G protein-coupled estrogen receptor in the rostral ventromedial medulla contributes to the chronification of postoperative pain.
G protein-coupled estrogen receptor in the rostral ventromedial medulla contributes to the chronification of postoperative pain.
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延髓头侧腹内侧区的 G 蛋白偶联雌激素受体有助于术后疼痛的慢性化
DOI：
10.1111/cns.13704
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发表时间：
2021-11
影响因子：
5.5
通讯作者：
Yang LQ
中科院分区：
文献类型：
--
作者：
Xu JJ;Gao P;Wu Y;Yin SQ;Zhu L;Xu SH;Tang D;Cheung CW;Jiao YF;Yu WF;Li YH;Yang LQ
术后疼痛慢性化是外科手术后常见的临床现象，困扰着广大患者。雌激素及其膜受体（G蛋白偶联雌激素受体，GPER）在疼痛调节中起着至关重要的作用。本研究旨在探讨延髓头端腹内侧区（RVM）GPER在慢性术后疼痛中的作用及其可能机制。通过足底切口手术在小鼠或大鼠中诱导术后疼痛。通过行为学测试检测热痛和机械痛，与疼痛恢复小鼠相比，小部分小鼠（16.2%）在切口手术后14天发展为持续性疼痛状态，且持续性低痛阈。免疫荧光染色结果显示，持续痛大鼠RVM内GPER阳性神经元明显激活。此外，RT-PCR和免疫印迹分析显示，在切口手术后14天，疼痛持续小鼠RVM中GPER和磷酸化μ-型阿片受体（p-莫尔）的水平明显升高。此外，Gper-Cre小鼠RVM中GPER阳性神经元的化学发生激活可逆转疼痛恢复小鼠的疼痛阈值。相反，RVM中GPER阳性神经元的化学发生抑制可以防止小鼠处于疼痛持续状态。我们的研究结果表明，GPER在RVM负责术后疼痛的慢性化和下游途径可能参与莫尔磷酸化。足底切口手术引起的伤害性刺激可上调RVM中GPER的表达，促进莫尔的磷酸化，从而激活RVM神经元，最终介导术后疼痛的慢性化。这些发现为预防术后急性疼痛向慢性疼痛的转变和慢性术后疼痛的治疗提供了新的靶点。
Chronification of postoperative pain is a common clinical phenomenon following surgical operation, and it perplexes a great number of patients. Estrogen and its membrane receptor (G protein‐coupled estrogen receptor, GPER) play a crucial role in pain regulation. Here, we explored the role of GPER in the rostral ventromedial medulla (RVM) during chronic postoperative pain and search for the possible mechanism. Postoperative pain was induced in mice or rats via a plantar incision surgery. Behavioral tests were conducted to detect both thermal and mechanical pain, showing a small part (16.2%) of mice developed into pain persisting state with consistent low pain threshold on 14 days after incision surgery compared with the pain recovery mice. Immunofluorescent staining assay revealed that the GPER‐positive neurons in the RVM were significantly activated in pain persisting rats. In addition, RT‐PCR and immunoblot analyses showed that the levels of GPER and phosphorylated μ‐type opioid receptor (p‐MOR) in the RVM of pain persisting mice were apparently increased on 14 days after incision surgery. Furthermore, chemogenetic activation of GPER‐positive neurons in the RVM of Gper‐Cre mice could reverse the pain threshold of pain recovery mice. Conversely, chemogenetic inhibition of GPER‐positive neurons in the RVM could prevent mice from being in the pain persistent state. Our findings demonstrated that the GPER in the RVM was responsible for the chronification of postoperative pain and the downstream pathway might be involved in MOR phosphorylation. Noxious stimulation induced by plantar incision surgery can upregulate GPER expression in RVM and promote the phosphorylation of MOR, leading to the activation of RVM neurons, which ultimately mediates the chronification of postoperative pain. These findings provide a new target for preventing the transition from acute pain to chronic pain after surgery and treatment of chronic postoperative pain.
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