Cannabinoid Modulation of Hyperalgesia

描述（由申请人提供）：在数百万接受癌症化疗的患者中，许多人发生疼痛性周围神经病变。事实上，疼痛是化疗的主要剂量限制性副作用，患者通常会接受较小的剂量或放弃影响生存的治疗。控制这种神经性疼痛是至关重要的，以便优化治疗。 这是一项旨在确定大麻素是否有助于治疗化疗相关疼痛的建议。大麻素受体（CB 1和CB 2）位于外周以及中枢神经系统，并调节伤害感受。我们将研究是否增加外周大麻素受体的激活，或增加内源性大麻素（endocannabinoids）的生物利用度，将减少化疗引起的神经性疼痛。我们使用化疗剂顺铂开发了神经性疼痛的小鼠模型，顺铂是最广泛使用的化疗剂，通常与神经病变相关。初步数据显示，顺铂后出现机械性痛觉过敏，给予后爪的大麻素可减轻痛觉过敏。 采用平行的行为，电生理学和细胞研究在小鼠中的多学科方法将被用来调查在外周内源性大麻素信号的变化，可能有助于顺铂诱发的痛觉过敏和大麻素可能减弱痛觉过敏的机制。具体来说，我们将确定是否注射大麻素或药物，阻止内源性大麻素降解到后爪减弱顺铂诱发的痛觉过敏和皮肤伤害感受器的敏化。在从顺铂处理的小鼠中分离的初级感觉神经元的细胞研究中，我们将确定顺铂是否改变大麻素信号传导和受体表达，这可能有助于痛觉过敏或大麻素的抗痛觉过敏作用。 这些研究的结果将提供有关化疗疼痛机制的新信息，并将为探索外周作用大麻素在治疗化疗相关疼痛中的应用提供理论基础。

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.