Colman A S, Miller J H
School of Biological Sciences, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand.
Respir Physiol. 2001 Sep;127(2-3):157-72. doi: 10.1016/s0034-5687(01)00240-7.
Opioid modulation of breathing during postnatal development through to the adult was investigated in the rat. Respiratory frequency, tidal volume and minute volume were recorded in unanesthetized, unrestrained rat pups and adults using barometric plethysmography. Subjects were administered the highly selective mu opioid agonists dermorphin and fentanyl. Fentanyl, which readily crosses the blood-brain barrier, was included to ensure that developmental changes in blood-brain barrier restrictions did not mask some of the dermorphin effects in older neonates. Drugs were administered subcutaneously in neonates and adults, although dermorphin was given by intracerebroventricular route only in adults. In neonates, mu agonist administration caused a gasping-like pattern of breathing, characterized by a marked fall in frequency and a smaller increase in tidal volume. The gasping response was prevented by pre-treatment with the long-acting mu1 antagonist naloxonazine (NALZ). In the presence of NALZ, mu agonists elicited only a small, but significant, reduction in tidal volume. Both dermorphin and fentanyl showed more potent activity in younger pups than in older pups, possibly in the case of dermorphin because of developmental maturation of blood-brain barrier function. In adults, fentanyl and dermorphin both caused a reduction in frequency and minute volume. The response of adults to fentanyl, but not dermorphin, was prevented by NALZ. These results suggest that both mu1 and mu2 receptors contribute to opioid-induced respiratory depression during neonatal and adult life.
在大鼠中研究了从出生后发育直至成年期阿片类药物对呼吸的调节作用。使用气压体积描记法在未麻醉、未束缚的幼鼠和成年大鼠中记录呼吸频率、潮气量和分钟通气量。给实验对象施用高选择性μ阿片受体激动剂德莫啡肽和芬太尼。纳入容易穿过血脑屏障的芬太尼，以确保血脑屏障限制的发育变化不会掩盖德莫啡肽对较大新生儿的某些作用。药物通过皮下注射给予新生儿和成年大鼠，不过德莫啡肽仅通过脑室内途径给予成年大鼠。在新生儿中，施用μ激动剂会导致一种类似喘息的呼吸模式，其特征是频率显著下降，潮气量有较小增加。长效μ1拮抗剂纳洛嗪（NALZ）预处理可预防喘息反应。在存在NALZ的情况下，μ激动剂仅引起潮气量有小幅但显著的减少。德莫啡肽和芬太尼在较年幼的幼鼠中均表现出比在较年长的幼鼠中更强的活性，就德莫啡肽而言，这可能是由于血脑屏障功能的发育成熟。在成年大鼠中，芬太尼和德莫啡肽均导致频率和分钟通气量降低。成年大鼠对芬太尼的反应可被NALZ阻断，但对德莫啡肽的反应则不能。这些结果表明，μ1和μ2受体在新生儿期和成年期均参与阿片类药物诱导的呼吸抑制。
