Evaluation of peripheral cannabinoid receptors as a target for pain management

摘要 慢性疼痛影响了11.2%的美国人口，并导致相当大的残疾。当前 慢性疼痛的药物治疗在很大程度上是无效的，严重依赖阿片类药物。处方过多 治疗疼痛障碍的阿片类化合物在美国造成了阿片类药物过量流行， 强调迫切需要开发更安全、更有效的疼痛疗法。内源性大麻素 由大麻素受体(CB1和CB2)及其内源性配体组成的系统已经出现 作为目前可用的止痛药的替代治疗靶点。外源性给药 在慢性疼痛的临床试验中，大麻素(CBS)表现出好坏参半的结果，提示该药物具有治疗作用 基于CB的疗法在疼痛障碍中的潜力在很大程度上是未知的。CB激动剂也表现出不受欢迎的副作用- 影响(如耐受性和精神活动)很大程度上是由于中枢CB1R的激活。背根神经节(DRG) 含有负责将外周伤害性信号传递给 脊髓。激活DRG中的外周CB1R受体被视为一种潜在的驾驭手段 CB1Rs的治疗作用，同时规避不受欢迎的中枢神经系统相关副作用。然而，已经有了 关于外周血CB配体的抗伤害作用的研究很少。在目前的提案中，我计划 结合药理学和新的基于遗传的方法来阐明外周血细胞的作用 CB1R受体在减少雄性和雌性小鼠疼痛的感觉和非反射成分中的作用。这个 Mentor的实验室先前证实了代谢性谷氨酸受体2/3受体的功能差异 培养的小鼠和人背根神经节神经元的活性。这表明 其他药理靶点的机制基础，如CBS，可能因物种而异。人与人 小鼠CB1在海马神经元培养中表现出差异信号。到目前为止只有一份报告被调查 人源性背根神经节中的CB信号，还没有关于CB受体信号的比较研究 在啮齿动物和人类之间进行了这一组织的研究。为了更好地了解靶向治疗的临床有效性 外围CB1RS I将利用一个极其独特的机会进行比较研究 CB受体在小鼠和人背根神经节中的功能。这些研究有可能产生变革性的数据 了解有关CBS外周抗伤害效应的临床前研究结果的可转移性。这个 中枢假说：背根神经节伤害性感受器上的CB1R参与了抗伤害性反应 在小鼠身上观察到外周CB给药，这一机制将转化为人类 在本提案中进行了评价。从拟议的实验中产生的数据将极大地帮助我们 理解外周CB1R激活促进抗伤害性LIKE的潜在机制 对小鼠的影响以及类似的方法是否会转化为人类；潜在地导致更好的 利用CB1R信号治疗慢性疼痛障碍的方法。

ABSTRACT Chronic pain impacts 11.2% of the U.S. population, and leads to considerable disability. Current pharmacotherapies for chronic pain are largely ineffective and rely heavily on opioids. Over-prescription of opioid-based compounds for pain disorders has contributed to an opioid overdose epidemic in the U.S., highlighting the urgent need to develop safer and more effective therapeutics for pain. The endocannabinoid system, which consists of cannabinoid receptors (CB1 and CB2) and their endogenous ligands, has emerged as an alternative therapeutic target to currently available pain medications. Exogenously administered cannabinoids (CBs) display mixed outcomes in clinical trials for chronic pain suggesting the therapeutic potential of CB-based therapies in pain disorders is largely unknown. CB agonists also exhibit unwanted side- effects (e.g. tolerance and psychoactivity) largely due to central CB1R activation. Dorsal root ganglion (DRG) contain the cell bodies of primary afferents responsible transmitting peripheral nociceptive signaling to the spinal cord. Activation of peripheral CB1R receptors in DRG has been viewed as a potential means to harness the therapeutic actions of CB1Rs while circumventing unwanted CNS-related side-effects. Yet, there have been few investigations regarding antinociceptive effects of peripheral CB ligands. In the present proposal I plan to incorporate pharmacological and novel genetic-based approaches to elucidate the contributions of peripheral CB1R receptors in reducing sensory and non-reflexive components of pain in both male and female mice. The mentor's lab previously demonstrated functional differences of metabotropic glutamate receptor 2/3 receptors activity in cultured neurons derived from mouse and human dorsal root ganglion. This suggests the mechanistic basis of other pharmacological targets, such as CBs, may differ between species. Human and mouse CB1 exhibit differential signaling in hippocampal autaptic cultures. Only one report to-date investigated CB signaling in human-derived DRG and no comparative studies regarding CB receptor signaling have ever been conducted between rodent and human in this tissue. To better understand the clinical validity of targeting peripheral CB1Rs I will take advantage of an extremely unique opportunity to conduct comparative studies of CB receptor function in mouse and human DRG. These studies have potential to generate transformative data in understanding transability of preclinical findings regarding peripheral antinociceptive effects of CBs. The central hypothesis that CB1R present on nociceptors in DRG are responsible for the antinociceptive effects of peripheral CB administration observed in mice and that this mechanism will translate to humans will be evaluated in the present proposal. The data generated from the proposed experiments will greatly aid in our understanding of the underlying mechanisms in which peripheral CB1R activation promotes antinociceptive like effects in mouse and whether or not similar approaches will translate into humans; potentially leading to better approaches of utilizing CB1R signaling for the treatment of chronic pain disorders.