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 [IC₅₀] 7.7 fM) compared to CCR5 (IC₅₀ < 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.

趋化因子信号传导在神经性疼痛中很重要，表达表达趋化因子（CC基序）受体CCR2，CCR5和CCR8的小胶质细胞均起关键作用。在以前的报告中（Padi等人，2012），口服短肽RAP-103 7天可完全预防机械性异常性疼痛，并在啮齿类动物的坐骨神经部分结扎后抑制热痛觉过敏的发展。关于RAP-103的抑制作用机理，推测是由于CCR2和CCR5的双重阻断。我们在这里报告，与CCR5（IC ₅₀）相比，RAP-103对CCR8表现出更强的拮抗作用（半数最大抑制浓度[IC ₅₀ ] 7.7 fM）。 使用原代培养的小鼠小胶质细胞进行趋化性（<100 pM）。此外，浓度为0.1 pM的RAP-103完全抑制了由趋化因子（CC基序）配体1（CCL1）（CCR8的激动剂）诱导的膜起伏和吞噬作用。已经表明，CCL1 / CCR8信号在神经结扎引起的触觉异常性疼痛中很重要。因此，在其他趋化因子受体（例如CCR2 / CCR5）中，CCR8可能是RAP-103的最有效靶标。RAP-103对多种趋化因子受体的抑制作用可能在神经性疼痛治疗的广泛临床应用中起重要作用。