Centre for Integrated Preclinical Drug Development, The University of Queensland, Level 3, Steele Building, St Lucia Campus, Brisbane, QLD, 4072, Australia.
Inflammopharmacology. 2013 Oct;21(5):339-63. doi: 10.1007/s10787-013-0183-7. Epub 2013 Aug 6.
Prostate cancer (PCa) has a high propensity for metastasis to bone. Despite the availability of multiple treatment options for relief of PCa-induced bone pain (PCIBP), satisfactory relief of intractable pain in patients with advanced bony metastases is challenging for the clinicians because currently available analgesic drugs are often limited by poor efficacy and/or dose-limiting side effects. Rodent models developed in the past decade show that the pathobiology of PCIBP comprises elements of inflammatory, neuropathic and ischemic pain arising from ectopic sprouting and sensitization of sensory nerve fibres within PCa-invaded bones. In addition, at the cellular level, PCIBP is underpinned by dynamic cross talk between metastatic PCa cells, cellular components of the bone matrix, factors associated with the bone microenvironment as well as peripheral components of the somatosensory system. These insights are aligned with the clinical management of PCIBP involving use of a multimodal treatment approach comprising analgesic agents (opioids, NSAIDs), radiotherapy, radioisotopes, cancer chemotherapy agents and bisphosphonates. However, a major drawback of most rodent models of PCIBP is their short-term applicability due to ethical concerns. Thus, it has been difficult to gain insight into the mal(adaptive) neuroplastic changes occurring at multiple levels of the somatosensory system that likely contribute to intractable pain at the advanced stages of metastatic disease. Specifically, the functional responsiveness of noxious circuitry as well as the neurochemical signature of a broad array of pro-hyperalgesic mediators in the dorsal root ganglia and spinal cord of rodent models of PCIBP is relatively poorly characterized. Hence, recent work from our laboratory to develop a protocol for an optimized rat model of PCIBP will enable these knowledge gaps to be addressed as well as identification of novel targets for drug discovery programs aimed at producing new analgesics for the improved relief of intractable PCIBP.
前列腺癌（PCa）有很高的转移到骨骼的倾向。尽管有多种治疗选择可以缓解 PCa 引起的骨痛（PCIBP），但对于临床医生来说，缓解晚期骨转移患者的顽固性疼痛仍然具有挑战性，因为目前可用的镇痛药物往往受到疗效差和/或剂量限制的副作用的限制。过去十年中开发的啮齿动物模型表明，PCIBP 的病理生物学包括源自 PCa 入侵骨骼中感觉神经纤维的异位发芽和敏化的炎症、神经病理性和缺血性疼痛的元素。此外，在细胞水平上，PCIBP 是由转移性 PCa 细胞、骨基质的细胞成分、与骨微环境相关的因素以及躯体感觉系统的外周成分之间的动态串扰所支撑的。这些见解与 PCIBP 的临床管理一致，包括使用包括镇痛药（阿片类药物、非甾体抗炎药）、放射疗法、放射性同位素、癌症化疗药物和双膦酸盐在内的多模式治疗方法。然而，由于伦理问题，大多数 PCIBP 啮齿动物模型的主要缺点是其短期适用性。因此，很难深入了解可能导致转移性疾病晚期顽固性疼痛的躯体感觉系统多个水平发生的不良（适应性）神经可塑性变化。具体来说，PCIBP 啮齿动物模型的伤害性电路的功能反应性以及广泛的促痛敏介质的神经化学特征相对较差。因此，我们实验室最近开发了一种优化的 PCIBP 大鼠模型的方案，这将能够解决这些知识空白，并确定用于药物发现计划的新靶点，旨在为改善 PCIBP 的顽固性疼痛提供新的镇痛药。
