title: Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype.
abstract: Blockade of prostaglandin (PG) production by COX inhibitors is the treatment of choice for inflammatory pain but is also prone to severe side effects. Identification of signaling elements downstream of COX inhibition, particularly of PG receptor subtypes responsible for pain sensitization (hyperalgesia), provides a strategy for better-tolerated analgesics. Here, we have identified PGE2 receptors of the EP2 receptor subtype as key signaling elements in spinal inflammatory hyperalgesia. Mice deficient in EP2 receptors (EP2-/- mice) completely lack spinal PGE2-evoked hyperalgesia. After a peripheral inflammatory stimulus, EP2-/- mice exhibit only short-lasting peripheral hyperalgesia but lack a second sustained hyperalgesic phase of spinal origin. Electrophysiological recordings identify diminished synaptic inhibition of excitatory dorsal horn neurons as the dominant source of EP2 receptor-dependent hyperalgesia. Our results thus demonstrate that inflammatory hyperalgesia can be treated by targeting of a single PG receptor subtype and provide a rational basis for new analgesic strategies going beyond COX inhibition.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Reinold
authors.forename: Seifollah
authors.initials: S
authors.lastname: Ahmadi
authors.forename: Ulrike B
authors.initials: UB
authors.lastname: Depner
authors.forename: Beate
authors.initials: B
authors.lastname: Layh
authors.forename: Cornelia
authors.initials: C
authors.lastname: Heindl
authors.forename: May
authors.initials: M
authors.lastname: Hamza
authors.forename: Andreas
authors.initials: A
authors.lastname: Pahl
authors.forename: Kay
authors.initials: K
authors.lastname: Brune
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Ulrike
authors.initials: U
authors.lastname: Müller
authors.forename: Hanns Ulrich
authors.initials: HU
authors.lastname: Zeilhofer
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005260:Female; D005998:Glycine / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000276:immunology* / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000378:metabolism; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000008:administration & dosage / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005998:Glycine
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