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 WC1E 6BT, UK Department of Anaesthesia, Institute of Child Heath, London WC1N 1EH, UK.
Pain. 1999 Jul;82(1):33-38. doi: 10.1016/S0304-3959(99)00029-9.
The aim of this study was to investigate the analgesic effects of epidural opioids upon persistent pain sensitivity in neonatal rat pups. Two models of persistent pain were used, subcutaneous injection of carrageenan, and topical application of capsaicin cream, both to the hind paw. The contribution of individual opioid receptor subtypes in the spinal cord to analgesia were tested at different developmental stages using epidural mu (morphine sulphate), delta (DPDPE) and kappa (U69593) opioid receptor agonists in neonatal rats aged P (postnatal day) 3, 10 and 21. Rat pups at all three ages displayed a reduction in mechanical (von Frey hair) threshold following carrageenan-induced inflammation of the hind paw that was evident at 3 h and was still present 5 h after application. This effect was greatest in magnitude at P21. This response was blocked by low doses of all three agonists at all ages, relative effectiveness varying with age. Comparison with potencies in acute tests (Marsh, D., Dickenson, A., Hatch, D. and Fitzgerald, M., Epidural opioid analgesia in infant rats I: mechanical and heat responses, Pain 82 (1999) 23-32) show that opioid potency is significantly greater in the presence of carrageenan inflammation at all ages. Topical capsaicin application to the hind paw produced a significant fall in withdrawal latencies to noxious heat. Generally, epidural opioid agonists did not block this C-fibre induced sensitization except at P3, when morphine and DPDPE did prevent the fall in threshold in a dose dependent manner. The results show that newborn rat pups are capable of displaying both allodynia and hyperalgesia following experimental inflammation that is blocked by epidural mu, delta and kappa opioids. The opioid potency is enhanced compared with antinociception in acute tests. This is not observed following capsaicin hyperalgesia and is therefore not a general consequence of C fibre induced increases in central excitability but relies upon mechanisms special to inflammatory pain.
本研究的目的是调查硬膜外给予阿片类药物对新生大鼠持续性疼痛敏感性的镇痛作用。使用了两种持续性疼痛模型，即在后爪皮下注射角叉菜胶和局部涂抹辣椒素乳膏。在出生后第3天、第10天和第21天的新生大鼠中，使用硬膜外给予μ（硫酸吗啡）、δ（DPDPE）和κ（U69593）阿片受体激动剂，在不同发育阶段测试脊髓中各阿片受体亚型对镇痛的贡献。所有三个年龄段的幼鼠在角叉菜胶诱导后爪炎症后，机械（von Frey毛发）阈值均降低，在3小时时明显，用药后5小时仍存在。这种效应在P21时最为显著。所有年龄段低剂量的三种激动剂均可阻断这种反应，相对效力随年龄而异。与急性试验中的效价比较（Marsh, D., Dickenson, A., Hatch, D. and Fitzgerald, M., Epidural opioid analgesia in infant rats I: mechanical and heat responses, Pain 82 (1999) 23 - 32）表明，在所有年龄段，角叉菜胶炎症存在时阿片类药物的效价显著更高。在后爪局部涂抹辣椒素会使对有害热刺激的撤针潜伏期显著缩短。一般来说，硬膜外阿片受体激动剂不会阻断这种C纤维诱导的敏化作用，除非在P3时，吗啡和DPDPE确实以剂量依赖的方式阻止了阈值下降。结果表明，新生大鼠幼崽在实验性炎症后能够表现出痛觉过敏和痛觉超敏，硬膜外给予μ、δ和κ阿片类药物可阻断这种反应。与急性试验中的抗伤害感受相比，阿片类药物的效价有所增强。辣椒素诱导的痛觉超敏后未观察到这种情况，因此这不是C纤维诱导的中枢兴奋性增加的普遍结果，而是依赖于炎症性疼痛特有的机制。
