title: Inflammation triggers production of dimethylsphingosine from oligodendrocytes.
abstract: Neuropathic pain is a chronic, refractory condition that arises after damage to the nervous system. We previously showed that an increased level of the endogenous metabolite N,N-dimethylsphingosine (DMS) in the central nervous system (CNS) is sufficient to induce neuropathic pain-like behavior in rats. However, several important questions remain. First, it has not yet been demonstrated that DMS is produced in humans and its value as a therapeutic target is therefore unknown. Second, the cell types within the CNS that produce DMS are currently unidentified. Here we provide evidence that DMS is present in human CNS tissue. We show that DMS levels increase in demyelinating lesions isolated from patients with multiple sclerosis, an autoimmune disease in which the majority of patients experience chronic pain. On the basis of these results, we hypothesized that oligodendrocytes may be a cellular source of DMS. We show that human oligodendrocytes produce DMS in culture and that the levels of DMS increase when oligodendrocytes are challenged with agents that damage white matter. These results suggest that damage to oligodendrocytes leads to increased DMS production which in turn drives inflammatory astrocyte responses involved in sensory neuron sensitization. Interruption of this pathway in patients may provide analgesia without the debilitating side effects that are commonly observed with other chronic pain therapies.
authors.affiliation: Department of Chemistry, Washington University, St. Louis, MO 63130, United States; Department of Genetics, Washington University, St. Louis, MO 63130, United States; Department of Medicine, Washington University, St. Louis, MO 63130, United States.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States; Department of Biology, University of Akron, Akron, OH 44325, United States.
authors.forename: S
authors.initials: S
authors.lastname: Hill
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States; Department of Biology, University of Akron, Akron, OH 44325, United States.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States; Department of Biology, University of Akron, Akron, OH 44325, United States.
authors.forename: A
authors.initials: A
authors.lastname: Taraboletti
authors.affiliation: Department of Chemistry, Washington University, St. Louis, MO 63130, United States; Department of Genetics, Washington University, St. Louis, MO 63130, United States; Department of Medicine, Washington University, St. Louis, MO 63130, United States.
authors.forename: K
authors.initials: K
authors.lastname: Cho
authors.affiliation: Department of Chemistry, Washington University, St. Louis, MO 63130, United States; Department of Genetics, Washington University, St. Louis, MO 63130, United States; Department of Medicine, Washington University, St. Louis, MO 63130, United States.
authors.forename: R
authors.initials: R
authors.lastname: Gallo
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, United States. Electronic address: mmanchester@ucsd.edu.
authors.forename: M
authors.initials: M
authors.lastname: Manchester
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States; Department of Biology, University of Akron, Akron, OH 44325, United States. Electronic address: lshriver@uakron.edu.
authors.forename: L P
authors.initials: LP
authors.lastname: Shriver
authors.affiliation: Department of Chemistry, Washington University, St. Louis, MO 63130, United States; Department of Genetics, Washington University, St. Louis, MO 63130, United States; Department of Medicine, Washington University, St. Louis, MO 63130, United States. Electronic address: gjpattij@wustl.edu.
authors.forename: G J
authors.initials: GJ
authors.lastname: Patti
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology; D002460:Cell Line; D006801:Humans; D009103:Multiple Sclerosis / Q000276:immunology; D009836:Oligodendroglia / Q000276:immunology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C061800:N,N-dimethylsphingosine
keywords: astrocytes; dimethylsphingosine; metabolomics; multiple sclerosis; neuropathic pain; oligodendrocytes