Mechanisms Mediating High-Molecular-Weight Hyaluronan-Induced Antihyperalgesia
Mechanisms Mediating High-Molecular-Weight Hyaluronan-Induced Antihyperalgesia
复制标题
DOI：
10.1523/jneurosci.0166-20.2020
复制
发表时间：
2020-08-19
影响因子：
5.3
通讯作者：
Levine, Jon D.
中科院分区：
文献类型：
--
作者：
Bonet, Ivan J. M.;Araldi, Dioneia;Levine, Jon D.
我们评估了在炎症情况下，高分子量透明质酸（HMWH）减轻伤害感受器致敏的机制。HMWH减轻了炎症介质前列腺素E2 （PGE(2)）引起的雄性和雌性大鼠的机械性痛觉过敏。鞘内给予同源透明质酸受体CD44 (cluster of differentiation 44) mRNA的寡脱氧核苷酸反义（AS-ODN），以及皮内给予CD44受体拮抗剂A5G27，均可减轻HMWH诱导的抗痛觉过敏。在雄性大鼠中，HIVIWH也通过toll样受体4 （TLR4）和TLR4 mRNA的AS-ODN传递信号，在鞘内给药，减轻hmwh诱导的抗痛觉过敏。由于HMWH信号依赖于CD44在脂质筏中的聚集，我们用甲基- β -环糊精（M β - CD）预处理动物，它会破坏脂质筏。M β - CD显著减弱hmwh诱导的抗痛觉过敏。CD44激活的细胞内信号通路组分的抑制剂，包括磷脂酶C和磷酸肌肽3-激酶（PI3K），也能减弱hmwh诱导的抗痛觉过敏。此外，在体外应用HMWH可减弱PGE(2)诱导的河豚毒素抗性钠电流在小直径背根神经节神经元中的致敏作用，该效应可被PI3K抑制剂减弱。我们的研究结果表明CD44信号在hmwh诱导的抗痛觉过敏中起着核心作用，并提出了CD44下游的新治疗靶点，用于治疗由伤害感受器致敏引起的疼痛。
We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated mechanical hyperalgesia induced by the inflammatory mediator prostaglandin E2 (PGE(2)) in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to mRNA for cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuated antihyperalgesia induced by HMWH. In male rats, HIVIWH also signals via Toll-like receptor 4 (TLR4), and AS-ODN for TLR4 mRNA administered intrathecally, attenuated HMWH-induced antihyperalgesia. Since HMWH signaling is dependent on CD44 clustering in lipid rafts, we pretreated animals with methyl-beta-cyclodextrin (M beta CD), which disrupts lipid rafts. M beta CD markedly attenuated HMWH-induced antihyperalgesia. Inhibitors for components of intra-cellular signaling pathways activated by CD44, including phospholipase C and phosphoinositide 3-kinase (PI3K), also attenuated HMWH-induced antihyperalgesia. Furthermore, in vitro application of HMWH attenuated PGE(2)-induced sensitization of tetrodotoxin-resistant sodium current, in small-diameter dorsal root ganglion neurons, an effect that was attenuated by a PI3K inhibitor. Our results indicate a central role of CD44 signaling in HMWH-induced antihyperalgesia and suggest novel therapeutic targets, downstream of CD44, for the treatment of pain generated by nociceptor sensitization.