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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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“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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“P2X7 inhibition has been associated with antidepressant-like effects, and IL-1β knockout mice failed to express these receptors [48,49].”
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Metadata
- 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 (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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