title: Prostacyclin regulates spinal nociceptive processing through cyclic adenosine monophosphate-induced translocation of glutamate receptors.
abstract: BACKGROUND
  Prostacyclin (PGI2) is known to be an important mediator of peripheral pain sensation (nociception) whereas little is known about its role in central sensitization.
  
  
  METHODS
  The levels of the stable PGI2-metabolite 6-keto-prostaglandin F1α (6-keto-PGF1α) and of prostaglandin E2 (PGE2) were measured in the dorsal horn with the use of mass spectrometry after peripheral inflammation. Expression of the prostanoid receptors was determined by immunohistology. Effects of prostacyclin receptor (IP) activation on spinal neurons were investigated with biochemical assays (cyclic adenosine monophosphate-, glutamate release-measurement, Western blot analysis) in embryonic cultures and adult spinal cord. The specific IP antagonist Cay10441 was applied intrathecally after zymosan-induced mechanical hyperalgesia in vivo.
  
  
  RESULTS
  Peripheral inflammation caused a significant increase of the stable PGI2 metabolite 6-keto-PGF1α in the dorsal horn of wild-type mice (n = 5). IP was located on spinal neurons and did not colocalize with the prostaglandin E2 receptors EP2 or EP4. The selective IP-agonist cicaprost increased cyclic adenosine monophosphate synthesis in spinal cultures from wild-type but not from IP-deficient mice (n = 5-10). The combination of fluorescence-resonance-energy transfer-based cyclic adenosine monophosphate imaging and calcium imaging showed a cicaprost-induced cyclic adenosine monophosphate synthesis in spinal cord neurons (n = 5-6). Fittingly, IP activation increased glutamate release from acute spinal cord sections of adult mice (n = 13-58). Cicaprost, but not agonists for EP2 and EP4, induced protein kinase A-dependent phosphorylation of the GluR1 subunit and its translocation to the membrane. Accordingly, intrathecal administration of the IP receptor antagonist Cay10441 had an antinociceptive effect (n = 8-11).
  
  
  CONCLUSIONS
  Spinal prostacyclin synthesis during early inflammation causes the recruitment of GluR1 receptors to membrane fractions, thereby augmenting the onset of central sensitization.
authors: From the Institute of Clinical Pharmacology, pharmazentrum Frankfurt/ZAFES, Hospital of the Goethe-University, Frankfurt, Germany.
authors: Claus Dieter
authors: CD
authors: Schuh
authors: Christian
authors: C
authors: Brenneis
authors: Dong Dong
authors: DD
authors: Zhang
authors: Carlo
authors: C
authors: Angioni
authors: Yannick
authors: Y
authors: Schreiber
authors: Nerea
authors: N
authors: Ferreiros-Bouzas
authors: Sandra
authors: S
authors: Pierre
authors: Marina
authors: M
authors: Henke
authors: Bona
authors: B
authors: Linke
authors: Rolf
authors: R
authors: Nüsing
authors: Klaus
authors: K
authors: Scholich
authors: Gerd
authors: G
authors: Geisslinger
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000502:physiology*; D000939:Epitopes; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D059225:Nociception / Q000502:physiology*; D010146:Pain / Q000523:psychology; D011247:Pregnancy; D044062:Prostaglandins I / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D053719:Tandem Mass Spectrometry; D014178:Translocation, Genetic
chemical_list: D002118:Calcium; D000242:Cyclic AMP; D000939:Epitopes; D044062:Prostaglandins I; D018091:Receptors, AMPA; D058307:Receptors, Prostaglandin E, EP2 Subtype