P2X7-Dependent Release of Interleukin-1β and Nociception in the Spinal Cord following Lipopolysaccharide
Open accessAbstract
The cytokine interleukin-1β (IL-1β) released by spinal microglia in enhanced response states contributes significantly to neuronal mechanisms of chronic pain. Here we examine the involvement of the purinergic P2X7 receptor in the release of IL-1β following activation of Toll-like receptor-4 (TLR4) in the dorsal horn, which is associated with nociceptive behavior and microglial activation. We observed that lipopolysaccharide (LPS)-induced release of IL-1β was prevented by pharmacological inhibition of the P2X7 receptor with A-438079, and was absent in spinal cord slices taken from P2X7 knock-out mice. Application of ATP did not evoke release of IL-1β from the dorsal horn unless preceded by an LPS priming stimulus, and this release was dependent on P2X7 receptor activation. Extensive phosphorylation of p38 MAPK in microglial cells in the dorsal horn was found to correlate with IL-1β secretion following both LPS and ATP. In behavioral studies, intrathecal injection of LPS in the lumbar spinal cord produced mechanical hyperalgesia in rat hindpaws, which was attenuated by concomitant injections of either a nonspecific (oxidized ATP) or a specific (A-438079) P2X7 antagonist. In addition, LPS-induced hypersensitivity was observed in wild-type but not P2X7 knock-out mice. These data suggest a critical role for the P2X7 receptor in the enhanced nociceptive transmission associated with microglial activation and secretion of IL-1β in the dorsal horn. We suggest that CNS-penetrant P2X7 receptor antagonists, by targeting microglia in pain-enhanced response states, may be beneficial for the treatment of persistent pain.
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IL-1β knockout mice failed to express P2X family receptors.
“P2X7 inhibition has been associated with antidepressant-like effects, and IL-1β knockout mice failed to express these receptors [48,49].”
From Selected biomarkers of depression: what are the effects of cytokines and inflammation (2022) · cites this paper as [49]
P2X7 inhibition is associated with antidepressant-like effects.
“P2X7 inhibition has been associated with antidepressant-like effects, and IL-1β knockout mice failed to express these receptors [48,49].”
From Selected biomarkers of depression: what are the effects of cytokines and inflammation (2022) · cites this paper as [49]
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“Activation of P2X4 in microglia facilitates BDNF release [74], while activation of P2X7 in microglia induces IL1b release and CXCL2 production [75,76].”
BackgroundP2X7 Receptors: Channels, Pores and More
Volonté, C., Apolloni, S., Skaper, S. D., & Burnstock, G. (2012) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152712803581137 · Cited by 254 · see citing works
Toll-like receptors in chronic pain
Nicotra, L. L., Loram, L. C., Watkins, L. R., & Hutchinson, M. R. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.09.038 · Cited by 251 · see citing works
“The studies that have succeeded in producing this exogenous TLR ligandinduced responses either required large doses (Cao, et al., 2009; Clark et al., 2010; Kehl et al., 2004; Loram et al., 2011 “in press”; Meller, et al., 1994; Reeve et al., 2000; Saito et al., 2010), chronic indwelling intrathecal…”
BackgroundThe mechanisms of microgliosis and pain following peripheral nerve injury
Calvo, M., & Bennett, D. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.08.018 · Cited by 224 · see citing works
“Moreover , there was a positive correlation between pain intensity (VAS scale rating) and pro-inflammatory cytokine levels and an inverse correlation with IL-10 (Backonja et al., 2008).”
BackgroundInfluentialMolecular and functional properties of P2X receptors—recent progress and persisting challenges
Kaczmarek-Hájek, K., Lörinczi, É., Hausmann, R., & Nicke, A. (2012) · Purinergic Signalling · doi:10.1007/s11302-012-9314-7 · Cited by 223 · see citing works
Beggs, S., Currie, G., Salter, M. W., Fitzgerald, M., & Walker, S. M. (2011) · Brain · doi:10.1093/brain/awr288 · Cited by 219 · see citing works
“Acute priming of spinal microglia with intrathecal lipopolysaccharide increases ATP-induced release of interleukin-1b 24 h later and phosphorylated p38 MAPK expression in microglia (Clark et al., 2010).”
BackgroundThe microglial ATP‐gated ion channel P2X7 as a CNS drug target
Bhattacharya, A., & Biber, K. (2016) · Glia · doi:10.1002/glia.23001 · Cited by 221 · see citing works
“In microglia P2X7 effects on reactive oxygen species (ROS) generation (Bartlett et al., 2013), cathepsin S release (Clark et al., 2010b), phagocytosis of amyloid-b (Ni et al., 2013) have been published.”
BackgroundThe Liberation of Fractalkine in the Dorsal Horn Requires Microglial Cathepsin S
Clark, A. K., Yip, P. K., & Malcangio, M. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0828-09.2009 · Cited by 219 · see citing works
Self-citationP2X ion channel receptors and inflammation
Burnstock, G. (2016) · Purinergic Signalling · doi:10.1007/s11302-015-9493-0 · Cited by 215 · see citing works
“P2X7 receptors play a transductional role in the development of inflammatory pain [101].”
BackgroundWen, Y., Tan, P.-H., Cheng, J., Liu, Y., & Ji, R. (2011) · Journal of the Formosan Medical Association · doi:10.1016/s0929-6646(11)60074-0 · Cited by 213 · see citing works
Gruber-Schoffnegger, D., Drdla-Schutting, R., Hönigsperger, C., Wunderbaldinger, G., Gassner, M., & Sandkühler, J. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5087-12.2013 · Cited by 207 · see citing works
“…activation pattern of microglia/macrophages found after stimulation with IFN- or LPS (Sun et al., 2004; Clark et al., 2006), including the release of CINC-2, IL-1 , IL-6, and/or TNF- (Nakagawa et al., 1996; Ishihara and Hirano, 2002; Town et al., 2005; Clark et al., 2010; Belarbi et al., 2012).”
BackgroundYang, Y., Li, H., Li, T., Luo, H., Gu, X., Lü, N., Ji, R., & Zhang, Y. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.5250-14.2015 · Cited by 206 · see citing works
“P2X7Rs are abundantly expressed in microglia, and play a pivotal role in the cross talk between microglia and neurons (Clark et al., 2010).”
BackgroundP2X receptor channels in chronic pain pathways
Bernier, L., Ase, A. R., & Séguéla, P. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13957 · Cited by 199 · see citing works
“It was later reported that LPS priming of microglia in the spinal cord is necessary for the P2X7/IL-1β release pathway to take place (Clark et al., 2010).”
BackgroundChen, M. J., Kress, B. T., Han, X., Moll, K., Peng, W., Ji, R., & Nedergaard, M. (2012) · Glia · doi:10.1002/glia.22384 · Cited by 197 · see citing works
“Activation of ATP receptors such as P2X7 receptors in microglia is essential for the release of proinflammatory cytokines (Clark et al., 2010).”
BackgroundPain hypersensitivity mechanisms at a glance
Gangadharan, V., & Kuner, R. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.011502 · Cited by 187 · see citing works
“Purinergic signaling, involving P2X4 (Beggs et al., 2012), P2X7 (Clark et al., 2010a; Clark et al., 2010b) and P2Y12 (Tozaki-Saitoh et al., 2008) receptors, plays a central role in the recruitment and activation of microglia, which have emerged as key regulators of central sensitization (see Poster, panel C, right-han…”
BackgroundInfluentialNeuronal P2X7 Receptors Revisited: Do They Really Exist?
Illes, P., Khan, T. M., & Rubini, P. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.3103-16.2017 · Cited by 179 · see citing works
“The primary mechanism of P2X7R stimulation in neuropathic/inflammatory pain may be the release of IL-1 from activated microglia/macrophages (Clark et al., 2010; Burnstock, 2016).”
BackgroundMicroglia and Spinal Cord Synaptic Plasticity in Persistent Pain
Taves, S., Berta, T., Chen, G., & Ji, R. (2013) · Neural Plasticity · doi:10.1155/2013/753656 · Cited by 179 · see citing works
Purinergic Mechanisms and Pain
Burnstock, G. (2015) · Advances in pharmacology · doi:10.1016/bs.apha.2015.09.001 · Cited by 174 · see citing works
“The authors suggested that the P2X7 receptor, via regulation of mature IL-1β production, plays an upstream transductional role in the development of neuropathic and inflammatory pain (see also Clark et al., 2010).”
BackgroundSelective activation of microglia facilitates synaptic strength
Clark, A. K., Gruber-Schoffnegger, D., Drdla-Schutting, R., Gerhold, K. J., Malcangio, M., & Sandkühler, J. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2061-14.2015 · Cited by 171 · see citing works
“Quantitative assessment of immunostaining in spinal cord sections was performed by counting the number of positive profiles within a fixed area of the dorsal horn (Clark et al., 2006, 2010, 2012).”
MethodSelf-citationStaniland, A. A., Clark, A. K., Wodarski, R., Sasso, O., Μaione, F., D’Acquisto, F., & Malcangio, M. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06837.x · Cited by 168 · see citing works
Self-citationChronic Pain States: Pharmacological Strategies to Restore Diminished Inhibitory Spinal Pain Control
Zeilhofer, H. U., Benke, D., & Yévenes, G. E. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010611-134636 · Cited by 161 · see citing works
From Mechanosensitivity to Inflammatory Responses: New Players in the Pathology of Glaucoma
Križaj, D., Ryskamp, D. A., Tian, N., Tezel, G., Mitchell, C. H., Slepak, V. Z., & Shestopalov, V. I. (2013) · Current Eye Research · doi:10.3109/02713683.2013.836541 · Cited by 158 · see citing works
Functions of p38 MAP Kinases in the Central Nervous System
Asih, P. R., Prikas, E., Stefanoska, K., Tan, A. R. P., Ahel, H. I., & Ittner, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.570586 · Cited by 158 · see citing works
“…functions downstream of different receptors. p38β acts downstream of glucagon-like peptide-1 receptors (Gong et al., 2014). p38δ was shown to act downstream of the ATP receptors P2 × 7 in microglia, enhancing the release of IL-1β and inflammation within the spinal cord (Clark et al., 2010).”
BackgroundRole of inflammatory cytokines in depression: Focus on interleukin-1β
Farooq, R. K., Asghar, K., Kanwal, S., & Zulqernain, A. (2016) · Biomedical Reports · doi:10.3892/br.2016.807 · Cited by 151 · see citing works
“In an in vivo experiment, where LPS induced sickness behavior in mice, it also led to an increase in the extracellular concentration of 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid in the rat hippocampus.”
InfluentialP2X7 Receptor Channels Allow Direct Permeation of Nanometer-Sized Dyes
Browne, L. E., Compan, V., Bragg, L., & North, R. A. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2235-12.2013 · Cited by 151 · see citing works
“Mice genetically modified to lack the P2X7 receptor show marked insensitivity in models of inflammatory or neuropathic pain (Chessell et al., 2005; Clark et al., 2010) and do not develop visceral afferent hypersensitivity in a model of postinfectious irritable bowel syndrome (Keating et al., 2011).”
BackgroundMicroglial signalling mechanisms: Cathepsin S and Fractalkine
Clark, A. K., & Malcangio, M. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.09.012 · Cited by 149 · see citing works
“pups as previously described (Clark et al., 2010).”
Self-citationCathepsin S release from primary cultured microglia is regulated by the P2X7 receptor
Clark, A. K., Wodarski, R., Guida, F., Sasso, O., & Malcangio, M. (2010) · Glia · doi:10.1002/glia.21042 · Cited by 146 · see citing works
“This study suggests that a reduced release of CatS in P2X7 knock-out mice, alongside reduced release of IL-1b in the spinal cord (Clark et al., 2010) is responsible for the attenuation of allodynia.”
BackgroundInfluentialSelf-citationActivated microglia in the spinal cord underlies diabetic neuropathic pain
Wang, D., Couture, R., & Hong, Y. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.01.057 · Cited by 146 · see citing works
“P38β is only expressed in microglia, but not in neurons and astrocytes (Svensson et al., 2005). p38 is essential for cytokine synthesis and release by microglia (Clark et al., 2006, 2010).”
Beaino, W., Janssen, B., Kooij, G., van der Pol, S. M. A., Hof, B. V. H., van Horssen, J., Windhorst, A. D., & de Vries, H. E. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-1034-z · Cited by 141 · see citing works
Eser, A., Colombel, J., Rutgeerts, P. J., Vermeire, S., Vogelsang, H., Braddock, M., Persson, T., & Reinisch, W. (2015) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000514 · Cited by 138 · see citing works
“Upper gastrointestinal involvement, n (%) Yes 2 (8) 2 (20) 4 (12)”
P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases
Illés, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21175996 · Cited by 141 · see citing works
Inhibition of the P2X7–PANX1 complex suppresses spreading depolarization and neuroinflammation
Chen, S., Qin, T., Seidel, J. L., Zheng, Y. Z., Eikermann, M., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Moskowitz, M. A., Ayata, C., & Eikermann‐Haerter, K. (2017) · Brain · doi:10.1093/brain/awx085 · Cited by 137 · see citing works
Melchior, B., Garcia, A., Hsiung, B., Lo, K. M., Doose, J. M., Thrash, J. C., Stalder, A. K., Staufenbiel, M., Neumann, H., & Carson, M. J. (2010) · ASN NEURO · doi:10.1042/an20100010 · Cited by 133 · see citing works
Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats
Kaan, T. K. Y., Yip, P. K., Patel, S., Davies, M., Marchand, F., Cockayne, D. A., Nunn, P. A., Dickenson, A. H., Ford, A. P. D. W., Zhong, Y., et al. (2010) · Brain · doi:10.1093/brain/awq194 · Cited by 130 · see citing works
“The determination of extracellular ATP release from MRMT-1 carcinoma cells was carried out using the CellTiter-Glo Luminescent Cell Viability Assay (Promega) similar to previously described protocols (Yip et al., 2009; Clark et al., 2010).”
MethodSelf-citationInduction of the P2X7 receptor in spinal microglia in a neuropathic pain model
Kobayashi, K., Takahashi, E., Miyagawa, Y., Yamanaka, H., & Noguchi, K. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.08.058 · Cited by 127 · see citing works
C terminus of the P2X7 receptor: treasure hunting
Costa‐Junior, H. M., Vieira, F. S., & Coutinho‐Silva, R. (2011) · Purinergic Signalling · doi:10.1007/s11302-011-9215-1 · Cited by 128 · see citing works
Martini, A. C., Berta, T., Forner, S., Chen, G., Bento, A. F., Ji, R., & Rae, G. A. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0540-8 · Cited by 125 · see citing works
Purinergic mechanisms and pain—An update
Burnstock, G. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.01.078 · Cited by 124 · see citing works
Wang, H., Hong, L., Huang, J., Jiang, Q., Tao, R., Tan, C., Lu, N., Wang, C., Ahmed, M. M., Lu, Y., et al. (2015) · Cell Research · doi:10.1038/cr.2015.61 · Cited by 123 · see citing works
Interleukin-1β in Central Nervous System Injury and Repair.
Hewett, S. J., Jackman, N. A., & Claycomb, R. (2012) · PubMed · Cited by 121 · see citing works
P2X Receptors and Their Roles in Astroglia in the Central and Peripheral Nervous System
Illés, P., Verkhratsky, A., Burnstock, G., & Franke, H. (2011) · The Neuroscientist · doi:10.1177/1073858411418524 · Cited by 121 · see citing works
Chu, Y., Zhang, Y., Zhang, Y., & Zhao, Z.-Q. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.06.001 · Cited by 117 · see citing works
“More recently, other investigators showed that activation of Src-family kinases (SFKs) in microglia in spinal dorsal horn controls the direction of TSS-induced LTP and that the cytokine tumor necrosis factor a (TNF-a) is involved in LTP induction (Zhong et al., 2010).”
BackgroundInfluentialHayashi, Y., Kawaji, K., Sun, L., Zhang, X., Koyano, K., Yokoyama, T., Kohsaka, S., Inoue, K., & Nakanishi, H. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4152-11.2011 · Cited by 112 · see citing works
“5A) (Raouf et al., 2007), expressed on reactive spinal microglia after nerve injury (Tsuda et al., 2003; Clark et al., 2010).”
BackgroundCentral nervous system myeloid cells as drug targets: current status and translational challenges
Biber, K. P. H., Möller, T., Boddeke, E., & Prinz, M. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.14 · Cited by 111 · see citing works
Facci, L., Barbierato, M., Marinelli, C., Argentini, C., Skaper, S. D., & Giusti, P. (2014) · Scientific Reports · doi:10.1038/srep06824 · Cited by 109 · see citing works
Neuron-immune mechanisms contribute to pain in early stages of arthritis
Nieto, F. R., Clark, A. K., Grist, J., Hathway, G. J., Chapman, V., & Malcangio, M. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0556-0 · Cited by 109 · see citing works
“In the spinal cord, microglia release IL-1β following activation of the P2X7 receptor and extracellular IL-1β exerts pro-nociceptive effects [29, 32].”
BackgroundMethodInfluentialSelf-citationMicroglia and intractable chronic pain
Tsuda, M., Beggs, S., Salter, M. W., & Inoue, K. (2013) · Glia · doi:10.1002/glia.22379 · Cited by 113 · see citing works
“Thus, microglial P2X7Rs might participate in the neuronal hyperexcitability of dorsal horn neurons and the development of neuropathic pain through production of proinflammatory cytokines and chemokines.”
BackgroundInfluentialSmith, P. A. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.05.044 · Cited by 108 · see citing works
Gu, Y., Chen, Y., Zhang, X., Li, G.-W., Wang, C., & Huang, L.-Y. M. (2010) · Neuron Glia Biology · doi:10.1017/s1740925x10000116 · Cited by 106 · see citing works
“Furthermore, in mice lacking P2X7Rs, thermal and mechanical hypersensitivity following inflammation, nerve ligation or lipopolysaccharide (LPS) treatment are absent (Chessell et al., 2005; Clark et al., 2010) and LPS- or BzATP-induced release of IL-1b is greatly diminished (Clark et al., 2010).”
BackgroundExtracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release
Zimmermann, H. (2015) · Purinergic Signalling · doi:10.1007/s11302-015-9483-2 · Cited by 105 · see citing works
Neuronal and glial purinergic receptors functions in neuron development and brain disease
del Puerto, A., Wandosell, F. G., & Garrido, J. J. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00197 · Cited by 101 · see citing works
“FIGURE 1 |The coordinated action of glial and neuronal purinergic receptors and purines in the CNS. Pre-synaptic terminals exocytotically release both glutamate (GLUT) and ATP as co-transmitters.”
BackgroundInfluentialChemokine mediated neuron–glia communication and aberrant signalling in neuropathic pain states
Old, E. A., & Malcangio, M. (2011) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2011.10.015 · Cited by 102 · see citing works
“Neuronal CX3CL1 is liberated by CatS, a lysosomal protease released by microglia following activation of the P2X7 receptor by high concentrations of ATP [24] likely to be neuronal in origin [25].”
BackgroundSelf-citationThe search for novel analgesics: targets and mechanisms
Yaksh, T. L., Woller, S. A., Ramachandran, R., & Sorkin, L. S. (2015) · F1000Prime Reports · doi:10.12703/p7-56 · Cited by 100 · see citing works
“Other approaches suppressing glial activation and injuryevoked hyperpathia include adenosine agonists [217,218], inhibitors of purinergic receptors including P2X7 [219–221] and P2Y12 [222,223], inhibitors of P38 MAPK [224,225], inhibitors of NF-kß [226], and inhibitors of TLR4 signaling [227–230].”
BackgroundThe A1 adenosine receptor as a new player in microglia physiology
Luongo, L., Guida, F., Imperatore, R., Napolitano, F., Gatta, L., Cristino, L., Giordano, C. S. D. S., Siniscalco, D., Marzo, V. D., Bellini, G., et al. (2013) · Glia · doi:10.1002/glia.22592 · Cited by 101 · see citing works
BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals
Chen, W., Walwyn, W. M., Ennes, H. S., Kim, H. Y., McRoberts, J. A., & Marvizón, J. C. G. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12516 · Cited by 100 · see citing works
“Sections were incubated overnight at room temperature with NK1R (1:3000) or Iba-1 (1:1000) antiserum in phosphatebuffered saline (PBS) containing 0.3% Triton X-100, 0.001% thimerosal and 5% normal goat serum (Jackson ImmunoResearch Laboratories, West Grove, PA, USA).”
MethodResultInfluentialBoakye, P. A., Tang, S.-J., & Smith, P. A. (2021) · Frontiers in Pain Research · doi:10.3389/fpain.2021.698157 · Cited by 102 · see citing works
“As mentioned above, release of IL-1β from microglia is primarily affected by activation of P2X7 receptors (166, 173, 311, 319) and/or by the action of fractalkine (167).”
BackgroundOgbonna, A. C., Clark, A. K., Gentry, C., Hobbs, C., & Malcangio, M. (2012) · European Journal of Pain · doi:10.1002/j.1532-2149.2012.00223.x · Cited by 93 · see citing works
“Lumbar dorsal horn slices with dorsal roots attached were obtained from mice as previously described (Lever et al., 2003; Clark et al., 2010; Minett et al., 2012).”
BackgroundMethodInfluentialSelf-citationChiang, C., Sessle, B. J., & Dostrovsky, J. O. (2012) · Neurochemical Research · doi:10.1007/s11064-012-0801-6 · Cited by 93 · see citing works
“For instance, a recent study showed that liposaccharideinduced hypersensitivity thought to be mediated by tolllike receptors can be observed in wild-type but not P2X7 knock-out mice [68], indicating that P2X7 receptors are essential elements for immune antigen-induced neuronal hypersensitivity.”
Toll-like receptors in central nervous system injury and disease: A focus on the spinal cord
Heiman, A., Pallottie, A., Heary, R. F., & Elkabes, S. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.06.203 · Cited by 91 · see citing works
Clark, A. K., Grist, J., Al‐Kashi, A., Perretti, M., & Malcangio, M. (2011) · Arthritis & Rheumatism · doi:10.1002/art.34351 · Cited by 88 · see citing works
Self-citationNeuron–microglia interaction by purinergic signaling in neuropathic pain following neurodegeneration
Tsuda, M., & Inoue, K. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.08.042 · Cited by 86 · see citing works
“In the SDH, IL-1β is released from LPS-primed microglia following ATP stimulation in a P2X7R-dependent manner (Clark et al., 2010a).”
BackgroundP2X7 receptor-deficient mice are susceptible to bone cancer pain
Hansen, R. R., Nielsen, C. K., Nasser, A., Thomsen, S. I. M., Eghorn, L. F., Pham, Y., Schulenburg, C., Syberg, S., Ding, M. L., Stojilković, S. S., et al. (2011) · Pain · doi:10.1016/j.pain.2011.03.024 · Cited by 86 · see citing works
“Sections were distributed evenly and stained with either antibody raised in rabbit against glial fibrillary acidic protein (GFAP; DakoCytomation, Glostrup, Denmark, Z0334, 1:500 in 2% BSA in T-PBS) or Iba1 (Wako Pure Chemical Industries Ltd, Osaka, Japan; 019-19741, 1:300 in 2% BSA in T-PBS) overnight at 4 C. Sections…”
BackgroundInfluentialBałkowiec-Iskra, E., Vermehren‐Schmaedick, A., & Bałkowiec, A. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.02.028 · Cited by 85 · see citing works
Chen, M., Cao, H., Chu, Y., Cheng, L., Liang, L., Zhang, Y., & Zhao, Z.-Q. (2012) · Journal of Pain · doi:10.1016/j.jpain.2012.06.007 · Cited by 84 · see citing works
Farooq, R. K., Tanti, A., Ainouche, S., Roger, S., Belzung, C., & Camus, V. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.07.016 · Cited by 83 · see citing works
Liu, C., Ma, H., Slitt, A. L., & Seeram, N. P. (2020) · Journal of Natural Products · doi:10.1021/acs.jnatprod.0c00138 · Cited by 83 · see citing works
Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery
Obeng, S., Hiranita, T., León, F., McMahon, L. R., & McCurdy, C. R. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00028 · Cited by 83 · see citing works
Berger, J. V., Knaepen, L., Janssen, S. P. M., Jaken, R. J. P., Marcus, M. A. E., Joosten, E. A. J., & Deumens, R. (2011) · Brain Research Reviews · doi:10.1016/j.brainresrev.2011.03.003 · Cited by 80 · see citing works
Nociceptive signaling mediated by P2X3, P2X4 and P2X7 receptors
Inoue, K., & Tsuda, M. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114309 · Cited by 78 · see citing works
Microglia-Mediated Regulation of Neuropathic Pain: Molecular and Cellular Mechanisms
Tsuda, M. (2019) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b19-00715 · Cited by 79 · see citing works
Enteric Glia: A New Player in Abdominal Pain
Morales‐Soto, W., & Gulbransen, B. D. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.11.005 · Cited by 78 · see citing works
Muñoz, F. M., Gao, R. Y., Tian, Y., Henstenburg, B. A., Barrett, J. E., & Hu, H. (2017) · Scientific Reports · doi:10.1038/s41598-017-03813-7 · Cited by 76 · see citing works
Optogenetic activation of spinal microglia triggers chronic pain in mice
Yi, M., Liu, Y., Umpierre, A. D., Chen, T., Ying, Y., Zheng, J., Dheer, A., Bosco, D. B., Dong, H., & Wu, L. (2021) · PLoS Biology · doi:10.1371/journal.pbio.3001154 · Cited by 75 · see citing works
Bravo, D., Maturana, C. J., Pélissier, T., Hernández, A., & Constandil, L. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.07.016 · Cited by 74 · see citing works
Liu, T., Jiang, C., Fujita, T., Luo, S., & Kumamoto, E. (2013) · Molecular Pain · doi:10.1186/1744-8069-9-16 · Cited by 74 · see citing works
“, microglia and astrocytes) in different chronic pain states [5,11,29,30].”
BackgroundSite-Specific Regulation of P2X7 Receptor Function in Microglia Gates Morphine Analgesic Tolerance
Leduc‐Pessah, H., Weilinger, N. L., Fan, C. Y., Burma, N. E., Thompson, R. J., & Trang, T. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.0852-17.2017 · Cited by 74 · see citing works
“A downstream consequence of activating P2X7R on microglia is the release of cytokines, chemokines, and a host of other signaling molecules whose activity may compromise the analgesic response to morphine (Clark et al., 2010a,b; Chen et al., 2012).”
BackgroundP2 receptors, microglial cytokines and chemokines, and neuropathic pain
Tsuda, M. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23816 · Cited by 71 · see citing works
“In the dorsal horn, lipopolysaccharide (LPS)-primed microglia stimulated by ATP released IL-1b in a manner dependent on P2X7Rs (Clark et al., 2010a).”
BackgroundInfluentialNeuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain
Biber, K. P. H., & Boddeke, E. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00210 · Cited by 72 · see citing works
“It is clear today that inhibition of various microgliaspecific receptors or effector molecules prevents the development of neuropathic pain (Jin et al., 2003; Schäfers et al., 2003; Tsuda et al., 2003; Terayama et al., 2008; Clark et al., 2009, 2010).”
Background
- Authors
- Clark, A. K., Staniland, A. A., Marchand, F., Kaan, T. K. Y., McMahon, S. B., & Malcangio, M.
- Affiliations
- King's College London (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-01-13
- Volume
- 30
- Issue
- 2
- Pages
- 573-582
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2880485
- OpenAlex
- W2046299505
- Cited by
- 291
- References
- 62
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 14 · 2023: 11 · 2022: 13 · 2021: 17 · 2020: 18 · 2019: 9 · 2018: 9 · 2017: 18 · 2016: 21 · 2015: 28 · 2014: 22 · 2013: 25 · 2012: 26
- FWCI
- 20.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- GlaxoSmithKline
- Wellcome Trust (081553, 83259)
- Versus Arthritis
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- P2X7 receptor, IL-1β, lipopolysaccharide, nociception, spinal microglia, TLR4, dorsal horn, mechanical hyperalgesia, p38 MAPK, purinergic signaling, ATP, chronic pain
- MeSH terms
- Adenosine Triphosphate, Analysis of Variance, Animals, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Hyperalgesia, Lipopolysaccharides, Male, Pain Measurement, Phosphopyruvate Hydratase, Pyridines, Spinal Cord, Tetrazoles, Theophylline, Time Factors, Rats, Wistar, Pain Threshold, Microglia, Receptors, Purinergic P2, Mice, Knockout, Mitogen-Activated Protein Kinase 13, Mice, Rats, Interleukin-1beta, Receptors, Purinergic P2X7, Purinergic P2 Receptor Agonists, Purinergic P2 Receptor Antagonists, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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