 13, 96 (2016).
Jin, X. H., Wang, L. N., Zuo, J. L., Yang, J. P. & Liu, S. L. P2X4 receptor in the dorsal horn partially contributes to brain-derived neurotrophic factor oversecretion and toll-like receptor-4 receptor activation associated with bone cancer pain. J. Neurosci. Res. 92, 1690–1702 (2014).
Matsumura, Y. et al. A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain. Sci. Rep. 6, 32461 (2016).
Hayashi, Y. et al. Diurnal spatial rearrangement of microglial processes through the rhythmic expression of P2Y12 receptors. J. Neurol. Disord. 1, 2 (2013).
Hayashi, Y. et al. The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S. Sci. Rep. 3, 2744 (2013).
Koyanagi, S. et al. Glucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia. Nat. Commun. 7, 13102 (2016).
Bhattacharya, A. & Biber, K. The microglial ATP-gated ion channel P2X7 as a CNS drug target. Glia 64, 1772–1787 (2016).
Hewitt, E. et al. Selective cathepsin S inhibition with MIV-247 attenuates mechanical allodynia and enhances the antiallodynic effects of gabapentin and pregabalin in a mouse model of neuropathic pain. J. Pharmacol. Exp. Ther. 358, 387–396 (2016).
Kato, Y. et al. Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain. Proc. Natl Acad. Sci. USA 114, E6297–E6305 (2017).
Moriconi, A. et al. Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief. Proc. Natl Acad. Sci. USA 111, 16937–16942 (2014).
Kawate, T., Michel, J. C., Birdsong, W. T. & Gouaux, E. Crystal structure of the ATP-gated P2X(4) ion channel in the closed state. Nature 460, 592–598 (2009).
Karasawa, A. & Kawate, T. Structural basis for subtype-specific inhibition of the P2X7 receptor. eLife 5, e22153 (2016).
Zhang, K. et al. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature 509, 115–118 (2014).
Ferrini, F. et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis. Nat. Neurosci. 16, 183–192 (2013).
This paper reports that spinal microglia critically contribute to opioid-induced hyperalgesia through the P2X4–BDNF–TRKB–KCC2 pathway.
Leduc-Pessah, H. et al. Site-specific regulation of P2X7 receptor function in microglia gates morphine analgesic tolerance. J. Neurosci. 37, 10154–10172 (2017).
Grace, P. M. et al. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc. Natl Acad. Sci. USA 113, E3441–E3450 (2016).
Muffat, J. et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat. Med. 22, 1358–1367 (2016).
Ohgidani, M. et al. Direct induction of ramified microglia-like cells from human monocytes: dynamic microglial dysfunction in Nasu-Hakola disease. Sci. Rep. 4, 4957 (2014).
Ohgidani, M. et al. Fibromyalgia and microglial TNF-alpha: translational research using human blood induced microglia-like cells. Sci. Rep. 7, 11882 (2017).
This paper reports that induced microglia-like cells of fibromyalgia patients show an inflammatory phenotype that is correlated with pain severity.
Garre, J. M., Silva, H. M., Lafaille, J. J. & Yang, G. CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-alpha. Nat. Med. 23, 714–722 (2017).
Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).
Del Valle, L., Schwartzman, R. J. & Alexander, G. Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome. Brain Behav. Immun. 23, 85–91 (2009).
Banati, R. B. et al. Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nat. Commun. 5, 5452 (2014).
Banati, R. B. et al. Long-term trans-synaptic glial responses in the human thalamus after peripheral nerve injury. Neuroreport 12, 3439–3442 (2001).
Loggia, M. L. et al. Evidence for brain glial activation in chronic pain patients. Brain 138, 604–615 (2015).
Jeon, S. Y. et al. [11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome: a pilot study. Medicine 96, e5735 (2017).
Wei, X. H. et al. The upregulation of translocator protein (18 kDa) promotes recovery from neuropathic pain in rats. J. Neurosci. 33, 1540–1551 (2013).
Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).
Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).
Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013).
Del Rio-Hortega, P. El tercer elemento de los centros nerviosos I La microglia en estado normal II Intervencíon de la microglia en los procesos patológicos III Naturaleza probable de la microglia [Spanish]. Bol. Soc. Biol. 9, 69–120 (1919).
Kettenmann, H., Hanisch, U. K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461–553 (2011).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).
Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).
Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
Salter, M. W. & Beggs, S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 158, 15–24 (2014).
Kierdorf, K. & Prinz, M. Microglia in steady state. J. Clin. Invest. 127, 3201–3209 (2017).
Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).
Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).
Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014).
Hoek, R. M. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000).
Ponomarev, E. D., Veremeyko, T., Barteneva, N., Krichevsky, A. M. & Weiner, H. L. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-alpha-PU.1 pathway. Nat. Med. 17, 64–70 (2011).
Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300–312 (2014).
Hutchinson, M. R. et al. Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacol. Rev. 63, 772–810 (2011).
Wang, Z., Ma, W., Chabot, J. G. & Quirion, R. Cell-type specific activation of p38 and ERK mediates calcitonin gene-related peptide involvement in tolerance to morphine-induced analgesia. Faseb J. 23, 2576–2586 (2009).
Horvath, R. J., Romero-Sandoval, E. A. & De Leo, J. A. Inhibition of microglial P2X4 receptors attenuates morphine tolerance, Iba1, GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED2. Pain 150, 401–413 (2010).
Zhou, D., Chen, M. L., Zhang, Y. Q. & Zhao, Z. Q. Involvement of spinal microglial P2X7 receptor in generation of tolerance to morphine analgesia in rats. J. Neurosci. 30, 8042–8047 (2010).
Fukagawa, H., Koyama, T., Kakuyama, M. & Fukuda, K. Microglial activation involved in morphine tolerance is not mediated by toll-like receptor 4. J. Anesth 27, 93–97 (2013).
Taylor, A. M. et al. Neuroimmune regulation of GABAergic neurons within the ventral tegmental area during withdrawal from chronic morphine. Neuropsychopharmacology 41, 949–959 (2016).
Corder, G. et al. Loss of mu opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nat. Med. 23, 164–173 (2017).
Kobayashi, K. et al. P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J. Neurosci. 28, 2892–2902 (2008).
Matsushita, K. et al. Chemokine (C-C motif) receptor 5 is an important pathological regulator in the development and maintenance of neuropathic pain. Anesthesiology 120, 1491–1503 (2014).
Lim, H., Kim, D. & Lee, S. J. Toll-like receptor 2 mediates peripheral nerve injury-induced NADPH oxidase 2 expression in spinal cord microglia. J. Biol. Chem. 288, 7572–7579 (2013).
Calvo, M. et al. Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J. Neurosci. 30, 5437–5450 (2010).
Tsuda, M. et al. Fibronectin/integrin system is involved in P2X4 receptor upregulation in the spinal cord and neuropathic pain after nerve injury. Glia 56, 579–585 (2008).
Zhuang, Z. Y., Gerner, P., Woolf, C. J. & Ji, R. R. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114, 149–159 (2005).
Calvo, M. et al. Following nerve injury neuregulin-1 drives microglial proliferation and neuropathic pain via the MEK/ERK pathway. Glia 59, 554–568 (2011).
Katsura, H. et al. Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury. J. Neurosci. 26, 8680–8690 (2006).
Tsuda, M. et al. Lyn tyrosine kinase is required for P2X4 receptor upregulation and neuropathic pain after peripheral nerve injury. Glia 56, 50–58 (2008).
Kim, D. et al. NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain. Proc. Natl Acad. Sci. USA 107, 14851–14856 (2010).
Zhu, X. & Eisenach, J. C. Cyclooxygenase-1 in the spinal cord is altered after peripheral nerve injury. Anesthesiology 99, 1175–1179 (2003).