Liu Tao-Yan, Cheng Yong, Qin Xiao-Yan, Yu Long-Chuan
Beijing Engineering Research Center of Food, Environment, and Health, Minzu University of China, Beijing, 100081, China.
College of Life and Environmental Sciences, Minzu University of China, Beijing, 100081, China.
Neurosci Bull. 2015 Oct;31(5):611-6. doi: 10.1007/s12264-015-1556-2. Epub 2015 Aug 6.
Neuropathic pain is of serious clinical concern and only about half of patients achieve partial relief with currently-available treatments, so it is critical to find new drugs for this condition. Recently, the cellsurface trafficking of pain-related receptors has been suggested as an important mechanism underlying persistent neuropathic pain. Here, we used the short peptide GluA2-3y, which specifically inhibits the GluA2-dependent endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and tested its anti-nociceptive effect in the periaqueductal grey (PAG) of intact rats and rats with neuropathic pain. Intra-PAG injection of 0.15, 1.5, 7.5, and 15 pmol of GluA2-3y induced dose-dependent increases in hindpaw withdrawal latencies to noxious thermal and mechanical stimuli in intact rats, suggesting that GluA2 cell-surface trafficking in the PAG is involved in pain modulation. Furthermore, GluA2-3y had much stronger anti-nociceptive effects in rats with neuropathic pain induced by sciatic nerve ligation. Interestingly, the intra-PAG injection of 15 pmol GluA2-3y had an analgesic effect similar to 10 μg (35 nmol) morphine in rats with neuropathic pain. Taken together, our results suggested that GluA2 trafficking in the PAG plays a critical role in pain modulation, and inhibiting GluA2 endocytosis with GluA2-3y has potent analgesic effects in rats with neuropathic pain. These findings strongly support the recent hypothesis that targeting receptor trafficking could be a new strategy for the treatment of neuropathic pain.
神经性疼痛是临床上严重关注的问题，目前可用的治疗方法仅能使约一半的患者获得部分缓解，因此寻找针对这种病症的新药至关重要。最近，疼痛相关受体的细胞表面运输被认为是持续性神经性疼痛的重要潜在机制。在此，我们使用了短肽GluA2-3y，它能特异性抑制α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体依赖于GluA2的内吞作用，并在完整大鼠和神经性疼痛大鼠的中脑导水管周围灰质（PAG）中测试了其抗伤害感受作用。向PAG内注射0.15、1.5、7.5和15 pmol的GluA2-3y可使完整大鼠对有害热刺激和机械刺激的后爪缩足潜伏期呈剂量依赖性增加，这表明PAG中GluA2的细胞表面运输参与疼痛调节。此外，GluA2-3y对坐骨神经结扎诱导神经性疼痛的大鼠具有更强的抗伤害感受作用。有趣的是，向神经性疼痛大鼠的PAG内注射15 pmol GluA2-3y产生的镇痛作用与10 μg（35 nmol）吗啡相似。综上所述，我们的结果表明PAG中GluA2的运输在疼痛调节中起关键作用，用GluA2-3y抑制GluA2内吞作用对神经性疼痛大鼠具有强效镇痛作用。这些发现有力地支持了最近的假说，即靶向受体运输可能是治疗神经性疼痛的新策略。
