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Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine
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Accumulating evidence suggests that microglial cells in the spinal cord play an important role in the development of neuropathic pain. However, it remains largely unknown how glia interact with neurons in the spinal cord after peripheral nerve injury. Recent studies suggest that the chemokine fractalkine may mediate neural/microglial interaction via its sole receptor CX3CR1. We have examined how fractalkine activates microglia in a neuropathic pain condition produced by spinal nerve ligation (SNL). SNL induced an upregulation of CX3CR1 in spinal microglia that began on day 1, peaked on day 3, and maintained on day 10. Intrathecal injection of a neutralizing antibody against CX3CR1 suppressed not only mechanical allodynia but also the activation of p38 MAPK in spinal microglia following SNL. Conversely, intrathecal infusion of fractalkine produced a marked p38 activation and mechanical allodynia. SNL also induced a dramatic reduction of the membrane-bound fractalkine in the dorsal root ganglion, suggesting a cleavage and release of this chemokine after nerve injury. Finally, application of fractalkine to spinal slices did not produce acute facilitation of excitatory synaptic transmission in lamina II dorsal horn neurons, arguing against a direct action of fractalkine on spinal neurons. Collectively, our data suggest that (a) fractalkine cleavage (release) after nerve injury may play an important role in neural-glial interaction, and (b) microglial CX3CR1/p38 MAPK pathway is critical for the development of neuropathic pain.
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“CX3CR1 and its chemokine ligand fractalkine (CX3CL1) have been implicated in the recruitment of mononuclear phagocytes to sites of inflammation and injury (7, 10, 11) and play roles in the pathogenesis of several inflammatory conditions, including atherosclerosis (12, 13), neuropathic pain (14), and asthma (15).”
From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [14]
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Self-citation
Metadata
- Authors
- Zhuang, Z.-Y., Kawasaki, Y., Tan, P.-H., Wen, Y.-R., Huang, J., & Ji, R.-R.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Ji, Ru-Rong
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 21
- Issue
- 5
- Pages
- 642-651
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC2084372
- OpenAlex
- W2006680088
- Semantic Scholar
- 64f3a09c34ad12759b6e063e279570703bf27e54
- Cited by
- 371
- References
- 51
- Citations by year
- 2026: 14 · 2025: 7 · 2024: 5 · 2023: 19 · 2022: 17 · 2021: 19 · 2020: 26 · 2019: 15 · 2018: 26 · 2017: 17 · 2016: 24 · 2015: 16 · 2014: 25 · 2013: 23 · 2012: 17
- FWCI
- 12.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Fogarty International Center (R03TW007180)
- National Institute of Neurological Disorders and Stroke (R01NS040698)
- National Institute of Dental and Craniofacial Research (R01DE017794, R01 DE17794)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- neuropathic pain, spinal microglia, CX3CR1, fractalkine, p38 MAPK, spinal nerve ligation, mechanical allodynia, dorsal root ganglia, microglial activation, excitatory synaptic transmission
- MeSH terms
- CX3C Chemokine Receptor 1, Analysis of Variance, Animals, Disease Models, Animal, Ligation, Male, Membrane Proteins, Neuralgia, Spinal Cord, Spinal Nerves, Signal Transduction, Rats, Sprague-Dawley, Pain Threshold, Microglia, Statistics, Nonparametric, Receptors, Chemokine, Chemokines, CX3C, Posterior Horn Cells, p38 Mitogen-Activated Protein Kinases, Rats, Chemokine CX3CL1
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