Lopez-Canul Martha, Palazzo Enza, Dominguez-Lopez Sergio, Luongo Livio, Lacoste Baptiste, Comai Stefano, Angeloni Debora, Fraschini Franco, Boccella Serena, Spadoni Gilberto, Bedini Annalida, Tarzia Giorgio, Maione Sabatino, Granados-Soto Vinicio, Gobbi Gabriella
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University Health Centre, McGill University, Montreal, QC, Canada Institute of Neuroethology, University Veracruzana, Xalapa, México Department of Experimental Medicine, Second University of Naples, Naples, Italy Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy Institute of Medicinal Chemistry, University Carlo Bo, Urbino, Italy Neurobiology of Pain Laboratory, Department of Pharmacobiology, Cinvestav-Sede Sur, México, D. F., Mexico.
Pain. 2015 Feb;156(2):305-317. doi: 10.1097/01.j.pain.0000460311.71572.5f.
Neuropathic pain is an important public health problem for which only a few treatments are available. Preclinical studies show that melatonin (MLT), a neurohormone acting on MT1 and MT2 receptors, has analgesic properties, likely through MT2 receptors. Here, we determined the effects of the novel selective MLT MT2 receptor partial agonist N-{2-([3-bromophenyl]-4-fluorophenylamino)ethyl}acetamide (UCM924) in 2 neuropathic pain models in rats and examined its supraspinal mechanism of action. In rat L5-L6 spinal nerve ligation and spared nerve injury models, UCM924 (20-40 mg/kg, subcutaneously) produced a prolonged antinociceptive effect that is : (1) dose-dependent and blocked by the selective MT2 receptor antagonist 4-phenyl-2-propionamidotetralin, (2) superior to a high dose of MLT (150 mg/kg) and comparable with gabapentin (100 mg/kg), but (3) without noticeable motor coordination impairments in the rotarod test. Using double staining immunohistochemistry, we found that MT2 receptors are expressed by glutamatergic neurons in the rostral ventrolateral periaqueductal gray. Using in vivo electrophysiology combined with tail flick, we observed that microinjection of UCM924 into the ventrolateral periaqueductal gray decreased tail flick responses, depressed the firing activity of ON cells, and activated the firing of OFF cells; all effects were MT2 receptor-dependent. Altogether, these data demonstrate that selective MT2 receptor partial agonists have analgesic properties through modulation of brainstem descending antinociceptive pathways, and MT2 receptors may represent a novel target in the treatment of neuropathic pain.
神经性疼痛是一个重要的公共卫生问题，目前仅有少数几种治疗方法。临床前研究表明，褪黑素（MLT）作为一种作用于MT1和MT2受体的神经激素，具有镇痛特性，可能是通过MT2受体发挥作用。在此，我们确定了新型选择性MLT MT2受体部分激动剂N-{2-([3-溴苯基]-4-氟苯基氨基)乙基}乙酰胺（UCM924）在大鼠的两种神经性疼痛模型中的作用，并研究了其脊髓上的作用机制。在大鼠L5-L6脊神经结扎和保留神经损伤模型中，UCM924（20-40mg/kg，皮下注射）产生了持久的镇痛作用，该作用：（1）呈剂量依赖性，且被选择性MT2受体拮抗剂4-苯基-2-丙酰胺基四氢萘阻断；（2）优于高剂量的MLT（150mg/kg），与加巴喷丁（100mg/kg）相当，但（3）在转棒试验中没有明显的运动协调障碍。通过双重染色免疫组织化学，我们发现MT2受体在延髓腹外侧导水管周围灰质的谷氨酸能神经元中表达。使用体内电生理学结合甩尾试验，我们观察到向腹外侧导水管周围灰质微量注射UCM924可降低甩尾反应，抑制ON细胞的放电活动，并激活OFF细胞的放电；所有这些作用均依赖于MT2受体。总之，这些数据表明，选择性MT2受体部分激动剂通过调节脑干下行镇痛通路具有镇痛特性，并且MT2受体可能是治疗神经性疼痛的一个新靶点。
