Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Neurochem Int. 2018 Oct;119:184-189. doi: 10.1016/j.neuint.2017.12.005. Epub 2017 Dec 14.
Chemokine signaling is important in neuropathic pain, with microglial cells expressing chemokine (C-C motif) receptor CCR2, CCR5 and CCR8, all playing key roles. In the previous report (Padi et al., 2012), oral administration of a short peptide, RAP-103, for 7 days fully prevents mechanical allodynia and inhibits the development of thermal hyperalgesia after partial ligation of the sciatic nerve in rodents. As for the mechanism of the inhibiting effect of RAP-103, it was speculated to be due to dual blockade of CCR2 and CCR5. We report here that RAP-103 exhibits stronger antagonism for CCR8 (half maximal inhibitory concentration [IC] 7.7 fM) compared to CCR5 (IC < 100 pM) in chemotaxis using primary cultured mouse microglia. In addition, RAP-103 at a concentration of 0.1 pM completely inhibits membrane ruffling and phagocytosis induced by chemokine (C-C motif) ligand 1 (CCL1), an agonist for CCR8. It has been shown that CCL1/CCR8 signaling is important in tactile allodynia induced by nerve ligation. Therefore, CCR8, among other chemokine receptors such as CCR2/CCR5, could be the most potent target for RAP-103. Inhibitory effects of RAP-103 on plural chemokine receptors may play important roles for broad clinical use in neuropathic pain treatment.
趋化因子信号在神经病理性疼痛中很重要，小胶质细胞表达趋化因子（C-C 基序）受体 CCR2、CCR5 和 CCR8，它们都发挥着关键作用。在之前的报告（Padi 等人，2012）中，口服短肽 RAP-103 7 天可完全预防机械性痛觉过敏，并抑制大鼠坐骨神经部分结扎后的热痛觉过敏发展。至于 RAP-103 抑制作用的机制，推测是由于双重阻断 CCR2 和 CCR5。我们在此报告，在使用原代培养的小鼠小胶质细胞进行趋化性研究时，与 CCR5（IC < 100 pM）相比，RAP-103 对 CCR8 的拮抗作用更强（半最大抑制浓度 [IC]7.7 fM）。此外，在浓度为 0.1 pM 时，RAP-103 可完全抑制趋化因子（C-C 基序）配体 1（CCL1）诱导的细胞膜皱襞和吞噬作用，CCL1 是 CCR8 的激动剂。已经表明，CCL1/CCR8 信号在神经结扎引起的触觉过敏中很重要。因此，CCR8 可能是 RAP-103 最有效的靶点，而不是其他趋化因子受体（如 CCR2/CCR5）。RAP-103 对多种趋化因子受体的抑制作用可能对神经病理性疼痛治疗的广泛临床应用具有重要作用。
