Glial activation and pathological pain

Wieseler-Frank, Julie; Maier, Steven F.; Watkins, Linda R.

doi:10.1016/j.neuint.2003.09.009

Cited by 247 publications

(134 citation statements)

References 62 publications

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“…Thus, NO generated by iNOS is thought to contribute to the pathology of Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, brain ischemia, and trauma (Liu et al, 2002). In addition, it is now thought that activation of glial cells within the CNS leads to alterations in neuronal excitability that help maintain the pain sensation even after the original injury or inflammatory event has subsided (Wieseler-Frank et al, 2004). Based on the importance of glial cells and iNOS expression in CNS diseases, it is likely that CGRP stimulation of iNOS activity and increased NO release from satellite glial cells within the trigeminal ganglia will play a main role in the underlying pathology of migraine as well as other diseases that involve trigeminal ganglia nerves.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

2008

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“…Thus, the inhibition of minocycline on astrocytic activation might be mediated by blocking microglial activation, which is supported by Reghavendra's study that only preemptive treatment but not postinjury administration of minocycline suppressed GFAP expression on the lumbar spinal cord in spinal nerve transection rats (Reghavendra et al, 2003). Either activated microglia or astrocytes can release proinflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, tumor necrosis factor α (TNFα), and other algesic substances to enhance neuronal transmission of nociception, leading to exaggerated pain (Raghavendra et al, 2003;Wieseler-Frank et al, 2004). …”

Section: Microglial Activation Contributes To the Initiation Of Exaggmentioning

confidence: 99%

Is functional state of spinal microglia involved in the anti-allodynic and anti-hyperalgesic effects of electroacupuncture in rat model of monoarthritis?

Sun¹,

Mao-Ying²,

Cao³

et al. 2007

Neurobiology of Disease

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Spinal microglia play a key role for creating exaggerated pain following tissues inflammation or injury. Electroacupuncture (EA) can effectively control the exaggerated pain both in humans with inflammatory disease and animals with experimental inflammatory pain. However, little is known about the relationship between spinal glial activation and EA analgesia. Using immunohistochemistry, RT-PCR analysis, and behavioral testing, the present study demonstrated that (1) Unilateral intra-articular injection of CFA produced an robust microglial activation and the up-regulation of the tumor necrosis factor (TNF)-α, interleukin (IL-1β), and IL-6 mRNA levels in the spinal cord; (2) Repeated intrathecal (i.t.) injection of minocycline (100 μg), a microglial inhibitor, or EA stimulation of ipsilateral "Huantiao"(GB30) and "Yanglingquan" (GB34) acupoints significantly suppressed CFA-induced nociceptive behavioral hypersensitivity and spinal microglial activation; (3) Combination of EA with minocycline significantly enhanced the inhibitory effects of EA on allodynia and hyperalgesia. For the first time, these data provide direct evidence for the involvement of spinal microglial functional state in anti-nociception of EA. Thus, antineuroinflammatory effect of EA might be considered as one of the mechanisms of its anti-arthritic pain effects, and thereby a multidisciplinary integrated approach to treating symptoms related to arthritis might be raised.

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“…There is a wealth of research detailing the production and secretion of many cytokines, chemokines and other proinflammatory mediators from microglia within the CNS following peripheral nerve injury (Wieseler-Frank et al, 2004;Tsuda et al, 2005;Moalem and Tracey, 2006) and many of these factors are also capable of contributing to the changes in second order neuronal excitability seen following nerve injury that underlie neuropathic pain behaviours (Watkins et al, 2001;Salter, 2005). The relative spatial distribution of injured peripheral nerve central terminals, microglial cells and second order dorsal horn cells within the spinal dorsal horn is, therefore, of key importance when considering a signalling pathway that involves these three elements.…”

Section: Introductionmentioning

confidence: 99%

Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury

Beggs

Salter

2007

Brain, Behavior, and Immunity

129

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The involvement of glia, and glia-neuronal signalling in enhancing nociceptive transmission has become an area of intense scientific interest. In particular, a role has emerged for activated microglia in the development and maintenance of neuropathic pain following peripheral nerve injury. Following activation, spinal microglia proliferate and release many substances which are capable of modulating neuronal excitability within the spinal cord. Here, we the investigated the response of spinal microglia to a unilateral spared nerve injury (SNI) in terms of the quantitative increase in cell number and the spatial distribution of the increase. Design-based stereological techniques were combined with iba-1 immunohistochemistry to estimate the total number of microglia in the spinal dorsal horn in naïve and peripheral nerve-injured adult rats. In addition, by mapping the central terminals of hindlimb nerves, the somatotopic distribution of the microglial response was mapped. Following SNI there was a marked increase in the number of spinal microglia: The total number of microglia (mean ± SD) in the dorsal horn sciatic territory of the naïve rat was estimated to be 28,591 ± 2715. Following SNI the number of microglia was 82,034 ± 8828. While the pattern of microglial activation generally followed somatotopic boundaries, with the majority of microglia within the territory occupied by peripherally axotomised primary afferents, some spread was seen into regions occupied by intact, 'spared' central projections of the sural nerve. This study provides a reproducible method of assaying spinal microglial dynamics following peripheral nerve injury both quantitatively and spatially.

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Glial activation and pathological pain

Cited by 247 publications

References 62 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

Is functional state of spinal microglia involved in the anti-allodynic and anti-hyperalgesic effects of electroacupuncture in rat model of monoarthritis?

Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury

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