Peripherally-restricted cannabinoids for cancer and chemotherapy-induced pain

 说明书(由申请人提供)人工合成和自然产生的大麻素(CBS)已经在人类和动物模型中证明了对许多慢性炎症性和神经性疾病的有效性。然而，基于CB的治疗广泛应用的主要障碍是其精神副作用，这些副作用由中枢神经系统(CNS)CB1受体(CB1Rs)的激活介导。最近，我们开发了一系列合成的外周限制性CBS(PRCBs)，并显示出在没有中枢神经系统介导的副作用的情况下，对慢性炎症性和神经病理性疼痛症状的有效可逆和重复抑制。PRCBs的治疗作用可能包括许多其他适应症，其中大脑暗示的CBS已被证明有效。癌症疼痛和化疗引起的神经病变是特别吸引人的靶点，因为脑源性CBS具有抗肿瘤作用，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，这项建议侧重于建立PRCBs的有效性和作用机制：a)口腔癌增殖，b)口腔癌引起的疼痛，c)化疗引起的周围神经病变(CIPN)。我们将通过使用创新和有效的可操作性分析来实现这些目标，这些分析提供了小鼠口腔癌和大鼠CIPN模型中大脑处理和口腔面部功能的衡量标准。癌症和CIPN疼痛敏感性的性别差异及其对PRCB的反应性将被确定。为了进一步确定PRCBs的特征，我们将进行药代动力学研究，并用组织特异性转基因小鼠确定它们的受体靶点。评估潜在的偏离目标的操作和外围设备 PRCBs的副作用我们将使用一套有创和无创的生理工具。我们还将评估慢性给药后对PRCBs的潜在耐受性，并确定PRCBs的预治疗是否真的可以防止CIPN症状的发生和维持。拟议研究的成功完成将使我们能够将临床前的发现转化为临床试验；这项工作将改善癌症患者的结局。

 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.