Fred Schwaller1, Simon Beggs, Suellen M Walker. 1. 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.).
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.
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: Praveen Anand; Ravikiran Shenoy; Joanne E Palmer; Amanda J Baines; Robert Y K Lai; Jonathan Robertson; Nick Bird; Thor Ostenfeld; Boris A Chizh Journal: Eur J Pain Date: 2011-05-14 Impact factor: 3.931
Authors: Suellen M Walker; Jacqueta Meredith-Middleton; Thomas Lickiss; Andrew Moss; Maria Fitzgerald Journal: Pain Date: 2006-10-23 Impact factor: 6.961
Authors: Vipin Arora; Thomas J Martin; Carol A Aschenbrenner; Kenichiro Hayashida; Susy A Kim; Renee A Parker; James C Eisenach; Christopher M Peters Journal: Neuroscience Date: 2018-04-22 Impact factor: 3.590
Authors: Adam J Dourson; Zachary K Ford; Kathryn J Green; Carolyn E McCrossan; Megan C Hofmann; Renita C Hudgins; Michael P Jankowski Journal: J Neurosci Date: 2021-04-22 Impact factor: 6.167
Authors: Xiaohua Liu; Kathryn J Green; Zachary K Ford; Luis F Queme; Peilin Lu; Jessica L Ross; Frank B Lee; Aaron T Shank; Renita C Hudgins; Michael P Jankowski Journal: Pain Date: 2017-02 Impact factor: 7.926
Authors: Nynke J van den Hoogen; Jacob Patijn; Dick Tibboel; Bert A Joosten; Maria Fitzgerald; Charlie H T Kwok Journal: Pain Date: 2018-06 Impact factor: 7.926