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- For Pain Patients and Professionals
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.