Papers of the Week

We tested the hypothesis that high molecular weight hyaluronan (HMWH) binds to and signals via cluster of differentiation 44 receptor (CD44), to attenuate nociceptor function, in the setting of inflammation. We found that HMWH attenuates prostaglandin E (PGE)-induced mechanical hyperalgesia, in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense to CD44 mRNA and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuate anti-hyperalgesia induced by HMWH. HMWH signaling is dependent on CD44 clustering in lipid rafts, leading to activation of downstream second messenger signaling pathways. Methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts, attenuates HMWH-induced anti-hyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K), also attenuates HMWH-induced anti-hyperalgesia. Our results demonstrate the central role of CD44 in HMWH-induced anti-hyperalgesia and establish its second messengers as novel therapeutic targets for the treatment of pain.We have previously demonstrated that high molecular weight hyaluronan (HMWH) attenuates inflammatory and neuropathic hyperalgesia. In this study we demonstrate that HMWH attenuates PGE-hyperalgesia is mediated by its action at CD44, and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1) and phospholipases (phospholipases Cε and Cγ1), in nociceptors of male and female rats. These findings contribute to our understanding of the anti-hyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory pain.