Schwaller Fred, Beggs Simon, Walker Suellen M
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.).
Anesthesiology. 2015 Jun;122(6):1377-90. doi: 10.1097/ALN.0000000000000659.
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.
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.
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.
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.
新生儿手术损伤会引发发育调控的长期变化，包括再次受伤后痛觉过敏增强和脊髓小胶质细胞反应性增强。为了进一步评估新生儿后爪切口引发的反应，作者研究了成年啮齿动物再次切口后脊髓小胶质细胞p38丝裂原活化蛋白激酶的功能作用。
在麻醉的成年大鼠中进行足底后爪切口，部分大鼠在出生后第3天曾有过切口。比较成年或新生儿加成年切口后，腰段背角中磷酸化p38（1、3、24小时）和磷酸化细胞外信号调节激酶（15分钟、24小时）免疫反应性细胞的数量和分布。通过鞘内注射SB203850抑制p38来评估切口诱导的痛觉过敏的逆转情况，以此评估撤药阈值。
新生儿损伤显著增加了成年大鼠切口后3小时的磷酸化p38表达（每切片55±4个细胞对35±4个细胞，平均值±标准误，n = 6至7，P < 0.01）。表达增加仅限于小胶质细胞，在整个腰段均有维持，且在1小时和24小时时也很明显。术前鞘内注射SB203850可预防有新生儿损伤史的成年大鼠机械性痛觉过敏增强，且在较低剂量（0.2对1 mg/kg，n = 8，P < 0.05）和较长时间（10对3天）时有效。腰段神经元磷酸化细胞外信号调节激酶表达反映了后爪初级传入纤维的分布，但术前切口对其无显著影响。
新生儿切口引发脊髓神经胶质信号，成年大鼠再次切口揭示了中枢介导的功能性小胶质细胞反应性增加和持续性痛觉过敏。早年受伤后，p38抑制剂作为多模式镇痛方案的一部分，可能具有特定益处，可降低术后持续性疼痛的风险。
