Bai Xue, Batallé Gerard, Pol Olga
Grup de Neurofarmacologia Molecular, Institut d'Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain.
Grup de Neurofarmacologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain.
Antioxidants (Basel). 2021 Jul 3;10(7):1074. doi: 10.3390/antiox10071074.
When neuropathic pain is maintained long term, it can also lead to the development of emotional disorders that are even more intense than pain perception and difficult to treat. Hydrogen sulfide (HS) donors relieve chronic pain, but their effects on the associated mood disorders are not completely elucidated. We evaluated if treatment with DADS (diallyl disulfide) or GYY4137 (morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate dichloromethane complex), two slow-releasing HS donors, inhibits the anxiety- and depressive-like behaviors that concur with chronic neuropathic pain generated by sciatic nerve injury in mice. The modulatory role of these drugs in the inflammatory, apoptotic, and oxidative processes implicated in the development of the affective disorders was assessed. Our results revealed the anxiolytic, antidepressant, and antinociceptive properties of DADS and GYY4137 during neuropathic pain by inhibiting microglial activation and the up-regulation of phosphoinositide 3-kinase/phosphorylated protein kinase B and BAX in the amygdala (AMG) and/or periaqueductal gray matter (PAG). Both treatments also normalized and/or activated the endogenous antioxidant system, but only DADS blocked ERK 1/2 phosphorylation. Both HS donors decreased allodynia and hyperalgesia in a dose-dependent manner by activating the Kv7 potassium channels and heme oxygenase 1 signaling pathways. This study provides evidence of the anxiolytic and antidepressant properties of DADS and GYY4137 during neuropathic pain and reveals their analgesic actions, suggesting that these therapeutic properties may result from the inhibition of the inflammatory, apoptotic, and oxidative responses in the AMG and/or PAG. These findings support the use of these treatments for the management of affective disorders accompanying chronic neuropathic pain.
当神经性疼痛长期持续时，它还会导致比疼痛感知更为强烈且难以治疗的情绪障碍的发生。硫化氢（HS）供体可缓解慢性疼痛，但其对相关情绪障碍的影响尚未完全阐明。我们评估了用两种缓释HS供体二烯丙基二硫醚（DADS）或4 - 甲氧基苯基（吗啉代）磷酰二硫代吗啉鎓二氯甲烷络合物（GYY4137）进行治疗，是否能抑制与小鼠坐骨神经损伤所产生的慢性神经性疼痛同时出现的焦虑样和抑郁样行为。评估了这些药物在情感障碍发生过程中所涉及的炎症、凋亡和氧化过程中的调节作用。我们的结果显示，在神经性疼痛期间，DADS和GYY4137具有抗焦虑、抗抑郁和抗伤害感受特性，其作用机制是抑制杏仁核（AMG）和/或导水管周围灰质（PAG）中的小胶质细胞活化以及磷酸肌醇3激酶/磷酸化蛋白激酶B和BAX的上调。两种治疗方法还使内源性抗氧化系统恢复正常和/或激活，但只有DADS阻断了细胞外信号调节激酶1/2（ERK 1/2）的磷酸化。两种HS供体均通过激活Kv7钾通道和血红素加氧酶1信号通路，以剂量依赖的方式减轻了异常性疼痛和痛觉过敏。本研究提供了DADS和GYY4137在神经性疼痛期间具有抗焦虑和抗抑郁特性的证据，并揭示了它们的镇痛作用，表明这些治疗特性可能源于对AMG和/或PAG中炎症、凋亡和氧化反应的抑制。这些发现支持将这些治疗方法用于管理伴随慢性神经性疼痛的情感障碍。
