Yamamizu Kohei, Hamada Yusuke, Narita Minoru
Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Br J Pharmacol. 2015 Jan;172(2):268-76. doi: 10.1111/bph.12573. Epub 2014 Jul 1.
Opioid systems mainly regulate physiological functions such as pain, emotional tone and reward circuitry in neural tissues (brain and spinal cord). These systems are also found in extraneural tissues (ganglia, gut, spleen, stomach, lung, pancreas, liver, heart, blood and blood vessels), and recent studies have elucidated their roles in various organs. The current review focuses on the roles of opioid systems in blood vessels, especially angiogenesis, during development and tumour malignancy. The balance between endogenous activators and inhibitors of angiogenesis delicately maintains a normally quiescent vasculature to sustain homeostasis. Disturbance of this balance causes pathogenic angiogenesis and, especially in tumours, several activators such as VEGF are highly expressed in the tumour microenvironment and strongly induce tumour angiogenesis, the so-called angiogenic switch. Recently, we demonstrated that κ opioid receptor agonists function as anti-angiogenic factors, which impede the angiogenic switch, in vascular development and tumour angiogenesis by inhibiting the expression of receptors for VEGF. In clinical medicine, angiogenesis inhibitors that target VEGF signalling such as bevacizumab are used as anti-cancer drugs. Although therapies that inhibit tumour angiogenesis have been highly successful for tumour therapy, most patients eventually develop resistance to this anti-angiogenic therapy. Thus, we must identify novel targets for anti-angiogenic agents to sustain inhibition of angiogenesis for tumour therapy. The regulation of responses to κ opioid receptor ligands could be useful for controlling vascular formation under physiological conditions and in cancers, and thus could offer therapeutic benefits beyond the relief of pain.
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
阿片类系统主要调节神经组织（脑和脊髓）中的生理功能，如疼痛、情绪基调及奖赏回路。这些系统也存在于神经外组织（神经节、肠道、脾脏、胃、肺、胰腺、肝脏、心脏、血液及血管）中，近期研究已阐明其在各器官中的作用。本综述聚焦于阿片类系统在血管中的作用，尤其是在发育及肿瘤恶性进展过程中的血管生成作用。血管生成的内源性激活剂与抑制剂之间的平衡精细地维持着正常静止的脉管系统以维持内环境稳态。这种平衡的紊乱会导致病理性血管生成，尤其是在肿瘤中，多种激活剂如血管内皮生长因子（VEGF）在肿瘤微环境中高表达，并强烈诱导肿瘤血管生成，即所谓的血管生成开关。近期，我们证明κ阿片受体激动剂在血管发育及肿瘤血管生成中作为抗血管生成因子发挥作用，通过抑制VEGF受体的表达来阻碍血管生成开关。在临床医学中，靶向VEGF信号传导的血管生成抑制剂如贝伐单抗被用作抗癌药物。尽管抑制肿瘤血管生成的疗法在肿瘤治疗中已取得巨大成功，但大多数患者最终会对这种抗血管生成疗法产生耐药性。因此，我们必须确定抗血管生成药物的新靶点，以持续抑制肿瘤血管生成用于肿瘤治疗。κ阿片受体配体反应的调节可能有助于在生理条件下及癌症中控制血管形成，从而可能带来除缓解疼痛之外的治疗益处。
本文是关于阿片类药物：功能选择性新途径主题部分的一部分。若要查看本部分的其他文章，请访问http://dx.doi.org/10.1111/bph.2015.172.issue-2 。
