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Jan 24, 2012

Upregulated Metabolite May Be Target for Neuropathic Pain Therapy

  • Blocking overproduction of the metabolite N,N-dimethylsphingosine (DMS) in the spinal cord could feasibly represent a therapeutic option for treating neuropathic pain, researchers claim. A team at Washington University School of Medicine, St. Louis, and The Scripps Research Institute used an MS-based metabolomics approaches to compare metabolite levels in specific tissues of tibial nerve-transacted (TNT) experimental rats and sham-operated control rats. Tissues analyzed included spinal cord dorsal horn and dorsal root ganglia, damaged tibial nerve, and blood plasma.

    Their results, reported in Nature Chemical Biology by Gary Siuzdak, Ph.D., and colleagues, demonstrated that 94% of metabolite differences between TNT rats and control rats occurred in the ipsilateral dorsal horn, rather than in the damaged nerve itself. When the team further characterized dysregulated metabolites in the dorsal horn tissue, they identified multiple alterations in sphingomyelin-ceramide metabolism 21 days after TNT injury. “We therefore hypothesized that dysregulated metabolites in this pathway may be linked to the physiological changes underlying neuropathic pain and represent possible new targets for therapeutic intervention,” they state.

    The changes in dorsal horn metabolite concentrations were consistent with degradation of sphingomyelin, and included significant upregulation of DMS, which hasn’t previously been investigated in the context of neuropathic pain, the authors add. Of significant interest was the finding that intrathecal injections of DMS in healthy rats led to the animals developing mechanical allodynia (pain resulting from a stimulus that wouldn’t normally be painful) in the hind paw. This effect occurred at injected concentrations of DMS that resulted in similar dorsal horn levels of the metabolite that were found in the TNT experimental mice.

    Additional immunohistochemical and ELISA assays indicated that DMS treatment triggered an increase in astrocyte activation, and the release by astrocytes of IL-1β, levels of which are already known to be elevated in the cerebrospinal fluid of patients with chronic pain. In vitro studies also showed that astrocytes treated with DMS release monocyte chemoattractant protein-1 (MCP-1), which recruits inflammatory cells to sites of injury and is also upregulated in spinal cord astrocytes after nerve injury.

    Previous work has implicated another ceramide derivative, sphingosine-1-phosphate (S1P) in nociceptive processing, and DMS effectively blocks production of S1P by inhibiting the enzyme sphingosine kinase. However, the investigators found no differences in S1P concentrations between the DMS-treated allodynic rats and control rats, or between TNT and sham-operated rats. These results demonstrate that DMS doesn’t inhibit sphingosine kinase at physiological concentrations, and support the notion that the metabolite sensitizes neurons in the CNS via an alternate mechanism that hasn’t yet been identified.

    “The data presented here show that DMS, an endogenous metabolite that has not been previously implicated in nociception, induces mechanical allodynia in rats in vivo and elicits cytokine release from astrocytes in vitro,” they conclude. “Further investigation is needed to determine the specific enzymes responsible for DMS biosynthesis...Our results therefore suggest that inhibition of endogenous DMS production, with a methyltransferase or ceramidase inhibitor, for example, may be an attractive therapeutic candidate to treat this debilitating condition.”

    Dr. Siuzdak et al’s published paper is titled “Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin.”


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