Marsh Deborah, Dickenson Anthony, Hatch David, Fitzgerald Maria
Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK Department of Pharmacology, University College London, London WC1E6BT, UK Department of Anaesthesia, Institute of Child Heath, London WC1N 1EH, UK.
Pain. 1999 Jul;82(1):23-32. doi: 10.1016/S0304-3959(99)00028-7.
The aim of this study was to investigate the analgesic effects of epidural opioids in neonatal rat pups. The contribution of individual opioid receptor subtypes in the spinal cord to analgesia at different developmental stages was investigated using epidural mu (morphine sulphate), delta (DPDPE) and kappa (U69593) opioid receptor agonists in neonatal rats aged postnatal day (P) 3, 10 and 21. Thresholds for flexion withdrawal reflexes to mechanical stimuli (von Frey hairs) and to noxious heating of the hind paw were low in neonates and increased with postnatal age. The analgesic action of each opioid receptor agonist followed an individual developmental pattern. In mechanical tests, all three opioid agonists were considerably more efficacious analgesics in younger animals and ED50s at P3 were always lower than at P21. In heat tests, the pattern differed. The efficacy of the kappa opioid agonist decreased with postnatal age, morphine efficacy increased over the same period and the effects of the delta agonist remained relatively unchanged. The distribution and concentration of tritiated morphine in the spinal cord following epidural administration did not alter significantly with postnatal age, suggesting that opioid access is not a major determinant of the effects reported here. It is concluded that whereas heat pain is particularly sensitive to spinal kappa opioids in neonates, mechanical sensory thresholds are generally sensitive to all spinal opioids in the newborn. The differing epidural opioid requirements compared to older subjects is likely to be due to developmental changes in spinal cord opioid receptor distribution or pharmacology.
本研究的目的是调查硬膜外给予阿片类药物对新生大鼠幼崽的镇痛效果。使用硬膜外给予μ型（硫酸吗啡）、δ型（DPDPE）和κ型（U69593）阿片受体激动剂，研究了脊髓中各阿片受体亚型在不同发育阶段对镇痛的作用，实验对象为出生后第3天、10天和21天的新生大鼠。新生大鼠对机械刺激（von Frey毛发）和后爪有害热刺激的屈肌反射阈值较低，且随出生后年龄增加而升高。每种阿片受体激动剂的镇痛作用遵循个体发育模式。在机械测试中，所有三种阿片激动剂在较年幼动物中作为镇痛药的效果明显更好，出生后第3天的半数有效剂量（ED50）总是低于出生后第21天。在热测试中，情况有所不同。κ型阿片激动剂的效果随出生后年龄增加而降低，吗啡的效果在同一时期增加，而δ型激动剂的效果相对保持不变。硬膜外给药后，脊髓中氚标记吗啡的分布和浓度不会随出生后年龄而显著改变，这表明阿片类药物的进入不是此处报道效果的主要决定因素。得出的结论是，虽然热痛对新生大鼠脊髓中的κ型阿片类药物特别敏感，但机械感觉阈值通常对新生大鼠的所有脊髓阿片类药物都敏感。与年长个体相比，硬膜外阿片类药物需求的差异可能是由于脊髓阿片受体分布或药理学的发育变化。
