Cannabinoid Modulation of Hyperalgesia

描述(申请人提供)：在数百万接受癌症化疗的患者中，许多人发展为疼痛的周围神经病变。事实上，疼痛是化疗的主要剂量限制副作用，患者通常会接受较小剂量或放弃治疗，这会影响生存。管理这种神经性疼痛是至关重要的，这样才能优化治疗。这是一项确定大麻类物质是否有益于治疗化疗相关疼痛的建议。大麻素受体(CB1和CB2)位于外周和中枢神经系统，调节伤害性感受。我们将研究增加外周大麻素受体的激活，或增加内源性大麻素(内源性大麻素)的生物利用度，是否会减少化疗引起的神经病理性疼痛。我们使用化疗药物顺铂开发了一种神经病理性疼痛的小鼠模型，顺铂是最广泛使用的化疗药物，通常与神经病变有关。初步数据显示，顺铂后会出现机械性痛觉过敏，后爪注射大麻类药物可减轻痛觉过敏。采用多学科的方法，在小鼠身上进行并行的行为、电生理和细胞研究，将被用来研究外周内源性大麻素信号的变化，这种变化可能有助于顺铂引起的痛敏，以及大麻素可以减轻痛敏的机制。具体地说，我们将确定大麻素或阻断内源性大麻素降解的药物是否能减弱顺铂引起的痛觉过敏和皮肤伤害性感受器的敏化。在对顺铂处理的小鼠初级感觉神经元的细胞研究中，我们将确定顺铂是否改变了大麻素信号和受体的表达，这可能有助于痛觉过敏或大麻素的抗痛敏作用。这些研究的结果将提供有关化疗疼痛潜在机制的新信息，并将为探索使用外周作用的大麻素来控制化疗相关疼痛提供理论基础。

DESCRIPTION (provided by applicant): Among the millions of patients who receive chemotherapy for cancer, many develop painful peripheral neuropathy. In fact, pain is the principal dose-limiting side effect of chemotherapy, and patients often will receive smaller doses or forego treatment which impacts survival. It is critical to manage this neuropathic pain so that treatment can be optimized. This is a proposal to determine whether cannabinoids may be beneficial for the treatment of chemotherapy-associated pain. Cannabinoid receptors (CB1 and CB2) are located in the periphery, as well as the central nervous system, and modulate nociception. We will investigate whether increased activation of peripheral cannabinoid receptors, or increasing the bioavailability of endogenous cannabinoids (endocannabinoids), will reduce neuropathic pain from chemotherapy. We developed a murine model of neuropathic pain using the chemotherapeutic agent cisplatin, the most widely used chemotherapeutic agent which is often associated with neuropathy. Preliminary data show that mechanical hyperalgesia develops following cisplatin, and cannabinoids given into the hindpaw reduce the hyperalgesia. A multidisciplinary approach employing parallel behavioral, electrophysiological, and cellular studies in mice will be used to investigate changes in endocannabinoid signaling in the periphery that may contribute to cisplatin-evoked hyperalgesia and mechanisms by which cannabinoids may attenuate hyperalgesia. Specifically, we will determine whether injection of cannabinoids or drugs that block degradation of endocannabinoids into the hindpaw attenuate cisplatin-evoked hyperalgesia and sensitization of cutaneous nociceptors. In cellular studies of primary sensory neurons isolated from cisplatin-treated mice, we will determine whether cisplatin alters cannabinoid signaling and receptor expression that may contribute to the hyperalgesia or to the antihyperalgesic effects of cannabinoids. Results from these studies will provide new information on the mechanisms underlying pain from chemotherapy, and will provide a rationale for exploring the use of peripherally-acting cannabinoids in managing pain associated with chemotherapy.