Glycosphingolipids involved in pain signaling: The contribution of sialic acids to mechanical allodynia

[Speaker] Shun Watanabe:1,2
[Co-author] Mami Sagawa:1,2, Motoki Morita:1,2, Natsumi Nomura:1,2, Misa Oayama:1,2, Takashi Iwai:1,2, Hideyoshi Higashi:3, Mitsuo Tanabe:1,2
1:Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Japan, 2:Medicinal Research Laboratories, School of Pharmacy, Kitasato University, Japan, 3:Division of Glyco-Signal Research Institute of Molecular Biomembrane and Glycobiology Tohoku Medical and Pharmaceutical University, Japan

The lipid bilayer consists of two-tailed lipids such as glycerophospholipids and sphingolipids that have the carbohydrate chain or phosphocholine as head group. There are the diverse species and tissue specific pattern of these carbohydrate chains, and nervous system has abundant sialyl conjugated glycosphingolipids. Sialyl conjugated glycosphingolipids are also known as gangliosides which are divided into four groups (o-, a-, b-, c-series gangliosides) based on the position and number of their sialic acids. Our previous study revealed that intraplantar injection of GT1b (b-series ganglioside) but not GM1a (a-series ganglioside) produced hyperalgesia against formalin and mechanical allodynia. Thus, it is suggested that sialyl residues are important in pain behavior.
We investigated whether sialyl conjugates in skin tissues are involved in the inflammatory pain. To cleave sialyl acids from sialyl conjugates, Arthrobacter ureafaciens sialidase were injected into the inflamed paw of ICR male mice 1 day after intraplantar injection of complete Freund's adjuvant (CFA). Sialidase reduced mechanical allodynia in the inflamed paw. Coincident with analgesic effects of sialidase, the morphology of nerve fibers in sialidase injected skin tissues was altered when compared with the vehicle injected inflamed paw. Next, we investigated the effects of sialidase on neurite morphology of F11 cells that are the dorsal root ganglia derived cell line. F11 cells were treated with forskolin to develop neurite and then sialidase was added to the culture medium. Sialidase reduced neurite length of F11 cells. Furthermore, the lipid analysis showed F11 cells with elongated neurites have abundant gangliosides when compared with no differentiated F11 cells. Several studies reported that inflammation leads to nerve fiber elongation in skin, which contribute to hyperalgesia and allodynia. These results suggested that sialidase affected the morphology of nerve fibers in skin, resulting in altered pain sensing.
qRT-PCR against glycosyltransferase genes revealed glycosphingolipids biosynthesis pathway in DRG and the spinal cord was altered in chronic and acute inflammatory pain (Morita M et al., presenting in this conference). Our present results and many previous studies that indicated gangliosides regulate neurite morphology suggested that upregulated glycosyltransferase in DRG contribute nerve fiber elongation observed in inflamed skin tissues.
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