High molecular weight hyaluronan (HMWH) is an agonist at cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, on nociceptors, where it acts to induce anti-hyperalgesia in preclinical models of inflammatory and neuropathic pain. In the present experiments we studied the CD44 second messengers that mediate HMWH-induced attenuation of pain associated with oxaliplatin and paclitaxel chemotherapy-induced peripheral neuropathy (CIPN). While HMWH attenuates CIPN only in male rats, following ovariectomy or intrathecal administration of an oligodeoxynucleotide (ODN) antisense to G-protein coupled estrogen receptor (GPR30) mRNA, female rats are also sensitive to HMWH. Intrathecal administration of ODN antisense to CD44 mRNA markedly attenuates HMWH-induced anti-hyperalgesia in male rats with CIPN induced by oxaliplatin or paclitaxel. Intradermal administration of inhibitors of CD44 second messengers, RhoGTPases (RhoA), phospholipase C (PLC) and PI3Kγ attenuates HMWH-induced anti-hyperalgesia, as does intrathecal administration of an oligodeoxynucleotide (ODN) antisense to PI3Kγ. Our results demonstrate that HMWH-induces anti-hyperalgesia in CIPN, mediated by its action at CD44, and downstream signaling by RhoA, PLC and PI3Kγ.
Copyright © 2021 International Association for the Study of Pain.

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