Peripherally-restricted cannabinoids for cancer and chemotherapy-induced pain

外周限制性大麻素用于治疗癌症和化疗引起的疼痛

• 批准号: 9056010
• 负责人: IGOR SPIGELMAN
• 金额: $ 55.99万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056010
• 关键词: Accounting; Address; Adopted; Adult; Adverse effects; Affect; Afferent Neurons; Affinity; Agonist; Analgesics; Animal Model; Animals; Apoptosis; Apoptotic; Behavioral Assay; Biological Assay; Blood Pressure; Body Temperature; Brain; CNR1 gene; CNR2 gene; Cancer Patient; Cannabinoids; Cell Line; Cerebrum; Chemotherapy-Oncologic Procedure; Chemotherapy-induced peripheral neuropathy; Chronic; Cisplatin; Clinical; Clinical Research; Clinical Trials; Detection; Development; Disease; Dose; Dose-Limiting; Drug Kinetics; Early Diagnosis; Effectiveness; Electrocardiogram; Endocannabinoids; Ensure; Exercise stress test; Exhibits; Fiber; Human; Inflammation; Inflammatory; Ligands; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mediating; Metabolic; Modeling; Molecular; Monitor; Mouth Carcinoma; Mus; Neuraxis; Neuropathy; Nociception; Opioid; Paclitaxel; Pain; Peripheral; Peripheral nerve injury; Persistent pain; Pharmaceutical Preparations; Physiological; Plants; Population; Process; Property; Pulse Oximetry; Radio; Rattus; Receptor Activation; Sensory; Series; Site; Specificity; Symptoms; Telemetry; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Translating; Tumor Burden; Withdrawal; Work; awake; base; cancer pain; cannabinoid receptor antagonist; chemotherapeutic agent; chemotherapy; chemotherapy induced neuropathy; chronic pain; electric impedance; endogenous cannabinoid system; experience; gender difference; implantable device; improved outcome; inflammatory neuropathic pain; innovation; malignant mouth neoplasm; mouse model; novel; orofacial; pain symptom; painful neuropathy; pre-clinical; prevent; public health relevance; receptor; research study; response; restoration; socioeconomics; synthetic cannabinoid; tool; tumor

 DESCRIPTION (provided by applicant) Synthetic and naturally occurring cannabinoids (CBs) have demonstrated effectiveness in numerous chronic inflammatory and neuropathic disorders in humans and in animal models. However, major impediments to the widespread use of CB-based therapies are their psychotropic side-effects, mediated by the activation of central nervous system (CNS) CB1 receptors (CB1Rs). Recently, we developed a series of synthetic peripherally-restricted CBs (PRCBs), and demonstrated potent reversible and repeated suppression of chronic inflammatory and neuropathic pain symptoms in the absence of CNS-mediated side effects. The therapeutic utility of PRCBs may include many other indications where brain-permeant CBs have been shown to be effective. Cancer pain and chemotherapy-induced neuropathy are particularly attractive targets since brain-permeant CBs possess antitumorigenic properties and have been shown to ameliorate the pain symptoms of cancer and chemotherapy-induced neuropathies mainly by peripheral mechanisms. Therefore, this proposal focuses on establishing effectiveness and mechanisms of action of PRCBs against: a) human oral carcinoma proliferation, b) oral carcinoma-induced pain, and c) chemotherapy-induced peripheral neuropathies (CIPNs). We will achieve these aims through the use of innovative and validated operant assays that provide a measure of cerebral processing and orofacial function in mouse oral cancer and rat CIPN models. Gender differences in cancer and CIPN pain sensitivity and their responsiveness to PRCBs will be determined. To further characterize PRCBs we will perform pharmacokinetic studies and determine their receptor targets with tissue-specific transgenic mice. To assess potential off-target actions and peripheral side effects of PRCBs we will use a suite of invasive and non-invasive physiological tools. We will also assess the potential development of tolerance to PRCBs after chronic administration and determine if pre-treatment with PRCBs may actually prevent the onset and maintenance of CIPN symptoms. Successful completion of the proposed studies would allow us to translate pre- clinical findings to a clinical trial; this work would improve outcome for cancer patients.

 描述（由申请人提供） 合成和天然存在的大麻素 (CB) 已在人类和动物模型中证明对多种慢性炎症和神经性疾病有效，然而，广泛使用基于 CB 的疗法的主要障碍是其精神副作用。 ，由中枢神经系统 (CNS) CB1 受体 (CB1R) 的激活介导。最近，我们开发了一系列合成的外周限制性 CB。 (PRCB)，并且在没有中枢神经系统介导的副作用的情况下，证明了对慢性炎症和神经性疼痛症状的有效可逆和重复抑制。PRCB 的治疗用途可能包括许多其他已证明脑渗透性 CB 有效的适应症。癌症疼痛和化疗引起的神经病变是特别有吸引力的目标，因为脑渗透性CB具有抗肿瘤发生特性，并且已被证明主要通过外周机制改善癌症和化疗引起的神经病变的疼痛症状。因此，本提案的重点是建立 PRCB 对抗以下疾病的有效性和作用机制：a) 人类口腔癌增殖，b) 口腔癌引起的疼痛，以及 c) 化疗引起的周围神经病变 (CIPN)。使用创新且经过验证的操作测定来测量小鼠口腔癌和大鼠 CIPN 模型中的大脑处理和口面功能，我们将确定癌症和 CIPN 疼痛敏感性的性别差异及其对 PRCB 的反应。将使用组织特异性转基因小鼠进行药代动力学研究并确定其受体靶标，以评估潜在的脱靶作用和外周作用。 针对 PRCB 的副作用，我们将使用一套侵入性和非侵入性生理工具，我们还将评估长期给药后对 PRCB 的潜在耐受性，并确定 PRCB 预处理是否可以真正预防 CIPN 症状的发生和维持。成功完成拟议的研究将使我们能够将临床前研究结果转化为临床试验；这项工作将改善癌症患者的治疗结果。