Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids

Carolina Muscoli, Tim Doyle, Concetta Dagostino, Leesa Bryant, Zhoumou Chen, Linda R. Watkins, Jan Ryerse, Erhard Bieberich, William Neumman, Daniela Salvemini

Research output: Contribution to journalArticlepeer-review

Abstract

The clinical efficacy of opiates for pain control is severely limited by analgesic tolerance and hyperalgesia. Herein we show that chronic morphine upregulates both the sphingolipid ceramide in spinal astrocytes and microglia, but not neurons, and spinal sphingosine-1-phosphate (S1P), the end-product of ceramide metabolism. Coadministering morphine with intrathecal administration of pharmacological inhibitors of ceramide and S1P blocked formation of spinal S1P and development of hyperalgesia and tolerance in rats. Our results show that spinally formed S1P signals at least in part by (1) modulating glial function because inhibiting S1P formation blocked increased formation of glial-related proinflammatory cytokines, in particular tumor necrosis factor-α, interleukin-1βα, and interleukin-6, which are known modulators of neuronal excitability, and (2) peroxynitrite-mediated posttranslational nitration and inactivation of glialrelated enzymes (glutamine synthetase and the glutamate transporter) known to play critical roles in glutamate neurotransmission. Inhibitors of the ceramide metabolic pathway may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain.

Original languageEnglish
Pages (from-to)15400-15408
Number of pages9
JournalJournal of Neuroscience
Volume30
Issue number46
DOIs
Publication statusPublished - Nov 17 2010

ASJC Scopus subject areas

  • Neuroscience(all)

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