Formaldehyde up-regulates TRPV1 through MAPK and PI3K signaling pathways in a rat model of bone cancer pain
Formaldehyde up-regulates TRPV1 through MAPK and PI3K signaling pathways in a rat model of bone cancer pain
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在骨癌疼痛大鼠模型中，甲醛通过 MAPK 和 PI3K 信号通路上调 TRPV1
DOI：
10.1007/s12264-012-1211-0
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发表时间：
2012-04-01
影响因子：
5.6
通讯作者：
Wan, You
中科院分区：
文献类型：
--
作者：
Han, Ying;Li, Yan;Wan, You
我们前期的研究表明，低浓度的肿瘤组织源性甲醛通过激活瞬时受体电位香草酸亚家族成员1（TRPV 1）在骨癌疼痛中发挥重要作用。本研究进一步探讨是否这种肿瘤组织来源的内源性甲醛调节TRPV 1的表达在大鼠模型的骨癌疼痛，如果是这样的话，什么可能的信号通路是在发展过程中的这种类型的pain.MethodsA骨癌疼痛的大鼠模型，通过注射活MRMT-1肿瘤细胞到胫骨。采用高效液相色谱法检测甲醛浓度，Western blot和RT-PCR检测TRPV 1的表达。在原代培养的背根神经节（DRG）神经元中，在预先加入或不加入PD 98059 [细胞外信号调节激酶抑制剂] SB 203580的情况下，用100 μmol/L甲醛处理后，评估TRPV 1的表达（p38抑制剂），SP 600125 [c-Jun N-末端激酶抑制剂]，BIM [蛋白激酶C（PKC）抑制剂]或LY 294002 [磷脂酰肌醇3-激酶（PI 3 K）抑制剂]。骨髓和脊髓。TRPV 1蛋白表达在DRG中也增加。在原代培养的DRG神经元中，100 μmol/L甲醛显著增加TRPV 1的表达水平。预孵育与PD 98059，SB 203580，SP 600125或LY 294002，但不是BIM，抑制甲醛诱导的TRPV 1 expression. ConclusionofFormaldehyde上调TRPV 1的表达通过丝裂原活化蛋白激酶和PI 3 K，但不是PKC，信号通路。这些结果进一步支持了我们之前的发现，即外周传入神经中的TRPV 1在骨癌疼痛中发挥作用。
ObjectiveOur previous study showed that tumor tissue-derived formaldehyde at low concentrations plays an important role in bone cancer pain through activating transient receptor potential vanilloid subfamily member 1 (TRPV1). The present study further explored whether this tumor tissue-derived endogenous formaldehyde regulates TRPV1 expression in a rat model of bone cancer pain, and if so, what the possible signal pathways are during the development of this type of pain.MethodsA rat model of bone cancer pain was established by injecting living MRMT-1 tumor cells into the tibia. The formaldehyde levels were determined by high performance liquid chromatography, and the expression of TRPV1 was examined with Western blot and RT-PCR. In primary cultured dorsal root ganglion (DRG) neurons, the expression of TRPV1 was assessed after treatment with 100 μmol/L formaldehyde with or without pre-addition of PD98059 [an inhibitor for extracellular signal-regulated kinase], SB203580 (a p38 inhibitor), SP600125 [an inhibitor for c-Jun N-terminal kinase], BIM [a protein kinase C (PKC) inhibitor] or LY294002 [a phosphatidylinositol 3-kinase (PI3K) inhibitor].ResultsIn the rat model of bone cancer pain, formaldehyde concentration increased in blood plasma, bone marrow and the spinal cord. TRPV1 protein expression was also increased in the DRG. In primary cultured DRG neurons, 100 μmol/L formaldehyde significantly increased the TRPV1 expression level. Pre-incubation with PD98059, SB203580, SP600125 or LY294002, but not BIM, inhibited the formaldehyde-induced increase of TRPV1 expression.ConclusionFormaldehyde at a very low concentration up-regulates TRPV1 expression through mitogen-activated protein kinase and PI3K, but not PKC, signaling pathways. These results further support our previous finding that TRPV1 in peripheral afferents plays a role in bone cancer pain.