Neurobiological Psychiatry Unit, McGill University, Montreal, Canada.
Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute University, Milan, Italy.
Curr Med Chem. 2018;25(32):3866-3882. doi: 10.2174/0929867324666170209104926.
Melatonin (MLT) has been implicated in several pathophysiological states, including pain. MLT mostly activates two G-protein coupled receptors, MT1 and MT2. In this review, we present the analgesic properties of MLT in preclinical and clinical studies, giving particular emphasis to the effects mediated by MT2 receptors and to recent investigations demonstrating the analgesic effects of MT2 receptor partial agonists in chronic and acute/inflammatory pain conditions. MT2 receptors are localized in specific brain areas, including the reticular and the ventromedial nuclei of the thalamus (part of the ascending nociceptive pathway) and the ventrolateral periaqueductal grey matter (vlPAG) (part of the descending antinociceptive pathway). MLT displays analgesic properties in several animal paradigms of chronic, acute, inflammatory and neuropathic pain; importantly, these effects are mediated by MT2 receptors since they are blocked by selective MT2 antagonists. In different pain paradigms, UCM924 and UCM765, two selective MT2 receptor partial agonists, produce analgesic effects with higher potency than MLT, thus confirming the involvement of MT2 receptors in pain. Notably, these compounds do not induce sedation and motor impairments. Although their analgesic mechanism of action is not yet completely elucidated, they act on antinociceptive descending pathways by stimulating MT2 receptors on glutamatergic neurons of the vlPAG, which in turn activate OFF cells and inhibit ON cells of the rostral ventromedial medulla (RVM). Collectively, there is strong preclinical evidence suggesting the pharmacological potential of MT2 receptor partial agonists, which also have a favorable toxicological profile. These compounds may be further developed as novel analgesic drugs.
褪黑素 (MLT) 与多种病理生理状态有关，包括疼痛。MLT 主要激活两种 G 蛋白偶联受体，MT1 和 MT2。在这篇综述中，我们介绍了 MLT 在临床前和临床研究中的镇痛特性，特别强调了 MT2 受体介导的作用，以及最近的研究表明 MT2 受体部分激动剂在慢性和急性/炎症性疼痛条件下具有镇痛作用。MT2 受体定位于特定的脑区，包括丘脑的网状核和腹内侧核（上行痛觉通路的一部分）和腹外侧导水管周围灰质（vlPAG）（下行抗伤害性通路的一部分）。MLT 在几种慢性、急性、炎症性和神经性疼痛的动物模型中显示出镇痛特性；重要的是，这些作用是由 MT2 受体介导的，因为它们被选择性 MT2 拮抗剂阻断。在不同的疼痛模型中，两种选择性 MT2 受体部分激动剂 UCM924 和 UCM765 产生比 MLT 更强效的镇痛作用，从而证实了 MT2 受体在疼痛中的参与。值得注意的是，这些化合物不会引起镇静和运动障碍。尽管它们的镇痛作用机制尚未完全阐明，但它们通过刺激 vlPAG 谷氨酸能神经元上的 MT2 受体作用于抗伤害性下行通路，从而激活 RVM 的 OFF 细胞并抑制 ON 细胞。总的来说，有强有力的临床前证据表明 MT2 受体部分激动剂具有药理学潜力，而且具有良好的毒理学特征。这些化合物可能进一步开发为新型镇痛药。
