title: Counter-regulation of opioid analgesia by glial-derived bioactive sphingolipids.
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 glial-related 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.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Muscoli
authors.forename: Tim
authors.initials: T
authors.lastname: Doyle
authors.forename: Concetta
authors.initials: C
authors.lastname: Dagostino
authors.forename: Leesa
authors.initials: L
authors.lastname: Bryant
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.forename: Jan
authors.initials: J
authors.lastname: Ryerse
authors.forename: Erhard
authors.initials: E
authors.lastname: Bieberich
authors.forename: William
authors.initials: W
authors.lastname: Neumman
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008246:Lysophospholipids / Q000502:physiology; D008297:Male; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013107:Sphingolipids / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D008246:Lysophospholipids; D013107:Sphingolipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine