Interactions between cancer chemotherapy and opioid abuse

癌症化疗与阿片类药物滥用之间的相互作用

• 批准号: 9258570
• 负责人: Luke Legakis
• 金额: $ 3.76万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-10 至 2021-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258570
• 关键词: Absence of pain sensation; Acute; Address; Adverse effects; Affective; Agonist; Analgesics; Anaphase; Animals; Antineoplastic Agents; Area; Autoradiography; Behavior; Behavioral; Behavioral Assay; Binding; Biological Assay; Brain; Brain region; Cancer Etiology; Cancer Patient; Cell division; Characteristics; Chemotherapy-Oncologic Procedure; Chronic; Chronic Cancer Pain; Clinical; Clinical Research; Corpus striatum structure; Dose; Drug Interactions; Dysesthesias; Effectiveness; Electrical Stimulation of the Brain; Female; Filament; Goals; Harvest; Imagery; Immunohistochemistry; Implant; Injection of therapeutic agent; Malignant Neoplasms; Malignant neoplasm of nasopharynx; Malignant neoplasm of ovary; Measures; Mechanics; Mediating; Mental Depression; Metaphase; Microelectrodes; Microtubules; Mitosis; Monitor; Morphine; Nerve Fibers; Neuraxis; Neuropathy; Nucleus Accumbens; Opioid; Opioid Analgesics; Paclitaxel; Pain; Pain management; Patients; Pattern; Performance; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Physiologic pulse; Polymers; Prevalence; Procedures; Public Health; Rattus; Receptor Signaling; Regimen; Reporting; Research; Rewards; Self Stimulation; Sex Characteristics; Skin; Slice; Solid Neoplasm; Spinal Cord; Sprague-Dawley Rats; Suggestion; Testing; Thalamic structure; Tissues; Toxic effect; Training; Ventral Tegmental Area; behavioral study; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; chemotherapy induced neuropathy; clinically significant; cohort; experimental study; improved; insight; male; malignant breast neoplasm; mechanical allodynia; midbrain central gray substance; mu opioid receptors; neurochemistry; novel; opioid abuse; opioid misuse; painful neuropathy; pre-clinical research; prevent; receptor function; response; sex; treatment duration; treatment effect

PROJECT SUMMARY: This new F30 application proposes preclinical research to examine interactions between opioid pharmacology and chemotherapy-induced neuropathy (CIPN) produced in male and female rats by the commonly administered antineoplastic drug paclitaxel (PTX). PTX is known to cause a CIPN frequently associated with behavioral depression that cannot be fully reversed by treatment with mu-opioid receptor (MOR) agonists. Recently, clinical studies have demonstrated an increased vulnerability to opioid abuse in patients treated with MOR agonists for chronic cancer pain, finding a high rate of abuse in this cohort. This application will test the hypothesis that PTX is able to alter MOR functioning in different regions of the central nervous system (CNS) resulting in depression of behavior, reduced efficacy of MOR agonists to produce analgesia, and increased sensitivity to abuse-related effects of MOR agonists. To evaluate this hypothesis, this proposal includes novel studies to investigate a sustained, neuropathy-associated depression of intracranial self-stimulation (ICSS) and of increase in mechanical allodynia in male and female rats. Behavioral studies will investigate the impact of PTX on the effectiveness of acute and repeated morphine to produce analgesic and abuse-related effects. Finally, complementary neurochemical studies will examine the effect of PTX on MOR signaling using the functional assay of agonist-stimulated [35S]GTPγS binding in regions of the CNS associated with pain, analgesia, and abuse. Completion of this project will provide an improved understanding of the mechanisms of CIPN-associated depression of behavior and the behavioral and neurochemical implications of PTX-treatment for MOR functioning and opioid abuse.

项目摘要： 这项新的F30应用程序提案临床前研究以检查阿片类药理学之间的相互作用 和化学疗法诱导的神经病变（CIPN）在男性和雌性大鼠中通过共同 施用的抗塑性药物紫杉醇（PTX）。已知PTX引起经常相关的CIPN 用MU-阿片受体（MOR）激动剂治疗无法完全逆转的行为抑郁症。 最近，临床研究表明，治疗患者的阿片类药物滥用脆弱性增加 慢性癌症疼痛的MOR激动剂，在该队列中发现高度滥用率。此应用程序将测试 假设PTX能够改变中枢神经系统不同区域（CNS）的MOR功能 导致行为抑郁，降低MOR激动剂产生镇痛的效率，并增加 对MOR激动剂的敏感性。为了评估这一假设，该提议包括新颖 研究研究持续的，神经病相关的颅内自刺激（ICS）和 雄性和雌性大鼠机械性异常症的增加。行为研究将研究 PTX关于急性和重复吗啡的有效性产生与镇痛和滥用相关的作用。 最后，完成的神经化学研究将检查PTX对使用MOR信号的影响 激动剂刺激的[35S]GTPγs结合的功能组装与疼痛相关的中枢神经系统的结合 镇痛和虐待。该项目的完成将提供对机制的改进的理解 CIPN相关的行为抑郁以及PTX处理的​​行为和神经化学含义 用于MOR功能和阿片类药物滥用。