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 (
PGE2) 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, HMWH 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-β-
cyclodextrin (MβCD), which disrupts
lipid rafts. MβCD markedly attenuated HMWH-induced antihyperalgesia. Inhibitors for components of intracellular 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 PGE2-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.SIGNIFICANCE STATEMENT High-molecular-weight-
hyaluronan (HMWH) is used to treat
osteoarthritis and other
pain syndromes. In this study we demonstrate that attenuation of inflammatory
hyperalgesia by HMWH is mediated by its action at cluster of differentiation 44 (CD44) and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1),
phospholipases (
phospholipases Cε and Cγ1), and
phosphoinositide 3-kinase, in nociceptors. These findings contribute to our understanding of the antihyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory
pain.