Glial–Cytokine–Neuronal Interactions Underlying the Mechanisms of Persistent Pain

Guo, Wei; Wang, Hu; Watanabe, Mineo; Shimizu, Kanichiro; Zou, Shiping; LaGraize, Stacey C.; Feng, Wei; Dubner, Ronald; Ren, Ke

doi:10.1523/jneurosci.0176-07.2007

Cited by 437 publications

(561 citation statements)

References 67 publications

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“…4). The concentrations of CGRP (1 μM) and CGRP 8-37 (10 μM) used in our study are similar to values used in other studies on the functional role of CGRP (Guo et al, 2007;Zhang et al, 2007). To demonstrate that NO production was being mediated primarily by iNOS activity and not nNOS, cultures were pretreated with the selective and potent nNOS inhibitor N ω -propyl-L-arginine 60 min prior to CGRP addition and the levels of NO in the medium determined.…”

Section: Cgrp Stimulates Inos and No Release From Cultured Glial Cellsmentioning

confidence: 82%

Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells

2008

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Clinical and basic science data support an integral role of calcitonin gene-related peptide (CGRP) in migraine pathology. Following trigeminal nerve activation, afferent release of CGRP causes vasodilation while efferent release leads to pain. Although CGRP can also be secreted from cell bodies of trigeminal neurons located within the ganglion, the function of CGRP released in the ganglion is poorly understood. Initially, we showed that SNAP-25, a protein required for CGRP release, was localized in cell bodies of trigeminal ganglia neurons. We also found that satellite glial cells in the ganglia express the CGRP1 receptor protein RAMP1. To determine whether CGRP could directly activate glial cells, primary cultures of rat trigeminal ganglia were utilized to study the effects of CGRP on glial nitric oxide (NO) synthesis and release. Under our culture conditions, >95% of the cells expressed glial fibrillary acidic protein and RAMP1. While weak iNOS staining was observed in glia under basal conditions, CGRP treatment greatly increased glial iNOS expression and NO release. This stimulatory effect was blocked by the CGRP1 receptor antagonist, CGRP 8-37 peptide. Treatment of glial cultures with forskolin or cAMP also increased iNOS expression and stimulated NO release to levels similar to CGRP. To our knowledge, this is the first evidence that activation of CGRP1 receptors regulates glial iNOS and NO release. We propose that following trigeminal nerve activation, CGRP secretion from neuronal cell bodies activates satellite glial cells that release NO and initiate inflammatory events in the ganglia that contribute to peripheral sensitization in migraine.

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Section: Cgrp Stimulates Inos and No Release From Cultured Glial Cellsmentioning

confidence: 82%

Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells

2008

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“…Functional coupling between NMDA receptors and IL-1␤ receptors in postsynaptic neurons in the brainstem was previously reported (47). We next determined the possible functional coupling between IL-1␤ receptors and presynaptic NMDA receptors at the primary afferent terminals.…”

Section: Endogenous Il-1␤ In Neuropathic Rats Enhances Glutamate Relementioning

confidence: 90%

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

Yan

严

Weng

et al. 2013

Journal of Biological Chemistry

106

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Background: Excessive activation of glutamate receptors is crucial to the genesis of neuropathic pain. Results: Endogenous IL-1␤ in neuropathic rats enhances glutamate release by increasing presynaptic NMDA receptor activities via sphingomyelinase signaling. Conclusion: Coupling between IL-1␤ receptors and presynaptic NMDA receptors contributes to the genesis of neuropathic pain. Significance: Interruption of such coupling could be an effective approach for the treatment of neuropathic pain.

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“…The interaction between immune/glial cells and neurons during the induction of chronic pain is a novel concept that has gained much attention in the last years. For instance, during peripheral inflammation, the increase in neuronal inputs from the periphery to the CNS results in an intense activation of glial cells (microglia and astrocytes), mainly at the spinal cord and trigeminal nucleus (19)(20)(21). These cells then produce and release a great number of substances, including proinflammatory cytokines (TNF-α and IL1-β), which directly or indirectly act upon the neurons of the nociceptive system to amplify the pain process (7).…”

Section: Discussionmentioning

confidence: 99%

Fractalkine mediates inflammatory pain through activation of satellite glial cells

Souza

Talbot

Lotufo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

129

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The activation of the satellite glial cells (SGCs) surrounding the dorsal root ganglion (DRG) neurons appears to play a role in pathological pain. We tested the hypothesis that fractalkine, which is constitutively expressed by primary nociceptive neurons, is the link between peripheral inflammation and the activation of SGCs and is thus responsible for the genesis of the inflammatory pain. The injection of carrageenin into the rat hind paw induced a decrease in the mechanical nociceptive threshold (hypernociception), which was associated with an increase in mRNA and GFAP protein expression in the DRG. Both events were inhibited by antifractalkine antibody administered directly into the DRG (L5) [intraganglionar (i.gl.)]. The administration of fractalkine into the DRG (L5) produced mechanical hypernociception in a dose-, time-, and CX3C receptor-1 (CX3CR1)-dependent manner. Fractalkine's hypernociceptive effect appears to be indirect, as it was reduced by local treatment with anti-TNF-α antibody, IL-1-receptor antagonist, or indomethacin. Accordingly, the in vitro incubation of isolated and cultured SGC with fractalkine induced the production/ release of TNF-α, IL-1β, and prostaglandin E 2 . Finally, treatment with i.gl. fluorocitrate blocked fractalkine (i.gl.)-and carrageenin (paw)-induced hypernociception. Overall, these results suggest that, during peripheral inflammation, fractalkine is released in the DRG and contributes to the genesis of inflammatory hypernociception. Fractalkine's effect appears to be dependent on the activation of the SGCs, leading to the production of TNFα, IL-1β, and prostanoids, which are likely responsible for the maintenance of inflammatory pain. Thus, these results indicate that the inhibition of fractalkine/ CX3CR1 signaling in SGCs may serve as a target to control inflammatory pain.cytokines | hyperalgesia | primary sensitization | nociception

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Glial–Cytokine–Neuronal Interactions Underlying the Mechanisms of Persistent Pain

Cited by 437 publications

References 67 publications

Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells

Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

Fractalkine mediates inflammatory pain through activation of satellite glial cells

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