title: Prostanoid receptor EP1 and Cox-2 in injured human nerves and a rat model of nerve injury: a time-course study.
abstract: BACKGROUND
  Recent studies show that inflammatory processes may contribute to neuropathic pain. Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for production of prostanoids, which may sensitise sensory neurones via the EP1 receptor. We have recently reported that while macrophages infiltrate injured nerves within days of injury, they express increased Cox-2-immunoreactivity (Cox-2-IR) from 2 to 3 weeks after injury. We have now investigated the time course of EP1 and Cox-2 changes in injured human nerves and dorsal root ganglia (DRG), and the chronic constriction nerve injury (CCI) model in the rat.
  
  
  METHODS
  Tissue sections were immunostained with specific antibodies to EP1, Cox-2, CD68 (human macrophage marker) or OX42 (rat microglial marker), and neurofilaments (NF), prior to image analysis, from the following: human brachial plexus nerves (21 to 196 days post-injury), painful neuromas (9 days to 12 years post-injury), avulsion injured DRG, control nerves and DRG, and rat CCI model tissues. EP1 and NF-immunoreactive nerve fibres were quantified by image analysis.
  
  
  RESULTS
  EP1:NF ratio was significantly increased in human brachial plexus nerve fibres, both proximal and distal to injury, in comparison with uninjured nerves. Sensory neurones in injured human DRG showed a significant acute increase of EP1-IR intensity. While there was a rapid increase in EP1-fibres and CD-68 positive macrophages, Cox-2 increase was apparent later, but was persistent in human painful neuromas for years. A similar time-course of changes was found in the rat CCI model with the above markers, both in the injured nerves and ipsilateral dorsal spinal cord.
  
  
  CONCLUSIONS
  Different stages of infiltration and activation of macrophages may be observed in the peripheral and central nervous system following peripheral nerve injury. EP1 receptor level increase in sensory neurones, and macrophage infiltration, appears to precede increased Cox-2 expression by macrophages. However, other methods for detecting Cox-2 levels and activity are required. EP1 antagonists may show therapeutic effects in acute and chronic neuropathic pain, in addition to inflammatory pain.
authors.affiliation: Peripheral Neuropathy Unit, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. p.durrenberger@imperial.ac.uk
authors.forename: Pascal F
authors.initials: PF
authors.lastname: Durrenberger
authors.forename: Paul
authors.initials: P
authors.lastname: Facer
authors.forename: Maria A
authors.initials: MA
authors.lastname: Casula
authors.forename: Yiangos
authors.initials: Y
authors.lastname: Yiangou
authors.forename: Roy A
authors.initials: RA
authors.lastname: Gray
authors.forename: Iain P
authors.initials: IP
authors.lastname: Chessell
authors.forename: Nicola C
authors.initials: NC
authors.lastname: Day
authors.forename: Sue D
authors.initials: SD
authors.lastname: Collins
authors.forename: Sharon
authors.initials: S
authors.lastname: Bingham
authors.forename: Alex W
authors.initials: AW
authors.lastname: Wilson
authors.forename: David
authors.initials: D
authors.lastname: Elliot
authors.forename: Rolfe
authors.initials: R
authors.lastname: Birch
authors.forename: Praveen
authors.initials: P
authors.lastname: Anand
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001917:Brachial Plexus / Q000276:immunology / Q000293:injuries*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009380:Neoplasms, Nerve Tissue / Q000276:immunology / Q000378:metabolism; D009463:Neuroma / Q000276:immunology / Q000378:metabolism; D009475:Neurons, Afferent / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D012584:Sciatic Nerve / Q000276:immunology / Q000293:injuries*; D012585:Sciatica / Q000276:immunology / Q000378:metabolism
chemical_list: C545635:PTGER1 protein, human; C545637:Ptger1 protein, rat; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D051546:Cyclooxygenase 2