Santoni Angela, Santoni Matteo, Arcuri Edoardo
Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Viale Regina Elena 291, 00161 Rome, Italy.
IRCCS Neuromed, 86077 Pozzilli, Italy.
Cancers (Basel). 2022 Apr 30;14(9):2253. doi: 10.3390/cancers14092253.
Pain can be a devastating experience for cancer patients, resulting in decreased quality of life. In the last two decades, immunological and pain research have demonstrated that pain persistence is primarily caused by neuroinflammation leading to central sensitization with brain neuroplastic alterations and changes in pain responsiveness (hyperalgesia, and pain behavior). Cancer pain is markedly affected by the tumor microenvironment (TME), a complex ecosystem consisting of different cell types (cancer cells, endothelial and stromal cells, leukocytes, fibroblasts and neurons) that release soluble mediators triggering neuroinflammation. The TME cellular components express opioid receptors (i.e., MOR) that upon engagement by endogenous or exogenous opioids such as morphine, initiate signaling events leading to neuroinflammation. MOR engagement does not only affect pain features and quality, but also influences directly and/or indirectly tumor growth and metastasis. The opioid effects on chronic cancer pain are also clinically characterized by altered opioid responsiveness (tolerance and hyperalgesia), a hallmark of the problematic long-term treatment of non-cancer pain. The significant progress made in understanding the immune-mediated development of chronic pain suggests its exploitation for novel alternative immunotherapeutic approaches.
疼痛对癌症患者来说可能是一种极具破坏性的体验，会导致生活质量下降。在过去二十年中，免疫学和疼痛研究表明，疼痛持续存在主要是由神经炎症引起的，神经炎症会导致中枢敏化，并伴有脑内神经可塑性改变以及疼痛反应性（痛觉过敏和疼痛行为）的变化。癌症疼痛受到肿瘤微环境（TME）的显著影响，肿瘤微环境是一个复杂的生态系统，由不同类型的细胞（癌细胞、内皮细胞和基质细胞、白细胞、成纤维细胞和神经元）组成，这些细胞会释放可溶性介质引发神经炎症。肿瘤微环境中的细胞成分表达阿片受体（即MOR），内源性或外源性阿片类物质（如吗啡）与这些受体结合后，会引发信号转导事件，导致神经炎症。MOR的激活不仅会影响疼痛的特征和性质，还会直接和/或间接影响肿瘤的生长和转移。阿片类物质对慢性癌症疼痛的影响在临床上还表现为阿片反应性改变（耐受性和痛觉过敏），这是长期治疗非癌性疼痛存在问题的一个标志。在理解慢性疼痛的免疫介导发展方面取得的重大进展表明，可以利用这一点开发新的替代免疫治疗方法。
