Fgr contributes to hemorrhage-induced thalamic pain by activating NF-κB/ERK1/2 pathways
Tianfeng Huang, … , Alex Bekker, Yuan-Xiang Tao
Tianfeng Huang, … , Alex Bekker, Yuan-Xiang Tao
Published October 15, 2020
Citation Information: JCI Insight. 2020;5(20):e139987. https://doi.org/10.1172/jci.insight.139987.
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Research Article Neuroscience

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

Abstract

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.

Authors

Tianfeng Huang, Ganglan Fu, Ju Gao, Yang Zhang, Weihua Cai, Shaogen Wu, Shushan Jia, Shangzhou Xia, Thomas Bachmann, Alex Bekker, Yuan-Xiang Tao

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Figure 1

Thalamic Fgr was increased in both collagenase IV– and autologous blood–induced thalamic pain models.

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Thalamic Fgr was increased in both collagenase IV– and autologous blood–...
(A) Level of Fgr mRNA in the ipsilateral thalamus at different days after microinjection of Coll IV or saline. n = 3 biological repeats/group/time point. **P < 0.01 versus the corresponding control group (day 0) by 2-way ANOVA with repeated measures followed by post hoc Tukey’s test. (B–E) Amounts of Fgr protein in the ipsilateral (Ipsi) and contralateral (Contral) thalamus at different days after microinjection of Coll IV (B and C) or saline (D and E). Representative Western blots (B and D). Statistical summary of the densitometric analysis (C and E). n = 3 biological repeats/group/time point. *P < 0.05 versus the corresponding control group (day 0) by 2-way ANOVA with repeated measures followed by post hoc Tukey’s test. (F and G) Fgr immunofluorescence stainings of the ipsilateral thalamus on day 7 postmicroinjection of Coll IV or saline. Representative immunofluorescence stainings. Scale bar: 100 μm (F). Statistical summary of the densitometric analysis (G). n = 3 biological repeats/group. **P < 0.01 versus the saline group by 2-tailed unpaired Student’s t test. (H) The level of Fgr protein in the ipsilateral thalamus on day 3 postmicroinjection of autologous blood or saline. Representative Western blots (top). Statistical summary of the densitometric analysis (bottom). n = 3 biological repeats/group. **P < 0.01 versus the saline group by 2-tailed unpaired Student’s t test. (I and J) Fgr immunofluorescence stainings in the ipsilateral thalamus on day 3 postmicroinjection of autologous blood or saline. Representative immunoflourescence stainings. Scale bar: 100 μm (I). A statistical summary of the densitometric analysis (J). n = 3 biological repeats/group. **P < 0.01 versus the saline group by 2-tailed unpaired Student’s t test. (K) Fgr is colocalized with Iba1, but not GFAP, in the ipsilateral thalamus on day 3 after microinjection of Coll IV. Representative samples of n = 3 biological repeats. Scale bar: 100 μm.