Sialic acid–containing glycosphingolipids: functional roles of gangliosides in pain signaling

Abstract

Gangliosides are sialic acid–containing glycosphingolipids that vary greatly in their glyco–chains and are present in biomembranes. Gangliosides are classified into four groups (asialo–, a–, b–, c–series) based on their biosynthetic pathway and on the number of sialic acids present on galactose residues in the second position from the ceramide. Complex gangliosides —gangliosides containing long glycol–chains— are especially abundant in neural tissues, suggesting that they are involved in neural functions such as axonal outgrowth, the preservation of myelin, and neural transmission.

We observed that intraplantar injection of GT1b ganglioside (b–series complex ganglio­side) induces nociceptive behavior, hyperalgesia against 0.05% formalin, and mechanical allodynia. This hyperalgesia is blocked by NMDA receptor antagonists or mGluR1 antagonists, and is suppressed by co–injection of glutamate dehydrogenase. 　Furthermore, GT1b raises glutamate concentration in skin. These results suggest that hyperalgesia results from the GT1b–enhanced elevation of glutamate in skin. This led us to hypothesize that gangliosides modulate pain signaling by regulating glutamate accumulation in skin. Interestingly, a–series gangliosides have no effect on nociceptive behavior. We surmised that this difference that are related to the different positions of sialic acid in a– and b–series gangliosides. Thus, we investigated whether sialidase, an enzyme that removes a–linked sialic acid residues from oligosaccharides, affects nociceptive behavior in a mouse inflammatory pain model produced by intraplantar injections of complete Freund’s adjuvant. Arthrobacter ureafaciens sialidase injection into inflamed paws reduced mechanical allodynia, whereas injection of heat–inactivated enzyme did not. This supports our hypothesis that sialic acid conjugates (e.g., gangliosides) in skin are involved in pain signaling. Although the mechanism by which GT1b regulates skin glutamate concentrations remains unclear, it may involve the formation of lipid rafts in membranes. Many studies report that sphingolipids, including ganglio­sides, form lipid rafts in membranes that regulate protein–protein interactions, which in turn produce changes in intracellular signal transduction, protein localization, and vesicular transport. Future studies are required to clarify how gangliosides regulate glutamate concentration via the lipid raft theory. Gangliosides might receive more attention in the future as potential therapeutic targets for pain management, because of their relationship with pain signaling.