Pi3k Gamma/Akt Signaling In High Molecular Weight Hyaluronan (Hmwh)-Induced Anti-Hyperalgesia And Reversal Of Nociceptor Sensitization

High molecular weight hyaluronan (HMWH), a well-established treatment for osteoarthritis pain, is anti-hyperalgesic in preclinical models of inflammatory and neuropathic pain. HMWH-induced anti-hyperalgesia is mediated by its action at cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, which can signal via phosphoinositide 3-kinase (PI3K), a large family of kinases involved in diverse cell functions. We demonstrate that intrathecal administration of an oligodeoxynucleotide (ODN) antisense to mRNA for PI3K gamma (a Class I PI3K isoform) expressed in dorsal root ganglia (DRGs), and intradermal administration of a PI3K gamma-selective inhibitor (AS605240), markedly attenuates HMWH-induced anti-prostaglandin E-2 (PGE(2)) hyperalgesia, in male and female rats. Intradermal administration of inhibitors of mammalian target of rapamycin (mTOR; rapamycin) and protein kinase B (AKT; AKT Inhibitor IV), signaling molecules downstream of PI3K gamma, also attenuates HMWH-induced anti-hyperalgesia. In vitro patch-clamp electrophysiology experiments on cultured nociceptors from male rats demonstrate that some HMWH-induced changes in generation of action potentials (APs) in nociceptors sensitized by PGE(2) are PI3K gamma dependent (reduction in AP firing rate, increase in latency to first AP and increase in slope of current ramp required to induce AP) and some are PI3K gamma independent [reduction in recovery rate of AP afterhyperpolarization (AHP)]. Our demonstration of a role of PI3K gamma in HMWH-induced anti-hyperalgesia and reversal of nociceptor sensitization opens a novel line of research into molecular targets for the treatment of diverse pain syndromes.