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The Journal of Neuroscience, May 30, 2007, 27(22):6006-6018; doi:10.1523/JNEUROSCI.0176-07.2007
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Behavioral/Systems/Cognitive
Glial–Cytokine–Neuronal Interactions Underlying the Mechanisms of Persistent Pain
Wei Guo, * Hu Wang, * Mineo Watanabe, * Kohei Shimizu, Shiping Zou, Stacey C. LaGraize, Feng Wei, Ronald Dubner, andKe Ren Department of Biomedical Sciences, Program in Neuroscience, Dental School, University of Maryland, Baltimore, Maryland 21201
Correspondence should be addressed to Dr. Ke Ren, Department of Biomedical Sciences, 650 West Baltimore Street, Dental-7 South, Baltimore, MD 21201-1586. Email: kren{at}umaryland.edu
The emerging literature implicates a role for glia/cytokines in persistent pain. However, the mechanisms by which these non-neural elements contribute to CNS activity-dependent plasticity and pain are unclear. Using a trigeminal model of inflammatory hyperalgesia, here we provide evidence that demonstrates a mechanism by which glia interact with neurons, leading to activity-dependent plasticity and hyperalgesia. In response to masseter inflammation, there was an upregulation of glial fibrillary acidic proteins (GFAPs), a marker of astroglia, and interleukin-1ß (IL-1ß), a prototype proinflammatory cytokine, in the region of the trigeminal nucleus specifically related to the processing of deep orofacial input. The activated astroglia exhibited hypertrophy and an increased level of connexin 43, an astroglial gap junction protein. The upregulated IL-1ß was selectively localized to astrocytes but not to microglia and neurons. Local anesthesia of the masseter nerve prevented the increase in GFAP and IL-1ß after inflammation, and substance P, a prototype neurotransmitter of primary afferents, induced similar increases in GFAP and IL-1ß, which was blocked by a nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester. Injection of IL-1 receptor antagonist and fluorocitrate, a glial inhibitor, attenuated hyperalgesia and NMDA receptor phosphorylation after inflammation. In vitro application of IL-1ß induced NR1 phosphorylation, which was blocked by an IL-1 receptor antagonist, a PKC inhibitor (chelerythrine), an IP3 receptor inhibitor (2-aminoethoxydiphenylborate), and inhibitors of phospholipase C [1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione] and phospholipase A2 (arachidonyltrifluoromethyl ketone). These findings provide evidence of astroglial activation by tissue injury, concomitant IL-1ß induction, and the coupling of NMDA receptor phosphorylation through IL-1 receptor signaling.
Key words: GFAP; IL-1ß; NMDA receptor; gap junction; inflammation; rat
Received Jan. 16, 2007; revised April 30, 2007; accepted April 30, 2007.
Correspondence should be addressed to Dr. Ke Ren, Department of Biomedical Sciences, 650 West Baltimore Street, Dental-7 South, Baltimore, MD 21201-1586. Email: kren{at}umaryland.edu
This article has been cited by other articles:
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[Abstract] [Full Text] [PDF]
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