Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress

本研究项目的前提是，伤害感受器神经可塑性是慢性化疗诱导的周围神经病变（CIPN）的重要机制，应激在诱导这种神经可塑性中起着关键作用。在这项研究中，我们将评估伤害感受器神经可塑性在两种临床上重要的癌症化疗（CTX）诱导的慢性CIPN中的作用，即，铂和紫杉烷化合物。实验将评估不同压力源的作用（即，CTX给药、早期生活应激、成人慢性应激、在CTX之前、期间或之后）、用于治疗也作用于应激轴介体受体的共病医学病症的药物（即，糖皮质激素和儿茶酚胺），以及弹性（即，抗应激）对慢性CIPN的发展的影响。此外，我们将研究慢性CIPN的另外两个临床重要特征中的神经可塑性和应激，这两个特征仍然知之甚少：1）铂诱导的冷异常性疼痛和2）“滑行”（即，停止CTX后CIPN恶化）。最后，我们将收获背根神经节（DRG），以及血液，从暴露于CTX和压力的大鼠，以评估血液和周围神经系统中基因表达的变化。这些分析将使我们能够更好地确定慢性CIPN的风险因素和潜在机制，并可用于帮助解释未来的临床研究，以确定患者对CIPN发展的易感性。临床前实验的结果具有重要的临床意义，包括：1）增加了对慢性CIPN的神经可塑性机制的作用的认识，这可以确定新的治疗靶点以预防和治疗慢性CIPN; 2）增加了对神经内分泌应激轴介质如何作用于感觉神经元上的同源受体的理解，从而有助于慢性CIPN; 3）理解阿片类镇痛剂在CIPN中失去功效的机制及其与伤害感受器神经可塑性诱导的关系; 4）理解奥沙利铂诱导的冷异常性疼痛的机制; 5）确定逐渐减少而不是停止CTX是否减轻了惯性滑行;以及6）阐明慢性CIPN发展的基因组生物标志物。

The premise of this research project is that nociceptor neuroplasticity is an important mechanism underlying chronic chemotherapy-induced peripheral neuropathy (CIPN) and that stress plays a key role in the induction of this neuroplasticity. In this grant, we will evaluate the role of nociceptor neuroplasticity in chronic CIPN induced by two clinically important classes of cancer chemotherapy (CTX), i.e., platinum and taxane compounds. Experiments will evaluate the role of diverse stressors (i.e., CTX administration, early life stress, adult chronic stress, prior to, during or after CTX), drugs used to treat co-morbid medical conditions that also act on stress axis mediator receptors (i.e., glucocorticoid and catecholamine), as well as resilience (i.e., resistance to stress) on the development of chronic CIPN. In addition, we will study neuroplasticity and stress in two other clinically important features of chronic CIPN that remain poorly understood: 1) platinum-induced cold allodynia and 2) “coasting” (i.e., worsening of CIPN after stopping CTX). Finally, we will harvest dorsal root ganglia (DRG), as well as blood, from rats exposed to CTX and stress to evaluate changes in gene expression in blood and the peripheral nervous system. These analyses will allow us to better identify risk factors for, and potential mechanisms of, chronic CIPN and could be used to help interpret future clinical studies to identify patients’ susceptibility for development of CIPN. The results of the proposed preclinical experiments have important clinical implications, including: 1) increased knowledge of the role of mechanisms of neuroplasticity underlying chronic CIPN that could identify new therapeutic targets to prevent and treat chronic CIPN; 2) increased understanding of how neuroendocrine stress axis mediators, acting at their cognate receptors on sensory neurons, contribute to chronic CIPN; 3) understanding mechanisms responsible for loss of efficacy of opioid analgesics in CIPN and its relationship to induction of nociceptor neuroplasticity; 4) understanding the mechanism of oxaliplatin-induced cold allodynia; 5) determining if tapering instead of stopping CTX mitigates coasting; and 6) elucidate genomic biomarkers for the development of chronic CIPN.