Microglial depletion under thalamic hemorrhage ameliorates mechanical allodynia and suppresses aberrant axonal sprouting

Hiraga, Shin‐ichiro; Itokazu, Takahide; Hoshiko, Maki; Takaya, Hironobu; Nishibe, Mariko; Yamashita, Toshio

doi:10.1172/jci.insight.131801

Cited by 21 publications

(25 citation statements)

References 70 publications

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“…Finally, we explored how the increased Fgr contributed to hemorrhage-induced thalamic pain genesis. Consistent with previous observations ( 9 , 10 , 19 ), Coll IV microinjection led to the activation of microglia and astrocytes as evidenced by significant increases in the levels of Iba1 and GFAP, respectively, in the ipsilateral thalami of Fgr scrambled siRNA–treated mice on day 5 post–Coll IV microinjection ( Figure 8A ). The increased expression of Iba1, but not of GFAP, was attenuated by thalamic premicroinjection of Fgr siRNA in the Coll IV–treated mice ( Figure 8A ).…”

Section: Resultssupporting

confidence: 92%

“…The production of TNF-α triggered via the activations of both NF-κB and ERK1/2 pathways in thalamic microglia may mediate the role of the increased Fgr in hemorrhage-induced thalamic pain. Prolonged microglial activation is implicated in thalamic pain development because microglial inhibition or depletion ameliorates pain hypersensitivities caused by thalamic microinjection of Coll IV ( 9 , 10 ). The chemokines and cytokines released from microglia are involved in hemorrhage-induced thalamic pain ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…In a mouse model of CPSP induced by injecting collagenase into the ventral posterior lateral nucleus (VPL) of the thalamus, prolonged microglial activation helped maintain mechanical allodynia and heat hyperalgesia, as intraperitoneal injection of minocycline, a microglial inhibitor, markedly ameliorated neuropathic pain-like behaviors ( 9 ). Microglial depletion effectively prevents mechanical allodynia caused by thalamic hemorrhage ( 10 ). Glial activation lasting for at least 3 months was also noted in adjacent areas following collagenase injection into the thalamic VPL of rhesus macaques, a primate model more directly comparable to humans ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Huang¹,

Fu²,

Gao³

et al. 2020

JCI Insight

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Thalamic pain, a type of central poststroke pain, frequently occurs following ischemia/hemorrhage in the thalamus. Current treatment of this disorder is often ineffective, at least in part due to largely unknown mechanisms that underlie thalamic pain genesis. Here, we report that hemorrhage caused by microinjection of type IV collagenase or autologous whole blood into unilateral ventral posterior lateral nucleus and ventral posterior medial nucleus of the thalamus increased the expression of Fgr, a member of the Src family nonreceptor tyrosine kinases, at both mRNA and protein levels in thalamic microglia. Pharmacological inhibition or genetic knockdown of thalamic Fgr attenuated the hemorrhage-induced thalamic injury on the ipsilateral side and the development and maintenance of mechanical, heat, and cold pain hypersensitivities on the contralateral side. Mechanistically, the increased Fgr participated in hemorrhage-induced microglial activation and subsequent production of TNF-α likely through activation of both NF-κB and ERK1/2 pathways in thalamic microglia. Our findings suggest that Fgr is a key player in thalamic pain and a potential target for the therapeutic management of this disorder.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Huang¹,

Fu²,

Gao³

et al. 2020

JCI Insight

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show abstract

“…The activation of the P2X4/P2RX7 receptors in microglia [ 59 – 61 ] and the activation of NLRP3 in microglia are both related to the occurrence of pain after cerebral hemorrhage and stroke [ 62 , 63 ]. In the thalamic hemorrhage model, depletion of microglia can effectively prevent the development of analgesia [ 64 ].…”

Section: Microglial Activation Plays An Important Role In Pain Post Hemorrhagic Strokementioning

confidence: 99%

Microglia in the Pathophysiology of Hemorrhagic Stroke and the Relationship Between Microglia and Pain After Stroke: A Narrative Review

Liu

Fan

et al. 2021

Pain Ther

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Stroke is a leading cause of death worldwide, and about a quarter of stroke patients are dead within 1 month. The prognosis is even worse for those with hemorrhagic stroke because the 1-month mortality approaches 50%. Besides, most patients who survive experience complications such as nausea, vomiting, and chronic pain. These adverse experiences, especially the existence of chronic pain, can lead to a decline in the patient's quality of life. In order to improve the treatment and prognosis of hemorrhagic stroke, there is an urgent need to understand its pathophysiological mechanism as well as the chronic pain it induces. This paper reviews studies of the molecular mechanisms of hemorrhagic stroke, especially the activation of microglia and the relationship between microglia and pain after stroke, which could shed new light on hemorrhagic stroke treatment.

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“…In the spinal cord, peripheral nerve injury induces axonal sprouting of primary afferent neurons (Woolf et al, 1992). In the thalamus, neuronal damage by local hemorrhage induces sprouting of thalamocortical axons (Hiraga et al, 2020). In hippocampal pyramidal cells, neuronal hyperexcitability caused by traumatic brain injury or axotomy promotes axonal sprouting (McKinney et al, 1997;Santhakumar et al, 2005).…”

Section: Peripheral Nerve Injury-induced Activation Of Neuronmicroglia Interaction In the Brainstemmentioning

confidence: 99%

Brainstem local microglia induce whisker map plasticity in the thalamus after peripheral nerve injury

Ueta

Miyata

2021

Cell Reports

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Microglial depletion under thalamic hemorrhage ameliorates mechanical allodynia and suppresses aberrant axonal sprouting

Cited by 21 publications

References 70 publications

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways

Microglia in the Pathophysiology of Hemorrhagic Stroke and the Relationship Between Microglia and Pain After Stroke: A Narrative Review

Brainstem local microglia induce whisker map plasticity in the thalamus after peripheral nerve injury

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