Kim Min Su, Kim Bo Yeon, Saghetlians Allen, Zhang Xiang, Okida Takuya, Kim So Yeon
Department of Rehabilitation Medicine, Wonkwang University College of Medicine, Iksan, Korea.
Salk Institute for Biological Studies, La Jolla, CA, USA.
Korean J Pain. 2022 Apr 1;35(2):173-182. doi: 10.3344/kjp.2022.35.2.173.
Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins' antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the antinociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens.
C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection.
Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds.
A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.
神经激肽-1（NK1）和降钙素基因相关肽（CGRP）在疼痛发病机制中起关键作用，这些蛋白的拮抗剂作为有前景的药物候选物已引起关注。作者研究了与传统单一疗法相比，联合使用CGRP拮抗剂和NK1拮抗剂对疼痛模型的镇痛作用。
C57Bl/6J小鼠用于制备坐骨神经结扎的神经病理性疼痛模型，并在后爪注射4%福尔马林制备炎性疼痛模型。每个模型分为四组：溶剂对照组、NK1拮抗剂组、CGRP拮抗剂组和联合治疗组。腹腔注射NK1拮抗剂阿瑞匹坦（BIBN4096，1mg/kg）或CGRP拮抗剂olcegepant（MK-0869，10mg/kg）。使用von Frey、热板和高架十字迷宫试验评估机械性异常性疼痛、热超敏反应和焦虑相关行为。福尔马林注射后还评估了退缩和舔舐反应。
与单独给药或溶剂对照组相比，联合使用阿瑞匹坦和olcegepant能更显著地减轻疼痛行为，提高机械阈值并改善反应潜伏期。与未处理小鼠或联合治疗组中的神经病理性疼痛模型相比，双重治疗后焦虑相关行为也明显改善。联合治疗组福尔马林注射后的退缩频率和舔舐反应显著降低。等效应线图分析显示两种化合物之间有显著的相加作用。
由多种神经肽拮抗剂组成的联合药物治疗可能是缓解神经病理性或炎性疼痛更有效的治疗策略。
