Hevin/Sparcl1 drives pathological pain through spinal cord astrocyte and NMDA receptor signaling
Gang Chen, Jing Xu, Hao Luo, Xin Luo, Sandeep K. Singh, Juan J. Ramirez, Michael L. James, Joseph P. Mathew, Miles Berger, Cagla Eroglu, Ru-Rong Ji
Gang Chen, Jing Xu, Hao Luo, Xin Luo, Sandeep K. Singh, Juan J. Ramirez, Michael L. James, Joseph P. Mathew, Miles Berger, Cagla Eroglu, Ru-Rong Ji
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Research Article Neuroscience

Hevin/Sparcl1 drives pathological pain through spinal cord astrocyte and NMDA receptor signaling

Abstract

High endothelial venule protein/SPARC-like 1 (hevin/Sparcl1) is an astrocyte-secreted protein that regulates synapse formation in the brain. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared with WT mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin-null mice have faster recovery than WT mice from neuropathic pain after nerve injury. Intrathecal injection of WT hevin was sufficient to induce persistent mechanical allodynia in naive mice. In hevin-null mice with nerve injury, adeno-associated-virus–mediated (AAV-mediated) re-expression of hevin in glial fibrillary acidic protein–expressing (GFAP-expressing) spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling. Hevin-potentiated N-Methyl-D-aspartic acid (NMDA) currents are mediated by GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing Ab against hevin alleviated acute and persistent inflammatory pain, postoperative pain, and neuropathic pain. Secreted hevin that was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid and substantial increases in SPARCL1/HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal Ab may provide a new therapeutic strategy for treating acute and chronic pain and NMDAR-medicated neurodegeneration.

Authors

Gang Chen, Jing Xu, Hao Luo, Xin Luo, Sandeep K. Singh, Juan J. Ramirez, Michael L. James, Joseph P. Mathew, Miles Berger, Cagla Eroglu, Ru-Rong Ji

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Figure 1

Baseline pain, inflammatory pain, and neuropathic pain in WT and hevin-KO mice.

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Baseline pain, inflammatory pain, and neuropathic pain in WT and hevin-K...
There are no significant differences in mechanical and thermal pain threshold between WT and hevin-KO male mice, as shown in von Frey test (A), radiant heat test (B), hot plate test (C) and tail immersion test (D). P > 0.05, unpaired Student’s t test, n = 11 mice/group. (E) Formalin-induced acute inflammatory pain was significantly reduced in hevin-KO male mice. Left, time-course of licking and flinching behavior following intraplantar injection of 5% formalin. Right, formalin-induced Phase I (1–10 min) and Phase II (10–45 min) responses. *P < 0.05, 2-way ANOVA followed by Bonferroni’s post hoc test. n = 6 mice/group. (F) Mechanical allodynia, induced by intraplantar injection of carrageenan, recovered faster in hevin-KO male mice than in WT male mice. Arrow indicates the time of carrageenan injection. *P < 0.05, **P < 0.01, ***P < 0.001, compared with baseline (BL) group; #P < 0.05, 2-way ANOVA followed by Bonferroni’s post hoc test. n = 5 mice/group. Data shown as mean ± SEM. (G) Hevin-KO male mice recovered faster from CCI-induced persistent mechanical allodynia than WT male mice. ***P < 0.001 compared with BL group; #P < 0.05, ##P < 0.01, ###P < 0.001, 2-way ANOVA followed by Bonferroni’s post hoc test. n = 11 mice/group. (H) Ongoing pain 3 weeks after CCI in WT and hevin-KO male mice were tested using a 2-chamber CPP. Ongoing pain was present in WT mice but absent in hevin-KO mice following clonidine treatment (10 μg, i.t.). *P < 0.05, unpaired Student’s t test, n = 6 mice/group. All data are shown as mean ± SEM.