Zhang Chi, Huang Qian, Ford Neil C, Limjunyawong Nathachit, Lin Qing, Yang Fei, Cui Xiang, Uniyal Ankit, Liu Jing, Mahabole Megha, He Hua, Wang Xuewei, Duff Irina, Wang Yiru, Wan Jieru, Zhu Guangwu, Raja Srinivasa N, Jia Hongpeng, Yang Dazhi, Dong Xinzhong, Cao Xu, Tseng Scheffer C, He Shaoqiu, Guan Yun
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, United States.
The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University, School of Medicine, Baltimore, United States.
Elife. 2024 Dec 13;13:RP101269. doi: 10.7554/eLife.101269.
Pain after surgery causes significant suffering. Opioid analgesics cause severe side effects and accidental death. Therefore, there is an urgent need to develop non-opioid therapies for managing post-surgical pain. Local application of Clarix Flo (FLO), a human amniotic membrane (AM) product, attenuated established post-surgical pain hypersensitivity without exhibiting known side effects of opioid use in mice. This effect was achieved through direct inhibition of nociceptive dorsal root ganglion (DRG) neurons via CD44-dependent pathways. We further purified the major matrix component, the heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) from human AM that has greater purity and water solubility than FLO. HC-HA/PTX3 replicated FLO-induced neuronal and pain inhibition. Mechanistically, HC-HA/PTX3-induced cytoskeleton rearrangements to inhibit sodium current and high-voltage activated calcium current on nociceptive DRG neurons, suggesting it is a key bioactive component mediating pain relief. Collectively, our findings highlight the potential of naturally derived biologics from human birth tissues as an effective non-opioid treatment for post-surgical pain. Moreover, we unravel the underlying neuronal mechanisms of pain inhibition induced by FLO and HC-HA/PTX3.
手术后疼痛会带来巨大痛苦。阿片类镇痛药会导致严重的副作用和意外死亡。因此，迫切需要开发用于管理术后疼痛的非阿片类疗法。局部应用Clarix Flo（FLO），一种人羊膜（AM）产品，可减轻已有的术后疼痛超敏反应，且在小鼠中未表现出使用阿片类药物的已知副作用。这种效果是通过经由CD44依赖性途径直接抑制伤害性背根神经节（DRG）神经元来实现的。我们进一步从人羊膜中纯化了主要基质成分，即重链透明质酸/五聚素3（HC-HA/PTX3），其纯度和水溶性均高于FLO。HC-HA/PTX3重现了FLO诱导的神经元和疼痛抑制作用。从机制上讲，HC-HA/PTX3诱导细胞骨架重排，以抑制伤害性DRG神经元上的钠电流和高电压激活的钙电流，这表明它是介导疼痛缓解的关键生物活性成分。总体而言，我们的研究结果突出了源自人类出生组织的天然生物制品作为术后疼痛有效非阿片类治疗方法的潜力。此外，我们揭示了FLO和HC-HA/PTX3诱导疼痛抑制的潜在神经元机制。
