Astrocytes are critical for maintaining the homeostasis of the CNS. Increasing evidence suggests that a number of neurological and neuropsychiatric disorders, including chronic pain, may result from astrocyte ‘gliopathy’. Indeed, in recent years there has been substantial progress in our understanding of how astrocytes can regulate nociceptive synaptic transmission via neuronal–glial and glial–glial cell interactions, as well as the involvement of spinal and supraspinal astrocytes in the modulation of pain signalling and the maintenance of neuropathic pain. A role of astrocytes in the pathogenesis of chronic itch is also emerging. These developments suggest that targeting the specific pathways that are responsible for astrogliopathy may represent a novel approach to develop therapies for chronic pain and chronic itch.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Neuroscience Bulletin Open Access 14 November 2022
Inhibition of Schwann cell pannexin 1 attenuates neuropathic pain through the suppression of inflammatory responses
Journal of Neuroinflammation Open Access 04 October 2022
The risk factors of neuropathic pain in neuromyelitis optica spectrum disorder: a retrospective case-cohort study
BMC Neurology Open Access 19 August 2022
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Herculano-Houzel, S. The glia/neuron ratio: how it varies uniformly across brain structures and species and what that means for brain physiology and evolution. Glia 62, 1377–1391 (2014).
Ben Haim, L. & Rowitch, D. H. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 18, 31–41 (2017).
Giaume, C. & McCarthy, K. D. Control of gap-junctional communication in astrocytic networks. Trends Neurosci. 19, 319–325 (1996).
Ji, R. R., Berta, T. & Nedergaard, M. Glia and pain: is chronic pain a gliopathy? Pain 154, S10–S28 (2013).
Mathewson, A. J. & Berry, M. Observations on the astrocyte response to a cerebral stab wound in adult rats. Brain Res. 327, 61–69 (1985).
Kimelberg, H. K. & Nedergaard, M. Functions of astrocytes and their potential as therapeutic targets. Neurotherapeutics 7, 338–353 (2010).
Iadecola, C. & Nedergaard, M. Glial regulation of the cerebral microvasculature. Nat. Neurosci. 10, 1369–1376 (2007).
Oberheim, N. A. et al. Loss of astrocytic domain organization in the epileptic brain. J. Neurosci. 28, 3264–3276 (2008).
Gao, Y. J. & Ji, R.-R. Targeting astrocyte signaling for chronic pain. Neurotherapeutics. 7, 482–493 (2010).
Bushong, E. A., Martone, M. E., Jones, Y. Z. & Ellisman, M. H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22, 183–192 (2002).
Oberheim, N. A. et al. Uniquely hominid features of adult human astrocytes. J. Neurosci. 29, 3276–3287 (2009).
Halassa, M. M., Fellin, T., Takano, H., Dong, J. H. & Haydon, P. G. Synaptic islands defined by the territory of a single astrocyte. J. Neurosci. 27, 6473–6477 (2007).
Oberheim, N. A., Wang, X., Goldman, S. & Nedergaard, M. Astrocytic complexity distinguishes the human brain. Trends Neurosci. 29, 547–553 (2006).
Han, X. et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12, 342–353 (2013).
Laug, D., Glasgow, S. M. & Deneen, B. A glial blueprint for gliomagenesis. Nat. Rev. Neurosci. 19, 393–403 (2018).
Clarke, L. E. & Barres, B. A. Emerging roles of astrocytes in neural circuit development. Nat. Rev. Neurosci. 14, 311–321 (2013).
Molofsky, A. V. et al. Astrocytes and disease: a neurodevelopmental perspective. Genes Dev. 26, 891–907 (2012).
Ji, R.-R., Xu, Z. Z. & Gao, Y. J. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13, 533–548 (2014).
Ransohoff, R. M. How neuroinflammation contributes to neurodegeneration. Science 353, 777–783 (2016).
Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).
Ji, R.-R., Chamessian, A. & Zhang, Y. Q. Pain regulation by non-neuronal cells and inflammation. Science 354, 572–577 (2016).
Grace, P. M., Hutchinson, M. R., Maier, S. F. & Watkins, L. R. Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 14, 217–231 (2014).
Costigan, M., Scholz, J. & Woolf, C. J. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32, 1–32 (2009).
Ji, R.-R., Nackley, A., Huh, Y., Terrando, N. & Maixner, W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology 129, 343–366 (2018).
Tsuda, M. Modulation of pain and itch by spinal glia. Neurosci. Bull. 34, 178–185 (2018).
Verkhratsky, A. et al. Neurological diseases as primary gliopathies: a reassessment of neurocentrism. ASN Neuro. 4, e0008 (2012).
Simard, M. & Nedergaard, M. The neurobiology of glia in the context of water and ion homeostasis. Neurosci. 129, 877–896 (2004).
Cui, Y. et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature 554, 323–327 (2018).
Cornell-Bell, A. H., Finkbeiner, S. M., Cooper, M. S. & Smith, S. J. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247, 470–473 (1990).
Nedergaard, M. & Verkhratsky, A. Artifact versus reality — how astrocytes contribute to synaptic events. Glia 60, 1013–1023 (2012).
Djukic, B., Casper, K. B., Philpot, B. D., Chin, L. S. & McCarthy, K. D. Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J. Neurosci. 27, 11354–11365 (2007).
Verkhratsky, A. & Nedergaard, M. Astroglial cradle in the life of the synapse. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369, 20130595 (2014).
Eroglu, C. & Barres, B. A. Regulation of synaptic connectivity by glia. Nature 468, 223–231 (2010).
Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).
Sun, W. et al. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339, 197–200 (2013).
Ding, F. et al. α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice. Cell Calcium 54, 387–394 (2013).
Srinivasan, R. et al. Ca2+ signaling in astrocytes from Ip3r2–/– mice in brain slices and during startle responses in vivo. Nat. Neurosci. 18, 708–717 (2015).
Paukert, M. et al. Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82, 1263–1270 (2014).
Wang, F. et al. Astrocytes modulate neural network activity by Ca2+-dependent uptake of extracellular K(+). Sci. Signal. 5, ra26 (2012).
Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012).
Nedergaard, M. Garbage truck of the brain. Science 340, 1529–1530 (2013).
Goldman, N. et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat. Neurosci. 13, 883–888 (2010).
Zhang, J. M. et al. ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 40, 971–982 (2003).
Foley, J. C., McIver, S. R. & Haydon, P. G. Gliotransmission modulates baseline mechanical nociception. Mol. Pain 7, 93 (2011). This study, together with Fujita et al. (2014) and Liu et al. (2016), provides evidence for the existence of an astrocyte-mediated pain suppression system under homeostatic conditions.
Fujita, T. et al. Neuronal transgene expression in dominant-negative SNARE mice. J. Neurosci. 34, 16594–16604 (2014).
Liu, C. C. et al. Interferon α inhibits spinal cord synaptic and nociceptive transmission via neuronal–glial interactions. Sci. Rep. 6, 34356 (2016).
Ohara, P. T., Vit, J. P., Bhargava, A. & Jasmin, L. Evidence for a role of connexin 43 in trigeminal pain using RNA interference in vivo. J. Neurophysiol. 100, 3064–3073 (2008).
Morioka, N. et al. Downregulation of spinal astrocytic connexin43 leads to upregulation of interleukin-6 and cyclooxygenase-2 and mechanical hypersensitivity in mice. Glia 66, 428–444 (2018).
Garrison, C. J., Dougherty, P. M., Kajander, K. C. & Carlton, S. M. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res. 565, 1–7 (1991). This study provides early evidence for a possible involvement of astrocytes in pain.
Garrison, C. J., Dougherty, P. M. & Carlton, S. M. GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp. Neurol. 129, 237–243 (1994).
Nesic, O. et al. Transcriptional profiling of spinal cord injury-induced central neuropathic pain. J. Neurochem. 95, 998–1014 (2005).
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). This study demonstrates that astrocytic JNK signalling contributes to the maintenance of nerve injury-induced neuropathic pain.
Song, P. & Zhao, Z. Q. The involvement of glial cells in the development of morphine tolerance. Neurosci. Res. 39, 281–286 (2001). This study provides early evidence for an involvement of astrocytes in chronic morphine-induced antinociceptive tolerance.
Raghavendra, V., Tanga, F. Y. & DeLeo, J. A. Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur. J. Neurosci. 20, 467–473 (2004).
Gao, Y. J. et al. The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition. Pain 148, 309–319 (2010).
Guo, W. et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J. Neurosci. 27, 6006–6018 (2007).
Sun, S. et al. New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 129, 64–75 (2007).
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. Neurosci. 98, 585–598 (2000).
Gao, Y. J. et al. Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model. Exp. Neurol. 219, 146–155 (2009).
Zhang, H., Yoon, S. Y., Zhang, H. & Dougherty, P. M. Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of Paclitaxel-induced painful neuropathy. J. Pain 13, 293–303 (2012).
Shi, Y., Gelman, B. B., Lisinicchia, J. G. & Tang, S. J. Chronic-pain-associated astrocytic reaction in the spinal cord dorsal horn of human immunodeficiency virus-infected patients. J. Neurosci. 32, 10833–10840 (2012). This study provides evidence for the persistent activation of spinal cord astrocytes in a human chronic pain condition.
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).
Gwak, Y. S., Kang, J., Unabia, G. C. & Hulsebosch, C. E. Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats. Exp. Neurol. 234, 362–372 (2012).
Tsuda, M. et al. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain 134, 1127–1139 (2011).
Kim, D. S. et al. Profiling of dynamically changed gene expression in dorsal root ganglia post peripheral nerve injury and a critical role of injury-induced glial fibrillary acidic protein in maintenance of pain behaviors [corrected]. Pain 143, 114–122 (2009).
DeLeo, J. A., Rutkowski, M. D., Stalder, A. K. & Campbell, I. L. Transgenic expression of TNF by astrocytes increases mechanical allodynia in a mouse neuropathy model. Neuroreport 11, 599–602 (2000).
Menetski, J. et al. Mice overexpressing chemokine ligand 2 (CCL2) in astrocytes display enhanced nociceptive responses. Neuroscience 149, 706–714 (2007).
Gao, Y. J., Zhang, L. & Ji, R. R. Spinal injection of TNF-α-activated astrocytes produces persistent pain symptom mechanical allodynia by releasing monocyte chemoattractant protein-1. Glia 58, 1871–1880 (2010).
Chiang, C. Y., Sessle, B. J. & Dostrovsky, J. O. Role of astrocytes in pain. Neurochem. Res. 37, 2419-2431 (2012).
Meller, S. T., Dykstra, C., Grzybycki, D., Murphy, S. & Gebhart, G. F. The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 33, 1471–1478 (1994).
Watkins, L. R., Martin, D., Ulrich, P., Tracey, K. J. & Maier, S. F. Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 71, 225–235 (1997).
Ji, R. R., Kawasaki, Y., Zhuang, Z. Y., Wen, Y. R. & Decosterd, I. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol. 2, 259–269 (2006).
Chiang, C. Y. et al. Astroglial glutamate–glutamine shuttle is involved in central sensitization of nociceptive neurons in rat medullary dorsal horn. J. Neurosci. 27, 9068–9076 (2007).
Okada-Ogawa, A. et al. Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J. Neurosci. 29, 11161–11171 (2009).
Ren, K. & Dubner, R. Interactions between the immune and nervous systems in pain. Nat. Med. 16, 1267–1276 (2010).
Nam, Y. et al. Reversible induction of pain hypersensitivity following optogenetic stimulation of spinal astrocytes. Cell Rep. 17, 3049–3061 (2016). This study demonstrates that sterile astrocyte activation using optogenetic stimulation alone is sufficient to produce pain behaviours in naïve rats.
Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).
Inoue, K. & Tsuda, M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat. Rev. Neurosci. 19, 138–152 (2018).
Scholz, J. & Woolf, C. J. The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10, 1361–1368 (2007).
McMahon, S. B. & Malcangio, M. Current challenges in glia–pain biology. Neuron 64, 46–54 (2009).
Chen, G., Zhang, Y. Q., Qadri, Y. J., Serhan, C. N. & Ji, R. R. Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron 100, 1292–1311 (2018).
Robinson, C. R., Zhang, H. & Dougherty, P. M. Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat. Neuroscience 274, 308–317 (2014).
Luo, X. et al. Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice. Brain Behav. Immun. 72, 34–44 (2018).
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).
Sorge, R. E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18, 1081–1083 (2015).
Chen, G., Luo, X., Qadri, M. Y., Berta, T. & Ji, R. R. Sex-dependent glial signaling in pathological pain: distinct roles of spinal microglia and astrocytes. Neurosci. Bull. 34, 98–108 (2018).
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).
Pappalardo, L. W. et al. Nav1.5 in astrocytes plays a sex-specific role in clinical outcomes in a mouse model of multiple sclerosis. Glia 66, 2174–2187 (2018).
Zhang, J. & De Koninck, Y. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J. Neurochem. 97, 772–783 (2006).
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).
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). This study demonstrates that astrocytes upregulate connexin 43 following nerve injury, driving the release of CXCL1, which induces central sensitization in nociceptive neurons to maintain neuropathic pain.
Obata, K. & Noguchi, K. MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci. 74, 2643–2653 (2004).
Ji, R. R., Gereau, R. W., Malcangio, M. & Strichartz, G. R. MAP kinase and pain. Brain Res. Rev. 60, 135–148 (2009).
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).
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).
Katsura, H. et al. Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. Glia 56, 723–733 (2008).
Mei, X. P. et al. Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain. J. Neuroinflammation 8, 6 (2011).
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).
Ji, R. R., Xu, Z. Z., Wang, X. & Lo, E. H. Matrix metalloprotease regulation of neuropathic pain. Trends Pharmacol. Sci. 30, 336–340 (2009).
Kawasaki, Y. et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat. Med. 14, 331–336 (2008). This paper demonstrates that MMP2 upregulation in spinal astrocytes after nerve injury contributes to neuropathic pain maintenance.
Kozai, T. et al. Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury. Glia 55, 595–603 (2007).
Jiang, L. et al. Selective suppression of the JNK–MMP2/9 signal pathway by tetramethylpyrazine attenuates neuropathic pain in rats. J. Neuroinflammation 14, 174 (2017).
Sung, B., Lim, G. & Mao, J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J. Neurosci. 23, 2899–2910 (2003).
Xin, W. J., Weng, H. R. & Dougherty, P. M. Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation. Mol. Pain 5, 15 (2009).
Liaw, W. J. et al. Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 115, 60–70 (2005).
Weng, H. R., Chen, J. H. & Cata, J. P. Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation. Neuroscience 138, 1351–1360 (2006).
Falnikar, A., Hala, T. J., Poulsen, D. J. & Lepore, A. C. GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury. Glia 64, 396–406 (2016).
Tackley, G. et al. Chronic neuropathic pain severity is determined by lesion level in aquaporin 4-antibody-positive myelitis. J. Neurol. Neurosurg. Psychiatry 88, 165–169 (2017).
Bao, F., Chen, M., Zhang, Y. & Zhao, Z. Hypoalgesia in mice lacking aquaporin-4 water channels. Brain Res. Bull. 83, 298–303 (2010).
Bradl, M. et al. Pain in neuromyelitis optica — prevalence, pathogenesis and therapy. Nat. Rev. Neurol. 10, 529–536 (2014).
Kang, J. et al. Connexin 43 hemichannels are permeable to ATP. J. Neurosci. 28, 4702–4711 (2008).
Chen, M. J. et al. Astrocytic CX43 hemichannels and gap junctions play a crucial role in development of chronic neuropathic pain following spinal cord injury. Glia 60, 1660–1670 (2012).
Spataro, L. E. et al. Spinal gap junctions: potential involvement in pain facilitation. J. Pain 5, 392–405 (2004).
Bennett, M. V., Contreras, J. E., Bukauskas, F. F. & Saez, J. C. New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci. 26, 610–617 (2003).
Cronin, M., Anderson, P. N., Cook, J. E., Green, C. R. & Becker, D. L. Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury. Mol. Cell Neurosci. 39, 152–160 (2008).
Huang, C. et al. Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury. J. Neurosci. 32, 3333–3338 (2012).
Garre, J. M. et al. FGF-1 induces ATP release from spinal astrocytes in culture and opens pannexin and connexin hemichannels. Proc. Natl Acad. Sci. USA 107, 22659–22664 (2010).
Koyanagi, S. et al. Glucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia. Nat. Commun. 7, 13102 (2016).
Mousseau, M. et al. Microglial pannexin-1 channel activation is a spinal determinant of joint pain. Sci. Adv. 4, eaas9846 (2018).
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).
Zhang, Z. J. et al. Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain. J. Neuroinflammation 9, 136 (2012).
Jiang, B. C. et al. CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5. J. Clin. Invest. 126, 745–761 (2016).
Yuan, S., Shi, Y. & Tang, S. J. Wnt signaling in the pathogenesis of multiple sclerosis-associated chronic pain. J. Neuroimmune Pharmacol. 7, 904–913 (2012).
Zhang, Y. K. et al. WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J. Clin. Invest. 123, 2268–2286 (2013).
Liu, S. et al. Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats. Pain 156, 2572–2584 (2015).
Patti, G. J. et al. Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin. Nat. Chem. Biol. 8, 232–234 (2012).
Stockstill, K. et al. Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. J. Exp. Med. 215, 1301–1313 (2018). This study demonstrates that chemotherapy-induced sphingolipid metabolites activate astrocytes to release pro-inflammatory mediators and drive neuropathic pain.
Zarpelon, A. C. et al. Spinal cord oligodendrocyte-derived alarmin IL-33 mediates neuropathic pain. FASEB J. 30, 54–65 (2016).
Liu, S. et al. Spinal IL-33/ST2 signaling contributes to neuropathic pain via neuronal camkii-creb and astroglial jak2-stat3 cascades in mice. Anesthesiology 123, 1154–1169 (2015).
Suter, M. R., Wen, Y. R., Decosterd, I. & Ji, R. R. Do glial cells control pain? Neuron Glia Biol. 3, 255–268 (2007).
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).
Lu, Y. et al. TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling. Pain 155, 2618–2629 (2014).
Liu, T., Gao, Y. J. & Ji, R. R. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci. Bull. 28, 131–144 (2012).
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).
Li, Y. et al. Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy. J. Pain 15, 712–725 (2014).
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).
Bartley, E. J. & Fillingim, R. B. Sex differences in pain: a brief review of clinical and experimental findings. Br. J. Anaesth. 111, 52–58 (2013).
Woolf, C. J. Evidence for a central component of post-injury pain hypersensitivity. Nature 306, 686–688 (1983).
Ji, R. R., Kohno, T., Moore, K. A. & Woolf, C. J. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 26, 696–705 (2003).
Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–S15 (2011).
Woolf, C. J. & Salter, M. W. Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1769 (2000).
Latremoliere, A. & Woolf, C. J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895–926 (2009).
Gao, Y. J. & Ji, R. R. Chemokines, neuronal–glial interactions, and central processing of neuropathic pain. Pharmacol. Ther. 126, 56–68 (2010).
White, F. A. et al. 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 102, 14092–14097 (2005).
Xie, R. G. et al. Spinal CCL2 promotes central sensitization, long-term potentiation, and inflammatory pain via CCR2: further insights into molecular, synaptic, and cellular mechanisms. Neurosci. Bull. 34, 13–21 (2018).
Gosselin, R. D. et al. Constitutive expression of CCR2 chemokine receptor and inhibition by MCP-1/CCL2 of GABA-induced currents in spinal cord neurones. J. Neurochem. 95, 1023–1034 (2005).
Zhang, Z. J., Cao, D. L., Zhang, X., Ji, R. R. & Gao, Y. J. Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain 154, 2185–2197 (2013).
Sommer, C., Schafers, M., Marziniak, M. & Toyka, K. V. Etanercept reduces hyperalgesia in experimental painful neuropathy. J. Peripher. Nerv. Syst. 6, 67–72 (2001).
Milligan, E. D. & Watkins, L. R. Pathological and protective roles of glia in chronic pain. Nat. Rev. Neurosci. 10, 23–36 (2009).
Ren, K. & Torres, R. Role of interleukin-1β during pain and inflammation. Brain Res. Rev. 60, 57–64 (2009).
Zhang, R. X. et al. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain 135, 232–239 (2008).
Li, W. W. et al. The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome. Pain 147, 277–286 (2009).
Kawasaki, Y., Zhang, L., Cheng, J. K. & Ji, R. R. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1β, interleukin-6, and tumor necrosis factor-α in regulating synaptic and neuronal activity in the superficial spinal cord. J. Neurosci. 28, 5189–5194 (2008).
Berta, T. et al. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion. J. Clin. Invest. 124, 1173–1186 (2014).
Zhang, H., Nei, H. & Dougherty, P. M. A p38 mitogen-activated protein kinase-dependent mechanism of disinhibition in spinal synaptic transmission induced by tumor necrosis factor-α. J. Neurosci. 30, 12844–12855 (2010).
Sandkuhler, J. Learning and memory in pain pathways. Pain 88, 113–118 (2000).
Sandkuhler, J. Models and mechanisms of hyperalgesia and allodynia. Physiol. Rev. 89, 707–758 (2009).
Liu, Y. L. et al. Tumor necrosis factor-α induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-κB, JNK and p38 MAPK. Neuropharmacology 52, 708–715 (2007).
Park, C. K. et al. Resolving TRPV1- and TNF-α-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J. Neurosci. 31, 15072–15085 (2011).
Gruber-Schoffnegger, D. et al. 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. 33, 6540–6551 (2013).
Chirila, A. M. et al. Long-term potentiation of glycinergic synapses triggered by interleukin 1β. Proc. Natl Acad. Sci. USA 111, 8263–8268 (2014).
Kronschlager, M. T. et al. Gliogenic LTP spreads widely in nociceptive pathways. Science 354, 1144–1148 (2016). This study identifies a diffusible form of LTP, induced by small, glia-derived mediators, which can be carried through the CSF to distant synapses.
Xie, Y. F. et al. Involvement of glia in central sensitization in trigeminal subnucleus caudalis (medullary dorsal horn). Brain Behav. Immun. 21, 634–641 (2007).
Kobayashi, A. et al. Mechanisms involved in extraterritorial facial pain following cervical spinal nerve injury in rats. Mol. Pain 7, 12 (2011).
Mah, W. et al. A role for the purinergic receptor P2X3 in astrocytes in the mechanism of craniofacial neuropathic pain. Sci. Rep. 7, 13627 (2017).
Alshelh, Z. et al. Chronic neuropathic pain: it’s about the rhythm. J. Neurosci. 36, 1008–1018 (2016).
Wei, F., Guo, W., Zou, S., Ren, K. & Dubner, R. Supraspinal glial–neuronal interactions contribute to descending pain facilitation. J. Neurosci. 28, 10482–10495 (2008).
Ni, H. D. et al. Astrocyte activation in the periaqueductal gray promotes descending facilitation to cancer-induced bone pain through the JNK MAPK signaling pathway. Mol. Pain 15, 1744806919831909 (2019).
Chen, F. L. et al. Activation of astrocytes in the anterior cingulate cortex contributes to the affective component of pain in an inflammatory pain model. Brain Res. Bull. 87, 60–66 (2012).
Kim, S. K. et al. Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain. J. Clin. Invest. 126, 1983–1997 (2016). This paper provides evidence that cortical astrocytes are activated following nerve injury, driving local synaptic plasticity and neuropathic pain via astrocytic TSP1.
Loggia, M. L. et al. Evidence for brain glial activation in chronic pain patients. Brain 138, 604–615 (2015). This neuroimaging study demonstrates that glial activation is observed in the pain-processing brain regions of patients with chronic lower back pain.
Takata, N. et al. Optogenetic astrocyte activation evokes BOLD fMRI response with oxygen consumption without neuronal activity modulation. Glia 66, 2013–2023 (2018).
LaMotte, R. H., Dong, X. & Ringkamp, M. Sensory neurons and circuits mediating itch. Nat. Rev. Neurosci. 15, 19–31 (2014).
Moser, H. R. & Giesler, G. J. Jr. Itch and analgesia resulting from intrathecal application of morphine: contrasting effects on different populations of trigeminothalamic tract neurons. J. Neurosci. 33, 6093–6101 (2013).
Lee, H. & Ko, M. C. Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates. Sci. Rep. 5, 11676 (2015).
Steinhoff, M. et al. Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus. J. Invest. Dermatol. 126, 1705–1718 (2006).
Dong, X. & Dong, X. Peripheral and central mechanisms of itch. Neuron 98, 482–494 (2018).
Sun, Y. G. & Chen, Z. F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448, 700–703 (2007).
Duan, B., Cheng, L. & Ma, Q. Spinal circuits transmitting mechanical pain and itch. Neurosci. Bull. 34, 186–193 (2018).
Ross, S. E. Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Curr. Opin. Neurobiol. 21, 880–887 (2011).
Liu, Y. et al. VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 68, 543–556 (2010).
Liu, T. & Ji, R.-R. in Itch: Mechanisms and Treatment (eds Carstens, E. & Akiyama, T.) 257-270 (CRC Press, 2014).
Yosipovitch, G. & Bernhard, J. D. Chronic pruritus. N. Engl. J. Med. 368, 1625–1634 (2013).
Han, Q. et al. miRNA-711 binds and activates TRPA1 extracellularly to evoke acute and chronic pruritus. Neuron 99, 449–463 (2018).
Liu, T. & Ji, R. R. New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? Pflug. Arch. 465, 1671–1685 (2013).
Ross, S. E. et al. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65, 886–898 (2010).
Green, D. & Dong, X. Supporting itch: a new role for astrocytes in chronic itch. Nat. Med. 21, 841–842 (2015).
Tsuda, M. Astrocytes in the spinal dorsal horn and chronic itch. Neurosci. Res. 126, 9–14 (2018).
Du, L. et al. Spinal IL-33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2-STAT3 cascade. Glia 67, 1680–1693 (2019).
Shiratori-Hayashi, M. et al. STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat. Med. 21, 927–931 (2015).
Liu, T. et al. Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice. Pain 157, 806–817 (2016). This study demonstrates that spinal astrocytes play an active role in regulating chronic but not acute itch.
Akiyama, T. et al. A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch. Pain 156, 1240–1246 (2015).
Bourane, S. et al. Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science 350, 550–554 (2015).
Miao, X. et al. TNF-α/TNFR1 signaling is required for the full expression of acute and chronic itch in mice via peripheral and central mechanisms. Neurosci. Bull. 34, 42–53 (2018).
Jing, P. B. et al. Chemokine receptor CXCR3 in the spinal cord contributes to chronic itch in mice. Neurosci. Bull. 34, 54–63 (2018).
Wilson, S. R. et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155, 285–295 (2013).
Liu, B. et al. IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy. Proc. Natl Acad. Sci. USA 113, E7572–E7579 (2016).
Paus, R., Schmelz, M., Biro, T. & Steinhoff, M. Frontiers in pruritus research: scratching the brain for more effective itch therapy. J. Clin. Invest. 116, 1174–1186 (2006).
Global Industry Analysts, Inc. Pain Management — A Global Strategic Business Report (GIA, 2011).
Gereau, R. W. T. et al. A pain research agenda for the 21st century. J. Pain 15, 1203–1214 (2014).
Ringelstein, M. et al. Long-term therapy with interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder. JAMA Neurol. 72, 756–763 (2015).
Sommer, C. [Animal studies on neuropathic pain: the role of cytokines and cytokine receptors in pathogenesis and therapy]. Schmerz 13, 315–323 (1999).
Sato, K. L., Johanek, L. M., Sanada, L. S. & Sluka, K. A. Spinal cord stimulation reduces mechanical hyperalgesia and glial cell activation in animals with neuropathic pain. Anesth. Analg. 118, 464–472 (2014).
Chen, G., Park, C. K., Xie, R. G. & Ji, R. R. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. J. Clin. Invest. 125, 3226–3240 (2015).
Saunders, A. et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015–1030.e1016 (2018).
Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e1022 (2018). This system-wide single-cell RNA-sequencing study demonstrates the existence of at least seven unique populations of astrocytes in the brain.
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). This study demonstrates that microglia, via the release of IL-1α, TNF and C1q, promote the acquisition of a pro-inflammatory ‘A1’ astrocyte phenotype.
Nahrendorf, M. & Swirski, F. K. Abandoning M1/M2 for a network model of macrophage function. Circ. Res. 119, 414–417 (2016).
Smith, M. T. & Haythornthwaite, J. A. How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive–behavioral clinical trials literature. Sleep Med. Rev. 8, 119–132 (2004).
Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013). This study demonstrates that enhanced glymphatic flow through channels formed by the perivascular endfeet of astrocytes drives the removal of proteinaceous waste from the extracellular space during sleep.
Plog, B. A. & Nedergaard, M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu. Rev. Pathol. 13, 379–394 (2018).
Louveau, A. et al. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J. Clin. Invest. 127, 3210–3219 (2017).
Ringstad, G., Vatnehol, S. A. S. & Eide, P. K. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain 140, 2691–2705 (2017).
Myllyla, T. et al. Assessment of the dynamics of human glymphatic system by near-infrared spectroscopy. J. Biophotonics 11, e201700123 (2018).
von Holstein-Rathlou, S., Petersen, N. C. & Nedergaard, M. Voluntary running enhances glymphatic influx in awake behaving, young mice. Neurosci. Lett. 662, 253–258 (2018).
Kimura, M. et al. Impaired pain-evoked analgesia after nerve injury in rats reflects altered glutamate regulation in the locus coeruleus. Anesthesiology 123, 899–908 (2015).
Jensen, T. S. et al. A new definition of neuropathic pain. Pain 152, 2204–2205 (2011).
van, H. O., Austin, S. K., Khan, R. A., Smith, B. H. & Torrance, N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain 155, 654–662 (2013).
Calvo, M., Dawes, J. M. & Bennett, D. L. The role of the immune system in the generation of neuropathic pain. Lancet Neurol. 11, 629–642 (2012).
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).
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).
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).
Decosterd, I. & Woolf, C. J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 (2000).
Flatters, S. J. & Bennett, G. J. Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain 109, 150–161 (2004).
Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003).
Coull, J. A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).
Clark, A. K. et al. P2X7-dependent release of interleukin-1β and nociception in the spinal cord following lipopolysaccharide. J. Neurosci. 30, 573–582 (2010).
Hochstim, C., Deneen, B., Lukaszewicz, A., Zhou, Q. & Anderson, D. J. Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell 133, 510–522 (2008).
Tsai, H. H. et al. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337, 358–362 (2012).
Hammond, T. R. et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50, 253–271.e256 (2019).
Bannenberg, G. & Serhan, C. N. Specialized pro-resolving lipid mediators in the inflammatory response: an update. Biochim. Biophys. Acta 1801, 1260–1273 (2010).
Abdelmoaty, S. et al. Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release. PLOS ONE 8, e75543 (2013).
Xu, Z. Z. et al. Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma. Ann. Neurol. 74, 490–495 (2013).
Singh, S. K. et al. Astrocytes assemble thalamocortical synapses by bridging NRX1α and NL1 via hevin. Cell 164, 183–196 (2016).
Mishra, S. K. & Hoon, M. A. The cells and circuitry for itch responses in mice. Science 340, 968–971 (2013).
Alexandre, C. et al. Decreased alertness due to sleep loss increases pain sensitivity in mice. Nat. Med. 23, 768–774 (2017).
Kim, D. S. et al. Thrombospondin-4 contributes to spinal sensitization and neuropathic pain states. J. Neurosci. 32, 8977–8987 (2012).
This work was supported by NIH grants DE17794, to R.-R.J., and DE22743, to R.-R.J. and M.N. M.N is also supported by the Lundbeck Foundation. C.R.D. is supported by a John J. Bonica Trainee Fellowship from the International Association for the Study of Pain and by NIH grant T32 GM08600.
The authors declare that there are no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
A localized form of inflammation occurring in the peripheral nervous system and/or CNS.
- Central sensitization
Forms of neuronal and/or synaptic plasticity characterized by increased responsiveness of nociceptive neurons in the CNS to their normal input.
Assemblies composed of six connexin proteins, which form a pore that allows for the bidirectional flow of ions and signalling molecules.
- Glymphatic system
A waste clearance system in the CNS that utilizes a unique network of perivascular tunnels formed by astrocytes.
A large and diverse class of small (<30 kDa) proteins, glycoproteins and peptides that are secreted by cells and exert specific biological functions, including pain modulations.
- Satellite glial cells
A cell type in the peripheral nervous system that is roughly equivalent in function to astrocytes in the CNS.
Pain in response to a stimulus that does not normally provoke pain. Mechanical allodynia is a cardinal feature of chronic pain.
Increased pain in response to a stimulus that ordinarily provokes pain.
The use of light to activate or inhibit genetically encoded ion channels expressed within a defined cell type of interest.
A specific family of immunomodulatory cytokines named for their ability to induce directed chemotaxis of immune effector cells.
The absence of pain in response to stimulation that would normally be painful.
A multimeric intracellular signalling complex responsible for the detection of pathogenic microorganisms and host-derived stressors, leading to the activation of caspase-1 and the induction of inflammation.
Specialized neurons of the somatosensory nervous system that are capable of transducing nociceptive stimuli.
A therapeutic agent used to treat a disease by activating or suppressing the immune system.
About this article
Cite this article
Ji, RR., Donnelly, C.R. & Nedergaard, M. Astrocytes in chronic pain and itch. Nat Rev Neurosci 20, 667–685 (2019). https://doi.org/10.1038/s41583-019-0218-1
This article is cited by
Antiallodynic effects of KDS2010, a novel MAO-B inhibitor, via ROS-GABA inhibitory transmission in a paclitaxel-induced tactile hypersensitivity model
Molecular Brain (2022)
The risk factors of neuropathic pain in neuromyelitis optica spectrum disorder: a retrospective case-cohort study
BMC Neurology (2022)
Inhibition of Schwann cell pannexin 1 attenuates neuropathic pain through the suppression of inflammatory responses
Journal of Neuroinflammation (2022)
Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling
Molecular Psychiatry (2022)