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Abstract：
OBJECTIVE: Cancer-induced bone pain (CIBP) is one of the most common symptoms of bone metastasis of tumor cells. The hypothalamus may play a pivotal role in the regulation of CIBP. However, little is known about the exact mechanisms.
METHODS: First, we established a CIBP model to explore the relationship among hypothalamic ghrelin, NPY and CIBP. Then, we exogenously administered NPY and NPY receptor antagonists to investigate whether hypothalamic NPY exerted an antinociceptive effect through binding to NPY receptors. Finally, we exogenously administered ghrelin to investigate whether ghrelin alleviated CIBP by inducing the production of hypothalamic NPY through the AMPK-mTOR pathway. Body weight, food intake and behavioral indicators of CIBP were measured every 3 days. Hypothalamic ghrelin, NPY and the AMPK-mTOR pathway were also measured.
RESULTS: The expression of hypothalamic ghrelin and NPY was simultaneously decreased in cancer-bearing rats, which was accompanied by CIBP. Intracerebroventricular (i.c.v.) administration of NPY significantly alleviated CIBP in the short term. The antinociceptive effect of NPY was reversed with the i.c.v. administration of the Y1R and Y2R antagonists. The administration of ghrelin activated the AMPK-mTOR pathway and induced hypothalamic NPY production to alleviate CIBP. This effect of ghrelin on NPY and antinociception was reversed with the administration of a GHS-R1α antagonist.
CONCLUSIONS: Ghrelin could induce the production of hypothalamic NPY through the AMPK-mTOR pathway to alleviate CIBP, which can provide a novel therapeutic mechanism for CIBP.
METHODS: First, we established a CIBP model to explore the relationship among hypothalamic ghrelin, NPY and CIBP. Then, we exogenously administered NPY and NPY receptor antagonists to investigate whether hypothalamic NPY exerted an antinociceptive effect through binding to NPY receptors. Finally, we exogenously administered ghrelin to investigate whether ghrelin alleviated CIBP by inducing the production of hypothalamic NPY through the AMPK-mTOR pathway. Body weight, food intake and behavioral indicators of CIBP were measured every 3 days. Hypothalamic ghrelin, NPY and the AMPK-mTOR pathway were also measured.
RESULTS: The expression of hypothalamic ghrelin and NPY was simultaneously decreased in cancer-bearing rats, which was accompanied by CIBP. Intracerebroventricular (i.c.v.) administration of NPY significantly alleviated CIBP in the short term. The antinociceptive effect of NPY was reversed with the i.c.v. administration of the Y1R and Y2R antagonists. The administration of ghrelin activated the AMPK-mTOR pathway and induced hypothalamic NPY production to alleviate CIBP. This effect of ghrelin on NPY and antinociception was reversed with the administration of a GHS-R1α antagonist.
CONCLUSIONS: Ghrelin could induce the production of hypothalamic NPY through the AMPK-mTOR pathway to alleviate CIBP, which can provide a novel therapeutic mechanism for CIBP.
摘要：
目的：癌性骨痛（CIBP）是肿瘤细胞骨转移的最常见症状之一。下丘脑可能在CIBP的调节中起关键作用。然而,对确切的机制知之甚少。
方法：首先，我们建立了aCI的BP模型来探讨下丘脑ghrelin之间的关系，NPY和CIBP。然后，我们外源性给予NPY和NPY受体拮抗剂,以研究下丘脑NPY是否通过与NPY受体结合而发挥抗伤害作用.最后,我们外源给予ghrelin,以研究ghrelin是否通过AMPK-mTOR通路诱导下丘脑NPY的产生而减轻CIBP.体重,每3天测量食物摄入量和CIBP行为指标。下丘脑生长素释放肽,还测量了NPY和AMPK-mTOR途径。
结果：荷癌大鼠下丘脑生长素释放肽和NPY的表达同时降低，伴有CIBP。侧脑室（i.c.v.）给予NPY可在短期内显着缓解CIBP。通过i.c.v.施用Y1R和Y2R拮抗剂,NPY的抗伤害作用被逆转。给予生长素释放肽激活AMPK-mTOR通路并诱导下丘脑NPY产生以减轻CIBP。使用GHS-R1α拮抗剂可以逆转ghrelin对NPY和抗伤害感受的作用。
结论：Ghrelin可通过AMPK-mTOR通路诱导下丘脑NPY的产生，从而减轻血压CI，这可以为CIBP提供新的治疗机制。
方法：首先，我们建立了aCI的BP模型来探讨下丘脑ghrelin之间的关系，NPY和CIBP。然后，我们外源性给予NPY和NPY受体拮抗剂,以研究下丘脑NPY是否通过与NPY受体结合而发挥抗伤害作用.最后,我们外源给予ghrelin,以研究ghrelin是否通过AMPK-mTOR通路诱导下丘脑NPY的产生而减轻CIBP.体重,每3天测量食物摄入量和CIBP行为指标。下丘脑生长素释放肽,还测量了NPY和AMPK-mTOR途径。
结果：荷癌大鼠下丘脑生长素释放肽和NPY的表达同时降低，伴有CIBP。侧脑室（i.c.v.）给予NPY可在短期内显着缓解CIBP。通过i.c.v.施用Y1R和Y2R拮抗剂,NPY的抗伤害作用被逆转。给予生长素释放肽激活AMPK-mTOR通路并诱导下丘脑NPY产生以减轻CIBP。使用GHS-R1α拮抗剂可以逆转ghrelin对NPY和抗伤害感受的作用。
结论：Ghrelin可通过AMPK-mTOR通路诱导下丘脑NPY的产生，从而减轻血压CI，这可以为CIBP提供新的治疗机制。
