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激活MrgC受体抑制骨癌痛大鼠脊髓背角和背根神经节神经化学改变

江剑平^*, 张科, 胡粉娟, 洪炎国

福建师范大学生命科学学院；福建省发育和神经生物学重点实验室，福州 350117

摘要

癌症疼痛是晚期癌症患者最常见的症状之一。本研究旨在探讨MrgC (Mas-related gene C)受体对骨癌痛的影响。将Walker 256乳腺癌细胞接种至成年Sprague-Dawley 大鼠胫骨制备骨癌痛模型，以机械撤足阈值和热撤足阈值观察其痛觉超敏情况。在第16 天和第17 天鞘内注射MrgC 受体激动剂牛肾上腺髓质8-22 (bovine adrenal medulla 8-22, BAM8-22)，观察其对机械刺激和热刺激等伤害性行为的影响。用免疫荧光染色方法检测脊髓背角胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)阳性细胞以及背根神经节(dorsal root ganglia, DRG)中降钙素基因相关肽(calcitonin gene related peptide, CGRP)、神经元型一氧化氮合酶(neuronal nitric oxide synthase, nNOS)和IL-1β 阳性神经元数量变化。用另一种MrgC 受体激动剂(Tyr6)-γ2-MSH-6-12 (MSH)同样处理后，通过蛋白质印迹法检测脊髓背角和DRG中nNOS和IL-1β 蛋白的表达。结果显示，鞘内注射BAM8-22 (30 nmol)减轻了大鼠骨癌痛模型中的机械痛觉超敏，即时效果可持续约60 min，连续两天单次给药BAM8-22在第三天减轻了约一半的机械痛阈。此外，脊髓背角中的GFAP阳性细胞以及DRG中CGRP、nNOS和IL-1β阳性神经元的数量也减少。同样，鞘内给予MSH (15 nmol)降低了脊髓背角和DRG中nNOS和IL-1β的表达。结果提示，激活MrgC受体有可能通过抑制脊髓背角星形胶质细胞的激活以及脊髓背角和/或DRG中CGRP、nNOS和IL-1β 的表达来减轻骨癌痛。这些发现有望为骨癌痛的治疗提供新策略。

关键词： MrgC受体; 痛觉超敏; 脊髓背角; 背根神经节; 神经化学; 骨癌痛

Mas-related gene C (MrgC) receptor activation induced inhibition of neurochemical alterations in the spinal dorsal horn and dorsal root ganglia in a rat model of bone cancer pain

JIANG Jian-Ping^*, ZHANG Ke, HU Fen-Juan, HONG Yan-Guo

College of Life Sciences, Fujian Normal University; Fujian Key Laboratory of Developmental and Neuro Biology, Fuzhou 350117, China

Abstract

Cancer pain is one of the most common symptoms in patients with advanced cancer. In this study, we aimed to investigate the effects of the Mas-related gene C (MrgC) receptors on bone cancer pain. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured after the inoculation of Walker 256 mammary gland carcinoma cells into the tibia of adult Sprague-Dawley rats. The effects of MrgC receptor agonist bovine adrenal medulla 8-22 (BAM8-22) on nociceptive behaviors were investigated after intrathecal injection on days 16 and 17. Glial fibrillary acidic protein (GFAP) -positive cells in the spinal dorsal cord, and calcitonin gene related peptide (CGRP)-, neuronal nitric oxide synthase (nNOS)- and IL-1β-positive neurons in the dorsal root ganglia (DRG) were examined by immunofluorescence staining. The expression of nNOS and IL-1β proteins in the spinal dorsal horn and the DRG was examined by Western blotting after treatment with (Tyr6) - γ2-MSH-6-12 (MSH), which was another MrgC receptor agonist. The results showed that intrathecal injection of BAM8-22 (30 nmol) attenuated mechanical allodynia in a rat model of bone cancer pain and the effects could last for about 60 min, and single administration of BAM8-22 for two consecutive days reduced mechanical allodynia by about half on the third day. Moreover, the number of GFAP-positive cells in the spinal dorsal horn, and the number of CGRP-, nNOS- and IL-1β-positive neurons in the DRG were decreased. Similarly, intrathecal administration of MSH (15 nmol) reduced the expression of nNOS and IL-1β in the spinal dorsal horn and the DRG. In conclusion, activation of MrgC receptors suppresses the activation of astrocytes in the spinal dorsal cord and the expression of CGRP, nNOS, and IL-1β in the spinal dorsal cord and/or DRG, which may underlie the inhibition of bone cancer pain. These findings provide a novel strategy for the treatment of bone cancer pain.

Key words: Mas-related gene C (MrgC) receptors; allodynia; spinal dorsal horn; dorsal root ganglion (DRG); neurochemistry; bone cancer pain

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通讯作者：江剑平　　E-mail:

引用本文：

江剑平, 张科, 胡粉娟, 洪炎国. 激活MrgC受体抑制骨癌痛大鼠脊髓背角和背根神经节神经化学改变[J]. 生理学报 2024; 76 (6): 953-969.

JIANG Jian-Ping, ZHANG Ke, HU Fen-Juan, HONG Yan-Guo. Mas-related gene C (MrgC) receptor activation induced inhibition of neurochemical alterations in the spinal dorsal horn and dorsal root ganglia in a rat model of bone cancer pain. Acta Physiol Sin 2024; 76 (6): 953-969