期刊
JOURNAL OF NEUROSCIENCE
卷 40, 期 34, 页码 6477-6488出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0166-20.2020
关键词
antihyperalgesia; cluster of differentiation 44 (CD44); high-molecular-weight hyaluronan (HMWH); hyaluronan; hyperalgesia; prostaglandin E2 (PGE(2))
资金
- National Institutes of Health [AR-075334]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据