Cited by 296Pain Mechanisms and TreatmentsAdenosine and Purinergic SignalingNeuroinflammation and Neurodegeneration Mechanisms

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P2X7-Dependent Release of Interleukin-1β and Nociception in the Spinal Cord following Lipopolysaccharide

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Clark, Anna K., Staniland, Amelia A., Marchand, Fabien, Kaan, Timothy K. Y., McMahon, Stephen B., Malcangio, Marzia·2010·The Journal of Neuroscience

DOI 10.1523/jneurosci.3295-09.2010PMC PMC2880485

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Abstract

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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Additional file 1 of Silencing PinX1 enhances radiosensitivity and antitumor-immunity of radiotherapy in non-small cell lung cancer
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BindingDB Entry 50043200: TBA
BindingDB (2014) · UC San Diego · doi:10.7270/q2jq12dd
BindingDB Entry 50039938: Structure-activity relationships and optimization of 3,5-dichloropyridine derivatives as novel P2X(7) receptor antagonists.
BindingDB (2013) · UC San Diego · doi:10.7270/q21g0nb3
BindingDB Entry 50001389: 1-Aryl-1H- and 2-aryl-2H-1,2,3-triazole derivatives blockade P2X7 receptor in vitro and inflammatory response in vivo.
BindingDB (2020) · UC San Diego · doi:10.7270/q2tx3hwc
BindingDB Entry 50047862: Identification of (R)-(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor.
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Investigating the contribution of the inflammasome to persistent pain states
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Authors: Clark, A. K., Staniland, A. A., Marchand, F., Kaan, T. K. Y., McMahon, S. B., & Malcangio, M.
Affiliations: King's College London (GB)
ORCID: Clark, Anna K.
Marchand, Fabien
McMahon, Stephen B.
Malcangio, Marzia
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
DOI: 10.1523/jneurosci.3295-09.2010
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: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 181 d)
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 (medical) › 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

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P2X7-Dependent Release of Interleukin-1β and Nociception in the Spinal Cord following Lipopolysaccharide

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