脊髓水平mGluR3和mGluR5调控星形胶质细胞活化在小鼠骨癌痛形成中的作用及中医药干预的研究
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摘要
目的：探讨脊髓水平代谢性谷氨酸受体亚型3和5(mGluR3和5)调节星形胶质细胞活化在骨癌痛形成中的作用以及丹参酮ⅡA和身痛逐瘀汤对骨癌痛的治疗作用及其可能的机制。
方法：C3H/HeNCrlVr雄性小鼠股骨骨髓腔注射NCTC 2472纤维肉瘤细胞制作骨癌痛模型,以等体积的最小必须培养基(a-MEM)代替NCTC 2472纤维肉瘤细胞骨髓腔内注射制作假手术模型,用自发性抬足次数/2min、机械刺激缩足反射阈值(PWMT)和热痛觉缩足潜伏期(PWTL)评估痛行为学表现,用胶质细胞纤维酸性蛋白(GFAP)和肿瘤坏死因子-a (TNF-a)的表达水平来反映星形胶质细胞的活化水平。鞘内置管给予mGluR3激动剂(2R,4R)-4-Aminop-yrrolidine-2,4-dicarboxylate (APDC), mGluR3拮抗剂(2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xan th-9-yl) propanoic acid (LY341495). mGluR5激动剂(RS)-2-Chloro-5-hydroxypheny-lglycine(CHPG)、mGluR5拮抗剂3-((2-Methyl-1,3-thiazol-4-yl) e-thynyl) pyridine hydrochloride(MTEP)和丹参酮ⅡA,灌胃给予身痛逐瘀汤水煎浓缩制剂进行干预。在不同时间点观察痛行为学变化,取脊髓腰膨大部位(L3-L5),分别应用Real-time quantitative RT-PCR和western blot检测mGluR3、mGluR5、GFAP、TNF-a mRNA与蛋白的表达变化。
结果：(1)小鼠左股骨骨髓腔注射NCTC 2472纤维肉瘤细胞可以诱发进行性的痛行为学变化,表现为自发性抬足次数增加,机械刺激缩足反射阈值降低、热痛觉缩足潜伏期缩短(P<0.05)；(2)小鼠股骨骨髓腔注射NCTC 2472纤维肉瘤细胞可以诱发脊髓水平星形胶质细胞活化,表现为GFAP、TNF-a mRNA和蛋白表达进行性增加(P<0.05)；(3)骨癌痛发生发展过程中小鼠脊髓水平mGluR3、mGluR5 mRNA和蛋白表达进行性增加(P<0.05)；(4)APDC和MTEP鞘内注射可以改善骨癌痛小鼠的痛行为学表现,同时可以抑制脊髓水平GFAP和TNF-a的表达(P<0.05)；而LY341495和CHPG则可以促进假手术组小鼠脊髓水平GFAP和TNF-a的表达(P<0.05)；(5)丹参酮ⅡA鞘内注射可以剂量依赖性地改善骨癌痛小鼠的痛行为学表现,同时可以抑制脊髓水平GFAP和TNF-a的表达(P<0.05)；(6)灌胃给予身痛逐瘀汤水煎浓缩制剂可以剂量依赖性地改善骨癌痛小鼠的痛行为学表现,同时可以抑制脊髓水平GFAP和TNF-a的表达P<0.05)。
结论：脊髓水平代谢性谷氨酸受体亚型3和5可以通过调节星形胶质细胞活化在骨癌痛中发挥重要作用；丹参酮ⅡA和身痛逐瘀汤可以改善骨癌痛小鼠的痛行为学表现,抑制脊髓水平星形胶质细胞活化可能是其机制之一。
Objective:To investigate the role of spinal metabotropic glutamate receptor subtypes 3 and 5 regulating astrocytes activation during the development of bone cancer pain and the analgesic effects of Shentong Zhuyu Decoction(SZD) and Tanshinone IIA and their possible mechanisms.
Methods:The femur marrow cavity of C3H/HeNCrlVr male mice were injected with NCTC 2472 fibrosarcoma cells to make bone cancer pain model and NCTC 2472 fibrosarcoma cells were replaced by the equal volum of a-MEM in the sham model.The number of spontaneous foot lifting/2 min, paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were used to assess pain behaviours performance.The level of spinal glial fibrillary acidic protein(GFAP) and tumor necrosis factor-a(TNF-a) mRNA and protein expression to reflect astrocytes activation level.To treat bone cancer pain with mGluR3 agonist (2R,4R)-4-Aminop-yrrolidine-2,4-dicarboxylate (APDC),mGluR3 receptor antagonist (2S)-2-Amino-2-[(1S,2S)-2-carbo-xycycloprop-1-yl]-3-(xan th-9-yl) propanoic acid (LY341495), mGluR5 agonist (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG),mGluR5 receptor antagonist 3-((2-Methyl-1,3-thiazol-4-yl) e-thynyl) pyridine hydrochloride (MTEP) and Tanshinone IIA by intrathecal catheter. Shentong Zhuyu Decoction was given by intragastric administration. To observe pain behaviors changes at different time points and the L3-L5 spinal cord segments of sacrificed mice were dissected to detect glial fibrillary acidic protein and tumor necrosis factor-a mRNA and protein expression by Real-time quantitative RT-PCR and western blot respectively.
Results:(1) NCTC 2472 fibrosarcoma cells inoculation of the left femur of the male C3H/HeNCrlVr mice produced progressive spontaneous flinches, mechanical hyperalgesia and thermal hyperalgesia(P<0.05);(2)NCTC 2472 fibrosarcoma cells inoculation of the left femur of the male C3H/HeNCrlVr mice induces spinal astrocytes activation, characterized by up-regulation of GFAP and TNF-a mRNA and protein expression(P<0.05);(3) The level of spinal mGluR3, mGluR5 mRNA and protein expression progressively increased during the development of bone cancer pain(P<0.05); (4) Intrathecal administration of APDC and MTEP could improve bone cancer pain behaviors performance and inhibit the expression of spinal GFAP and TNF-a, but LY341495 and CHPG could promote the expression of spinal GFAP and TNF-a in the sham groups(P<0.05);(5) Intrathecal injection of tanshinone IIA could improve the bone cancer pain behaviors performance and inhibit the expression of spinal GFAP and TNF-a dose-dependently(P<0.05); (6) Given SZD orally could dose-dependently improve the bone cancer pain behaviors performance, and could suppress the expression of spinal GFAP and TNF-a (P<0.05).
Conclusion:The spinal metabotropic glutamate receptor subtypes 3 and 5 play important roles in the development of bone cancer pain by regulating the activation of spinal astrocytes.Tanshinone IIA and SZD could improve bone cancer pain behaviors performance, and the inhibition of activation of spinal astrocytes may be one of their mechanisms.
方法：C3H/HeNCrlVr雄性小鼠股骨骨髓腔注射NCTC 2472纤维肉瘤细胞制作骨癌痛模型,以等体积的最小必须培养基(a-MEM)代替NCTC 2472纤维肉瘤细胞骨髓腔内注射制作假手术模型,用自发性抬足次数/2min、机械刺激缩足反射阈值(PWMT)和热痛觉缩足潜伏期(PWTL)评估痛行为学表现,用胶质细胞纤维酸性蛋白(GFAP)和肿瘤坏死因子-a (TNF-a)的表达水平来反映星形胶质细胞的活化水平。鞘内置管给予mGluR3激动剂(2R,4R)-4-Aminop-yrrolidine-2,4-dicarboxylate (APDC), mGluR3拮抗剂(2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xan th-9-yl) propanoic acid (LY341495). mGluR5激动剂(RS)-2-Chloro-5-hydroxypheny-lglycine(CHPG)、mGluR5拮抗剂3-((2-Methyl-1,3-thiazol-4-yl) e-thynyl) pyridine hydrochloride(MTEP)和丹参酮ⅡA,灌胃给予身痛逐瘀汤水煎浓缩制剂进行干预。在不同时间点观察痛行为学变化,取脊髓腰膨大部位(L3-L5),分别应用Real-time quantitative RT-PCR和western blot检测mGluR3、mGluR5、GFAP、TNF-a mRNA与蛋白的表达变化。
结果：(1)小鼠左股骨骨髓腔注射NCTC 2472纤维肉瘤细胞可以诱发进行性的痛行为学变化,表现为自发性抬足次数增加,机械刺激缩足反射阈值降低、热痛觉缩足潜伏期缩短(P<0.05)；(2)小鼠股骨骨髓腔注射NCTC 2472纤维肉瘤细胞可以诱发脊髓水平星形胶质细胞活化,表现为GFAP、TNF-a mRNA和蛋白表达进行性增加(P<0.05)；(3)骨癌痛发生发展过程中小鼠脊髓水平mGluR3、mGluR5 mRNA和蛋白表达进行性增加(P<0.05)；(4)APDC和MTEP鞘内注射可以改善骨癌痛小鼠的痛行为学表现,同时可以抑制脊髓水平GFAP和TNF-a的表达(P<0.05)；而LY341495和CHPG则可以促进假手术组小鼠脊髓水平GFAP和TNF-a的表达(P<0.05)；(5)丹参酮ⅡA鞘内注射可以剂量依赖性地改善骨癌痛小鼠的痛行为学表现,同时可以抑制脊髓水平GFAP和TNF-a的表达(P<0.05)；(6)灌胃给予身痛逐瘀汤水煎浓缩制剂可以剂量依赖性地改善骨癌痛小鼠的痛行为学表现,同时可以抑制脊髓水平GFAP和TNF-a的表达P<0.05)。
结论：脊髓水平代谢性谷氨酸受体亚型3和5可以通过调节星形胶质细胞活化在骨癌痛中发挥重要作用；丹参酮ⅡA和身痛逐瘀汤可以改善骨癌痛小鼠的痛行为学表现,抑制脊髓水平星形胶质细胞活化可能是其机制之一。
Objective:To investigate the role of spinal metabotropic glutamate receptor subtypes 3 and 5 regulating astrocytes activation during the development of bone cancer pain and the analgesic effects of Shentong Zhuyu Decoction(SZD) and Tanshinone IIA and their possible mechanisms.
Methods:The femur marrow cavity of C3H/HeNCrlVr male mice were injected with NCTC 2472 fibrosarcoma cells to make bone cancer pain model and NCTC 2472 fibrosarcoma cells were replaced by the equal volum of a-MEM in the sham model.The number of spontaneous foot lifting/2 min, paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were used to assess pain behaviours performance.The level of spinal glial fibrillary acidic protein(GFAP) and tumor necrosis factor-a(TNF-a) mRNA and protein expression to reflect astrocytes activation level.To treat bone cancer pain with mGluR3 agonist (2R,4R)-4-Aminop-yrrolidine-2,4-dicarboxylate (APDC),mGluR3 receptor antagonist (2S)-2-Amino-2-[(1S,2S)-2-carbo-xycycloprop-1-yl]-3-(xan th-9-yl) propanoic acid (LY341495), mGluR5 agonist (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG),mGluR5 receptor antagonist 3-((2-Methyl-1,3-thiazol-4-yl) e-thynyl) pyridine hydrochloride (MTEP) and Tanshinone IIA by intrathecal catheter. Shentong Zhuyu Decoction was given by intragastric administration. To observe pain behaviors changes at different time points and the L3-L5 spinal cord segments of sacrificed mice were dissected to detect glial fibrillary acidic protein and tumor necrosis factor-a mRNA and protein expression by Real-time quantitative RT-PCR and western blot respectively.
Results:(1) NCTC 2472 fibrosarcoma cells inoculation of the left femur of the male C3H/HeNCrlVr mice produced progressive spontaneous flinches, mechanical hyperalgesia and thermal hyperalgesia(P<0.05);(2)NCTC 2472 fibrosarcoma cells inoculation of the left femur of the male C3H/HeNCrlVr mice induces spinal astrocytes activation, characterized by up-regulation of GFAP and TNF-a mRNA and protein expression(P<0.05);(3) The level of spinal mGluR3, mGluR5 mRNA and protein expression progressively increased during the development of bone cancer pain(P<0.05); (4) Intrathecal administration of APDC and MTEP could improve bone cancer pain behaviors performance and inhibit the expression of spinal GFAP and TNF-a, but LY341495 and CHPG could promote the expression of spinal GFAP and TNF-a in the sham groups(P<0.05);(5) Intrathecal injection of tanshinone IIA could improve the bone cancer pain behaviors performance and inhibit the expression of spinal GFAP and TNF-a dose-dependently(P<0.05); (6) Given SZD orally could dose-dependently improve the bone cancer pain behaviors performance, and could suppress the expression of spinal GFAP and TNF-a (P<0.05).
Conclusion:The spinal metabotropic glutamate receptor subtypes 3 and 5 play important roles in the development of bone cancer pain by regulating the activation of spinal astrocytes.Tanshinone IIA and SZD could improve bone cancer pain behaviors performance, and the inhibition of activation of spinal astrocytes may be one of their mechanisms.
引文
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