Identification of an Adenylyl Cyclase Inhibitor for Treating Neuropathic and Inflammatory Pain
Identification of an Adenylyl Cyclase Inhibitor for Treating Neuropathic and Inflammatory Pain
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DOI：
10.1126/scitranslmed.3001269
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发表时间：
2011-01-12
影响因子：
17.1
通讯作者：
Zhuo, Min
中科院分区：
文献类型：
--
作者：
Wang, Hansen;Xu, Hui;Zhuo, Min
神经病理性疼痛通常是由神经损伤引起的，在不同疾病的患者中常见。由于人们对其基本机制知之甚少，有效的药物有限。以往对疼痛基本机制的研究和药物开发主要集中在早期的感觉神经元，如背根神经节和脊髓背角神经元，很少有突触水平的研究或新药针对伴随神经病理性疼痛的损伤相关的皮质可塑性。我们以前的工作已经证明，钙刺激的腺苷环化酶1(AC1)在神经损伤诱导的前扣带回皮质突触变化中起关键作用。通过合理的药物设计和化学筛选，我们已经确定了一种领先的候选AC1抑制剂NB001，它对AC1比其他腺苷环化酶异构体具有相对选择性。利用各种行为测试和毒性研究，我们发现NB001在动物神经病理性疼痛模型中，无论是经腹膜内给药还是口服给药，都有止痛作用，没有明显的副作用。因此，我们的研究表明，AC1可能是神经病理性疼痛的有效治疗靶点，并为可能的神经病理性疼痛的治疗提供了一种新的药物。
Neuropathic pain, often caused by nerve injury, is commonly observed among patients with different diseases. Because its basic mechanisms are poorly understood, effective medications are limited. Previous investigations of basic pain mechanisms and drug discovery efforts have focused mainly on early sensory neurons such as dorsal root ganglion and spinal dorsal horn neurons, and few synaptic-level studies or new drugs are designed to target the injury-related cortical plasticity that accompanies neuropathic pain. Our previous work has demonstrated that calcium-stimulated adenylyl cyclase 1 (AC1) is critical for nerve injury-induced synaptic changes in the anterior cingulate cortex. Through rational drug design and chemical screening, we have identified a lead candidate AC1 inhibitor, NB001, which is relatively selective for AC1 over other adenylate cyclase isoforms. Using a variety of behavioral tests and toxicity studies, we have found that NB001, when administered intraperitoneally or orally, has an analgesic effect in animal models of neuropathic pain, without any apparent side effects. Our study thus shows that AC1 could be a productive therapeutic target for neuropathic pain and describes a new agent for the possible treatment of neuropathic pain.