title: Targeting p38 Mitogen-activated Protein Kinase to Reduce the Impact of Neonatal Microglial Priming on Incision-induced Hyperalgesia in the Adult Rat.
abstract: BACKGROUND
  Neonatal surgical injury triggers developmentally regulated long-term changes that include enhanced hyperalgesia and spinal microglial reactivity after reinjury. To further evaluate priming of response by neonatal hindpaw incision, the authors investigated the functional role of spinal microglial p38 mitogen-activated protein kinase after reincision in adult rodents.
  
  
  METHODS
  Plantar hindpaw incision was performed in anesthetized adult rats, with or without previous incision on postnatal day 3. Numbers and distribution of phosphorylated-p38 (1, 3, 24 h) and phosphorylated extracellular signal-regulated kinase (15 min, 24 h) immunoreactive cells in the lumbar dorsal horn were compared after adult or neonatal plus adult incision. Withdrawal thresholds evaluated reversal of incision-induced hyperalgesia by p38 inhibition with intrathecal SB203850.
  
  
  RESULTS
  Neonatal injury significantly increased phosphorylated-p38 expression 3 h after adult incision (55 ± 4 vs. 35 ± 4 cells per section, mean ± SEM, n = 6 to 7, P < 0.01). Increased expression was restricted to microglia, maintained across lumbar segments, and also apparent at 1 and 24 h. Preincision intrathecal SB203850 prevented the enhanced mechanical hyperalgesia in adults with previous neonatal injury and was effective at a lower dose (0.2 vs. 1 mg/kg, n = 8, P < 0.05) and for a longer duration (10 vs. 3 days). Lumbar neuronal phosphorylated extracellular signal-regulated kinase expression reflected the distribution of hindpaw primary afferents, but was not significantly altered by previous incision.
  
  
  CONCLUSIONS
  Neonatal incision primes spinal neuroglial signaling, and reincision in adult rats unmasks centrally mediated increases in functional microglial reactivity and persistent hyperalgesia. After early life injury, p38 inhibitors may have specific benefit as part of multimodal analgesic regimes to reduce the risk of persistent postsurgical pain.
authors: From Pain Research (Respiratory Critical Care and Anaesthesia), UCL Institute of Child Health and Department of Anaesthesia and Pain Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom (F.S., S.M.W.); Neuroscience, Physiology and Pharmacology, UCL, London, United Kingdom (F.S., S.M.W.); and the Program in Neurosciences and Mental Health, The Hospital for Sick Children and Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada (S.B.).
authors: Fred
authors: F
authors: Schwaller
authors: Simon
authors: S
authors: Beggs
authors: Suellen M
authors: SM
authors: Walker
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005528:Foot / Q000601:surgery; D018409:Foot Injuries / Q000473:pathology*; D006930:Hyperalgesia / Q000473:pathology*; D007278:Injections, Spinal; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D017628:Microglia / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*
chemical_list: D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases