Modulation of breathing by μ1 and μ2 opioid receptor stimulation in neonatal and adult rats

Atalie S. Colman, John H. Miller
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引用次数: 30

Abstract

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 μ 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, μ 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 μ1 antagonist naloxonazine (NALZ). In the presence of NALZ, μ 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 μ1 and μ2 receptors contribute to opioid-induced respiratory depression during neonatal and adult life.

μ1和μ2阿片受体刺激对新生大鼠和成年大鼠呼吸的调节作用
研究了大鼠出生后发育至成年期间阿片类药物对呼吸的调节作用。采用气压体积描记仪记录未麻醉、不受约束的大鼠幼鼠和成年大鼠的呼吸频率、潮气量和分气量。受试者给予高选择性μ阿片受体激动剂dermorphin和芬太尼。芬太尼很容易穿过血脑屏障,它被包括在内是为了确保血脑屏障限制的发育变化不会掩盖一些老年新生儿的真吗啡效应。新生儿和成人皮下给药,而dermorphin仅在成人中通过脑室内途径给药。在新生儿中,μ激动剂引起类似喘气的呼吸模式,其特征是频率明显下降,潮气量增加较小。用长效μ1拮抗剂纳洛唑嗪(NALZ)预处理,可抑制喘息反应。在NALZ存在的情况下,μ激动剂仅引起小而显著的潮量减少。dermorphin和芬太尼在幼崽中都比在老年幼崽中表现出更强的活性,这可能是因为dermorphin的血脑屏障功能发育成熟。在成人中,芬太尼和真吗啡都引起频率和分钟容量的减少。NALZ可阻止成人对芬太尼的反应,而非dermorphin。这些结果表明,μ1和μ2受体都参与了新生儿和成年期阿片类药物诱导的呼吸抑制。
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