摘要
慢性痛中,最严重、最难以控制的是由恶性肿瘤引起的疼痛,即癌痛。最常见的癌痛成因是乳腺癌、前列腺癌、肺癌和卵巢癌的骨转移引起的疼痛。癌痛早期,由于肿瘤细胞和周围组织炎症细胞持续释放神经活性物质可引起类似炎症痛的反应：癌痛中、后期,由于肿瘤生长引起的神经浸润和压迫,可出现类似神经病理性疼痛的特征,这提示癌痛与炎症痛和神经病理性痛可能分享着某种类似的细胞和分子机制。
细胞外信号调节激酶(Extracellular signal-regulated kinase, ERK)和p38是有丝裂原激活的蛋白激酶(mitogen-activated protein kinase, MAPK)家族的两个重要成员。它们在脊髓背角神经元和胶质细胞的激活是炎症痛和神经病理性疼痛产生痛觉敏化的重要机制。但在癌痛状态下,ERK和p38在脊髓背角及其与胶质激活相关的时间依赖性变化尚不清楚。因此,本论文在大鼠胫骨骨髓腔内接种Walker256乳腺癌细胞建立的骨癌痛模型上,应用形态学、免疫组织化学、免疫印迹分析及行为学等方法,对骨癌痛发生和发展过程中脊髓ERK/MAPK和p38/MAPK信号分子在不同细胞中激活的时间过程及其在骨癌痛中枢敏化产生中的可能机制进行了初步探索。主要结果如下：
将Walker256大鼠乳腺癌细胞(4×104)接种至雌性Wistar大鼠胫骨骨髓腔内。随着肿瘤的生长,术侧胫骨在接种后14和21天出现骨质损伤和破坏；术侧后肢表现出明显的自发痛体征；双侧后肢出现机械触诱发痛及热痛过敏,呈现出典型的镜像痛特征。
接种肿瘤细胞14及21天后,双侧脊髓背角小胶质细胞和星形胶质细胞均被大量激活；鞘内给予胶质细胞抑制剂丙戊茶碱(propentofylline, PPF)和小胶质细胞抑制剂美满霉素(minocycline)均可显著抑制骨癌痛。
随骨癌痛的发生和发展,双侧脊髓背角p38和ERK大量激活,在肿瘤细胞接种后3、7、14及21天,磷酸化的ERK (pERK)和p38(p-p38)在脊髓的表达水平明显高于对照组；免疫荧光双标记结果显示,肿瘤细胞接种后3天和7天,pERK主要表达在神经元和小胶质细胞,接种后14和21天,脊髓背角神经元、小胶质细胞和星形胶质细胞均可表达pERK;与ERK的激活稍有不同,p38在肿瘤细胞接种后3-21天在双侧脊髓背角神经元和小胶质细胞均有激活,但骨癌痛早期主要分布在神经元,而晚期主要分布在小胶质细胞；行为学测试显示,瘤细胞接种前2天预先腰穿给予p38抑制剂SB203580(10μg),并在术后每天一次,持续两周,可以阻断骨癌诱导的机械触诱发痛形成；在肿瘤接种14天,行为痛敏已出现后,单次鞘内给予p38抑制剂SB203580(10μg)和SB39063(100μg),或MEK (ERK的激酶)的抑制剂U0126(1、3μg)也可翻转已形成的机械触诱发痛；提示MAPK在骨癌痛的发展和维持中均发挥重要作用。
综上所述,在接种Walker256大鼠乳腺癌细胞引起的大鼠胫骨转移性骨癌痛模型,ERK/MAPK和p38/MAPK在双侧脊髓背角的激活参与了骨癌痛的发展与维持；MAPK对骨癌痛的调制作用可能是通过活化脊髓胶质细胞实现的。本研究提示,MAPK可能是治疗骨癌痛的一个重要靶点。
Cancer pain is one of the most severe types of chronic pain, and the most common type of cancer pain is bone cancer pain, which is caused by tumors that metastasize from distant sites such as breast, prostate, and lung to the bone. Compared with neuropathic and inflammatory pain, cancer pain might share similar physiological and pathological changes. At its earlier phase, an inflammatory response is inevitable, while in its later phase, nerve infiltration and compression by tumour cells, cancer pain may also be characterized as neuropathic pain. Thus, cancer pain, neuropathic pain and inflammatory pain may share some similar molecular and cellular mechanisms.
Excellular signal-regulated kinase (ERK) and p38MAPK are main family members of mitogen-activated protein kinases (MAPKs), a reserved serine/ threonine kinase family. The activation of MAPKs in spinal neuronal and glial cells has been demonstrated to be involved in the mechanisms of inflammatory and neuropathic pain. However, as to the relationship of the two MAPKs and spinal glial activation during the development of bone cancer pain, our knowledge is very limited. Therefore, in a rat model induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells, we inverstigated the temporal change of ERK and p38 activation in different cell types in the spinal dorsal horn following the development of bone cancer pain.
Syngeneic Walker 256 mammary gland carcinoma cells (4×104) were injected into the tibia medullary cavity via intercondylar eminence. Series of tests were carried out including bone radiology, bone histology and behavioral tests. The rats inoculated with carcinoma cells showed significant spontaneous pain, mechanical allodynia and thermal hyperalgesia. The pain hypersensitive behaviors were aggravated with time and destruction of bone. Interestingly, mechanical allodynia was also observed in the contralateral limb, indicating the involvement of'mirror image'pain in bone cancer pain.
Following the inoculation with Walker 256 cells, microglia and astrocytes were robustly activated in the bilateral spinal dorsal horn at days 14, and 21. Intrathecal injection of propentofylline (PPF), a glial inhibitor, and minocycline, a microglial inhibitor, significantly suppressed glial activation and bone cancer-induced mechanical allodynia.
At days 14, and 21 after inoculation of tumour cells, the expressions of phosph-p38 (p-p38) and phosph-ERK (pERK) in both side of the spinal dorsal horn were remarkably increased. Double immunofluorescence showed that pERK was expressed in neurons and microglia of the spinal cord at days 3 and 7 after inoculation; while at days 14 and 21, pERK was detected in all the neurons, microglia and astrocytes of the spinal cord. Differentlly, p-p38 colocalized with NeuN (a neuronal marker) and OX-42 (a microglial marker) in the spinal dorsal horn at all days we observed. Preferentially, p-p38 expressed in neurons in early phase and in microglia in late phase respectively. To address the effects of inactivating p38/MAPK on the development of behavioral hypersensitivity in rats inoculated with carcinoma cells, repeated intrathecal injection of p-p38 inhibitor SB203580 (1,5, and 10μg) were carried out once daily for 2 weeks, with the first application 2 days before inoculation. At a dose of 10μg, SB203580 significantly suppressed the development of bone cancer pain. To address the effects of inactivating p38/MAPK and ERK/MAPK on the existed behavioral hypersensitivity evoked by bone cancer, intrathecal administrations of p-p38 inhibitor SB203580 (10μg), SB239063 (100μg) or MEK inhibitor U0126 (3μg) were performed at 14 days after inoculation. The bone cancer-induced mechanical allodynia was reversed by either p38 inhibitor or MEK inhibitor. These results suggest that MAPKs in spinal cord may be involved in both development and maintenance of bone cancer pain.
Taken together, the present study indicates that activation of ERK/MAPK and p38/MAPK in spinal dorsal horn contributes to the development and maintenance of bone cancer pain. And the modulation of MAPKs to bone cancer pain may be involved in the activation of spinal glial cells. Thus, MAPK might become a novel target for treating bone cancer pain.
引文
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