Peripherally-restricted cannabinoids for cancer and chemotherapy-induced pain

 描述（由申请人提供）合成的和天然存在的大麻素（CB）已在人类和动物模型中的许多慢性炎症和神经性疾病中证明有效。然而，基于CB的疗法的广泛使用的主要障碍是它们的精神副作用，其由中枢神经系统（CNS）CB 1受体（CB 1 R）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），并证明了在没有CNS介导的副作用的情况下，对慢性炎症和神经性疼痛症状的有效可逆和重复抑制。PRCB的治疗效用可以包括许多其他适应症，其中脑渗透CB已被证明是有效的。癌症疼痛和化疗诱导的神经病变是特别有吸引力的目标，因为脑渗透CB具有抗肿瘤特性，并已被证明主要通过外周机制改善癌症和化疗诱导的神经病变的疼痛症状。因此，本提案重点在于确定PRCB针对以下各项的有效性和作用机制：a）人口腔癌增殖，B）口腔癌诱导的疼痛，以及c）化疗诱导的周围神经病变（CIPN）。我们将实现这些目标，通过使用创新和验证的操作性测定，提供了一个衡量大脑处理和orofacial功能在小鼠口腔癌和大鼠CIPN模型。将确定癌症和CIPN疼痛敏感性及其对PRCB反应性的性别差异。为了进一步表征PRCB，我们将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点。评估潜在的脱靶动作和外周 我们将使用一套侵入性和非侵入性的生理工具来评估PRCB的副作用。我们还将评估长期给药后对PRCB耐受性的潜在发展，并确定PRCB预治疗是否可以实际预防CIPN症状的发作和维持。成功完成拟议的研究将使我们能够将临床前发现转化为临床试验;这项工作将改善癌症患者的结果。

 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.