Microglial Regulation of Neuropathic Pain

Tsuda, Makoto; Masuda, Takahiro; Tozaki‐Saitoh, Hidetoshi; Inoue, Kazuhide

doi:10.1254/jphs.12r14cp

Cited by 105 publications

(73 citation statements)

References 52 publications

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“…Activation of microglia occurs in most pathological processes, which is often accompanied by morphologic change and production of cytotoxic molecules, and upregulation of phagocytosis and immune surface antigens [8][9][10]. Activation of microglia is also involved in the pain transmission pathway of acute and chronic pains such as neuropathic pain, inflammatory pain and cancerous pain [11][12][13]. It has been found that the activated spinal microglia release bioactive molecules including interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), nitric oxide (NO), and brain-derived neurotrophic factor (BDNF), which aggravate the range and duration of pain [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Paeoniflorin Attenuates Inflammatory Pain by Inhibiting Microglial Activation and Akt-NF-κB Signaling in the Central Nervous System

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Paeoniflorin (PF) is known to have anti-inflammatory and paregoric effects, but the mechanism underlying its analgesic effect remains unclear. The aim of this study was to clarify the effect of PF on Freund’s complete adjuvant (CFA)-induced inflammatory pain and explore the underlying molecular mechanism. Methods: An inflammatory pain model was established by intraplantar injection of CFA in C57BL/6J mice. After intrathecal injection of PF daily for 8 consecutive days, thermal and mechanical withdrawal thresholds, the levels of inflammatory factors TNF-α, IL-1β and IL-6, microglial activity, and the expression of Akt-NF-κB signaling pathway in the spinal cord tissue were detected by animal ethological test, cell culture, enzyme-linked immunosorbent assay, immunofluorescence histochemistry, and western blot. Results: PF inhibited the spinal microglial activation in the CFA-induced pain model. The production of proinflammatory cytokines was decreased in the central nervous system after PF treatment both in vivo and in vitro. PF further displayed a remarkable effect on inhibiting the activation of Akt-NF-κB signaling pathway in vivo and in vitro. Conclusion: These results suggest that PF is a potential therapeutic agent for inflammatory pain and merits further investigation.

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Section: Introductionmentioning

confidence: 99%

Paeoniflorin Attenuates Inflammatory Pain by Inhibiting Microglial Activation and Akt-NF-κB Signaling in the Central Nervous System

Zhang

et al. 2018

Cell Physiol Biochem

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“…However, recent studies indicate that microglia can function as key players in the modulation of neuronal network excitability [2]. Furthermore, neuropathic pain pathogenesis depends on both changes in the activity of neuronal systems as well as microglia activation [3]. During the pathogenesis of neuropathic pain, resident microglia become activated [4], exhibiting up-regulation of the expression of cell surface receptors (including purinergic receptors and CD11b) [5,6], enhanced migratory ability [7] and pro-inflammatory cytokine release (including tumor necrosis factor (TNF)-α and brain-derived neurotropic factor (BDNF)) [8,9], which can enhance synaptic transmission.…”

Section: Introductionmentioning

confidence: 99%

Positive Feedback Loop of Autocrine BDNF from Microglia Causes Prolonged Microglia Activation

Zhang¹,

Zeng²,

Yu³

et al. 2014

Cell Physiol Biochem

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Background/Aims: Microglia, which represent the immune cells of the central nervous system (CNS), have long been a subject of study in CNS disease research. Substantial evidence indicates that microglial activation functions as a strong neuro-inflammatory response in neuropathic pain, promoting the release of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α. In addition, activated microglia release brain-derived neurotrophic factor (BDNF), which acts as a powerful cytokine. In this study, we performed a series of in vitro experiments to examine whether a positive autocrine feedback loop existed between microglia-derived BDNF and subsequent microglial activation as well as the mechanisms underlying this positive feedback loop. Methods: Because ATP is a classic inducer of microglial activation, firstly, we examined ATP-activated microglia in the present study. Secondly, we used TrkB/Fc, the BDNF sequester, to eliminate the effects of endogenous BDNF. ATP-stimulated microglia without BDNF was examined. Finally, we used exogenous BDNF to further determine whether BDNF could directly activate BV2 microglia. In all experiments, to quantify BV2 microglia activation, the protein levels of CD11b, a microglial activation marker, were measured by western blot. A Transwell migration assay was used to examine microglial migration. To assess the synthesis and release of proinflammatory cytokines, western blot was used to measure BDNF synthesis, and ELISA was used to quantify TNF-α release. Results: In our present research, we have observed that ATP dramatically activates microglia, enhancing microglial migration, increasing the synthesis of BDNF and up-regulating the release of TNF-α. Microglial activation is inhibited following the sequestration of endogenous BDNF, resulting in impaired microglial migration and decreased TNF-α release. Furthermore, exogenous BDNF can also activate microglia to subsequently enhance migration and increase TNF-α release. Conclusion: Therefore, we suggest that microglial activation increases the synthesis of BDNF and that the release of BDNF can, in turn, activate microglia. A positive autocrine BDNF feedback loop from microglia may contribute to prolonged microglial activation.

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“…Recent evidence suggests that neuropathic pain is associated with activation of spinal glial cells including microglia and astrocytes (2 -5). Microglia in the spinal cord rapidly respond to peripheral nerve injury and become in the active state (6), enabling them to send signals to astrocytes (7). Activated microglia and astrocytes secrete various biologically active pronociceptive mediators including proinflammatory cytokines and chemokines, which lead to hyperexcitability of spinal dorsal horn neurons (8).…”

Section: Introductionmentioning

confidence: 99%

Preventive and Alleviative Effect of Tramadol on Neuropathic Pain in Rats: Roles of α2-Adrenoceptors and Spinal Astrocytes

et al. 2014

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Abstract.The acute analgesic effect of tramadol has been extensively investigated; however, its long-term effect on neuropathic pain has not been well clarified. In this study, we examined the effects of repeated administration of tramadol on partial sciatic nerve ligation-induced neuropathic pain in rats. Each drug was administered once daily from 0 -6 days (preventive effect) or 7 -14 days (alleviative effect) after the surgery. Mechanical allodynia was evaluated just before (preventive or alleviative effect) and 1 h after (analgesic effect) drug administration. Like morphine, first administration of tramadol (20 mg/kg) showed an acute analgesic effect on the developed mechanical allodynia, which was diminished by naloxone. Like amitriptyline, repeated administration of tramadol showed preventive and alleviative effects on the mechanical allodynia that was diminished by yohimbine, but not naloxone. The alleviative effects of tramadol lasted even after drug cessation or in the presence of yohimbine. Repeated administration of tramadol increased the dopamine b-hydroxylase immunoreactivity in the spinal cord. Furthermore, tramadol inhibited the nerve ligation-induced activation of spinal astrocytes, which was reduced by yohimbine. These results suggest that tramadol has both m-opioid receptor-mediated acute analgesic and a 2 -adrenoceptor-mediated preventive and alleviative effects on neuropathic pain, and the latter is due to a 2 -adrenoceptor-mediated inhibition of astrocytic activation.

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Microglial Regulation of Neuropathic Pain

Cited by 105 publications

References 52 publications

Paeoniflorin Attenuates Inflammatory Pain by Inhibiting Microglial Activation and Akt-NF-κB Signaling in the Central Nervous System

Paeoniflorin Attenuates Inflammatory Pain by Inhibiting Microglial Activation and Akt-NF-κB Signaling in the Central Nervous System

Positive Feedback Loop of Autocrine BDNF from Microglia Causes Prolonged Microglia Activation

Preventive and Alleviative Effect of Tramadol on Neuropathic Pain in Rats: Roles of α2-Adrenoceptors and Spinal Astrocytes

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