Neuropathic vs. inflammatory pain in chronic pancreatitis: can unique biomarkers be identified to guide mechanistic approaches to pain treatment?

摘要 慢性胰腺炎(CP)常伴有难以治疗的极度虚弱的疼痛。 临床上还没有工具可以正确地描述患者所经历的疼痛的亚型 选择一种最有可能改善患者疼痛症状的疗法。有两种外围机制 可引起炎症性疼痛(IP)和神经病理性疼痛(NP)。IP的一个主要驱动力是神经源性的 炎症，由于神经活动增加而导致的炎症，促使神经肽的释放 招募/激活免疫细胞。NP是由直接神经损伤(压迫或损伤)引起的。重要的是，两者 疼痛的类型伴随着细胞因子表达的独特变化，这些变化可以用来识别 导致患者疼痛的机制(IP和/或NP)。区分IP和NP的工具的发展 最终可以简化CP疼痛管理，因为有证据表明，某些治疗方法 对一种类型的疼痛比对另一种类型的疼痛更有效。例如，阿片类药物对IP更有效 而加巴喷丁类化合物对NP更有用。这项提议是为了比较一种新的动物模型 哪种胰腺炎疼痛是单纯由IP(光遗传)和常用的CP动物模型诱导的 (慢性蓝蛋白)疼痛是IP和NP共同作用的结果。目标是确定相关的细胞因子图谱 与特定的疼痛表型进行比较，并与具有良好特征的临床队列的遗留样本进行比较 脑性瘫痪患者。我们还将测试患者细胞因子特征与疼痛之间是否存在相关性。 特点。长期计划是使用一种迭代的方法，使用患者数据来改进动物 CP的模型，然后可以用来开发疼痛类型的特定疗法。 除了将新技术(光遗传)纳入CP的研究之外，该项目还将提供深入的 在处理和分析人类数据方面的培训，并将为未来的人类提供基础 研究将包括专门为诊断炎症性和神经病理性疼痛而设计的调查工具 患有CP的人类。

Abstract Chronic pancreatitis (CP) is often accompanied by profoundly debilitating pain that is quite difficult to treat. There are no tools available in clinics to properly characterize the subtype of pain a patient is experiencing to choose a therapy most likely to benefit a patient’s pain symptoms. There are two peripheral mechanisms that could contribute, inflammatory pain (IP) and neuropathic pain (NP). A major driver of IP is neurogenic inflammation, inflammation resulting from increased neural activity that drives release of neuropeptides that recruit/activate immune cells. NP results from direct nerve injury (compression or lesion). Importantly, both types of pain are accompanied by unique changes in cytokine expression that can be used to identify mechanisms (IP and/or NP) contributing to a patient’s pain. The development of tools to differentiate IP and NP in the clinic could ultimately streamline CP pain management because there is evidence that certain therapies are far more efficacious for one type of pain versus the other. For example, opioids are more effective for IP while gabapentinoids are more useful for NP. This proposal is designed to compare a novel animal model in which pancreatitis pain is induced purely by IP (optogenetic) and a commonly used animal model of CP (chronic cerulein) in which pain is a result of both IP and NP. The goal is to identify cytokine profiles associated with the specific pain phenotypes and compare to legacy samples from a well-characterized clinical cohort of CP patients. We will also test whether patients show correlations between cytokine profiles and pain characteristics. The long-term plan is to use an iterative approach that uses patient data to refine animal models of CP that can then be used to develop pain-type specific therapies. In addition to incorporating new technologies (optogenetic) to the study of CP, this project will provide in depth training in handling and analyzing human data and will provide a foundation for future prospective human studies that will include survey tools specifically designed for diagnosis of inflammatory and neuropathic pain in humans with CP.