RT Journal Article
SR Electronic
T1 Counter-Regulation of Opioid Analgesia by Glial-Derived Bioactive Sphingolipids
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 15400
OP 15408
DO 10.1523/JNEUROSCI.2391-10.2010
VO 30
IS 46
A1 Carolina Muscoli
A1 Tim Doyle
A1 Concetta Dagostino
A1 Leesa Bryant
A1 Zhoumou Chen
A1 Linda R. Watkins
A1 Jan Ryerse
A1 Erhard Bieberich
A1 William Neumman
A1 Daniela Salvemini
YR 2010
UL http://www.jneurosci.org/content/30/46/15400.abstract
AB 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.