Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress

本研究的前提是伤害性感受器神经可塑性是慢性化疗所致周围神经病(CIPN)的重要机制，而应激在这种神经可塑性的诱导中起着关键作用。在这项资助中，我们将评估伤害性感受器神经可塑性在两种临床重要的癌症化疗(CTX)诱导的慢性CIPN中的作用。实验将评估不同的应激源(即CTX应用、早期生活应激、成人慢性应激，在CTX之前、期间或之后)、用于治疗同时作用于应激轴介体受体的药物(即糖皮质激素和儿茶酚胺)以及弹性(即对应激的抵抗力)在慢性CIPN发展中的作用。此外，我们将研究慢性CIPN的另外两个临床上仍然知之甚少的重要特征的神经可塑性和应激：1)铂诱导的冷性超敏和2)“滑行”(即停止CTX后CIPN的恶化)。最后，我们将采集暴露于环磷酰胺和应激的大鼠的背根节(DRG)以及血液，以评估血液和周围神经系统基因表达的变化。这些分析将使我们能够更好地识别慢性CIPN的危险因素和潜在机制，并可用于帮助解释未来的临床研究，以确定患者发生CIPN的易感性。拟议的临床前实验结果具有重要的临床意义，包括：1)增加了对慢性CIPN潜在神经可塑性机制的了解，可确定预防和治疗慢性CIPN的新的治疗靶点；2)增加了对神经内分泌应激轴介质通过作用于其感觉神经元上的同源受体而促进慢性CIPN的作用的理解；3)了解了阿片类止痛药在CIPN中失效的机制及其与诱导伤害性感受器神经可塑性的关系；4)了解了奥沙利铂诱导冷性异位痛症的机制；5)确定逐渐减少而不是停止CTX是否可以缓解慢性CIPN的症状；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.