Selective activation of metabotropic glutamate receptor 7 blocks paclitaxel-induced acute neuropathic pain and suppresse
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ORIGINAL INVESTIGATION
Selective activation of metabotropic glutamate receptor 7 blocks paclitaxel-induced acute neuropathic pain and suppresses spinal glial reactivity in rats Jiali Wang 1 & Changyu Jiang 2 & Xiyuan Ba 2 & Shimin Yang 1 & Jiaman Wu 1 & Zelin Huang 1 & Guangyi Jin 3 & Yue Hao 1 Received: 6 December 2019 / Accepted: 10 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale Paclitaxel-induced acute pain syndrome (P-APS), characterized by deep muscle aches and arthralgia, occurs in more than 70% of patients who receive paclitaxel. P-APS can be debilitating for patients and lead to reductions and discontinuation of potentially curable therapy. Despite being relatively common in clinical practice, no clear treatment exists for P-APS and the underlying mechanisms remain poorly defined. Regulation of glutamatergic transmission by metabotropic glutamate receptors (mGluRs) has received growing attention with respect to its role in neuropathic pain. To our knowledge, no study has been conducted on alterations and functions of group III mGluR7 signaling in P-APS. Objectives In the present study, we determined whether a single administration of paclitaxel induces glutamatergic alterations and whether mGluR7 activation blocks paclitaxel-induced neuropathic pain by suppressing glial reactivity in the spinal cord. Results A single paclitaxel injection dose-dependently induced acute mechanical and thermal hypersensitivity, and was associated with increased glutamate level accompanied by reduction in mGluR7 expression in the spinal cord. Selective activation of mGluR7 by its positive allosteric modulator, AMN082, blocked the development of paclitaxel-induced acute mechanical and thermal hypersensitivity, without affecting the normal pain behavior of control rats. Moreover, activation of mGluR7 by AMN082 inhibited glial reactivity and decreased pro-inflammatory cytokine release during P-APS. Abortion of spinal glial reaction to paclitaxel alleviated paclitaxel-induced acute mechanical and thermal hypersensitivity. Conclusions There results support the hypothesis that spinal mGluR7 signaling plays an important role in P-APS; Selective activation of mGluR7 by its positive allosteric modulator, AMN082, blocks P-APS in part by reducing spinal glial reactivity and neuroinflammatory process. Keywords Paclitaxel-induced acute pain syndrome . Metabotropic glutamate receptor 7 . AMN082 . Glutamate . Astrocyte . Microglia . Pro-inflammatory cytokines
Abbreviations P-APS Paclitaxel-induced acute pain syndrome mGluRs Metabotropic glutamate receptors TNF-α Tumor necrosis factor-α IL Interleukin DRGs Dorsal root ganglia Jiali Wang and Changyu Jiang are the co-first authors Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00213-020-05662-1) contains supplementary material, which is available to authorized users. * Yue Hao [email protected] Extended author information available on the last page of the article
AMN082 MMPIP ELISA
N,N0-Bis(diphe
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