Department of Physiology, Faculty of Medicine, University of Toronto Centre for the Study of Pain, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S1A8, Canada.
Sci Transl Med. 2011 Jan 12;3(65):65ra3. doi: 10.1126/scitranslmed.3001269.
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.
神经性疼痛通常由神经损伤引起，在患有不同疾病的患者中很常见。由于其基本机制尚未被充分理解，有效的药物治疗非常有限。之前对基础疼痛机制的研究和药物发现工作主要集中在背根神经节和脊髓背角神经元等早期感觉神经元上，很少有针对伴随神经性疼痛的损伤相关皮质可塑性的突触级研究或新药物设计。我们之前的工作表明，钙刺激的腺苷酸环化酶 1（AC1）对于前扣带皮层中的神经损伤诱导的突触变化至关重要。通过合理的药物设计和化学筛选，我们已经确定了一种先导候选 AC1 抑制剂 NB001，它对 AC1 相对于其他腺苷酸环化酶同工型具有相对选择性。通过使用各种行为测试和毒性研究，我们发现 NB001 经腹腔内或口服给药时，在神经性疼痛动物模型中具有镇痛作用，没有明显的副作用。因此，我们的研究表明，AC1 可能是治疗神经性疼痛的一个有前途的治疗靶点，并描述了一种可能用于治疗神经性疼痛的新型药物。
