BACKGROUND Recent studies showed partial reversal of opioid-induced respiratory depression in the pre-Bötzinger complex and the parabrachial nucleus/Kölliker-Fuse complex. The hypothesis for this study was that opioid antagonism in the parabrachial nucleus/Kölliker-Fuse complex plus pre-Bötzinger complex completely reverses respiratory depression from clinically relevant opioid concentrations. METHODS Experiments were performed in 48 adult, artificially ventilated, decerebrate rabbits. The authors decreased baseline respiratory rate ~50% with intravenous, "analgesic" remifentanil infusion or produced apnea with remifentanil boluses and investigated the reversal with naloxone microinjections (1 mM, 700 nl) into the Kölliker-Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex. In another group of animals, naloxone was injected only into the pre-Bötzinger complex to determine whether prior parabrachial nucleus/Kölliker-Fuse complex injection impacted the naloxone effect. Last, the µ-opioid receptor agonist [d-Ala,2N-MePhe,4Gly-ol]-enkephalin (100 μM, 700 nl) was injected into the parabrachial nucleus/Kölliker-Fuse complex. The data are presented as medians (25 to 75%). RESULTS Remifentanil infusion reduced the respiratory rate from 36 (31 to 40) to 16 (15 to 21) breaths/min. Naloxone microinjections into the bilateral Kölliker-Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex increased the rate to 17 (16 to 22, n = 19, P = 0.005), 23 (19 to 29, n = 19, P < 0.001), and 25 (22 to 28) breaths/min (n = 11, P < 0.001), respectively. Naloxone injection into the parabrachial nucleus/Kölliker-Fuse complex prevented apnea in 12 of 17 animals, increasing the respiratory rate to 10 (0 to 12) breaths/min (P < 0.001); subsequent pre-Bötzinger complex injection prevented apnea in all animals (13 [10 to 19] breaths/min, n = 12, P = 0.002). Naloxone injection into the pre-Bötzinger complex alone increased the respiratory rate to 21 (15 to 26) breaths/min during analgesic concentrations (n = 10, P = 0.008) but not during apnea (0 [0 to 0] breaths/min, n = 9, P = 0.500). [d-Ala,2N-MePhe,4Gly-ol]-enkephalin injection into the parabrachial nucleus/Kölliker-Fuse complex decreased respiratory rate to 3 (2 to 6) breaths/min. CONCLUSIONS Opioid reversal in the parabrachial nucleus/Kölliker-Fuse complex plus pre-Bötzinger complex only partially reversed respiratory depression from analgesic and even less from "apneic" opioid doses. The lack of recovery pointed to opioid-induced depression of respiratory drive that determines the activity of these areas. EDITOR’S PERSPECTIVE

中文翻译：

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瑞芬太尼在兔臂旁核/Kölliker-Fuse 复合体和 Pre-Bötzinger 复合体中的剂量依赖性呼吸抑制。

背景 最近的研究表明，在前 Bötzinger 复合体和臂旁核/Köllliker-Fuse 复合体中，阿片类药物诱导的呼吸抑制部分逆转。本研究的假设是臂旁核/Kölliker-Fuse 复合物加上 pre-Bötzinger 复合物中的阿片样物质拮抗作用完全逆转了临床相关阿片样物质浓度的呼吸抑制。方法 在 48 只成年、人工通风、去大脑的兔子中进行实验。作者通过静脉内“镇痛”瑞芬太尼输注或使用瑞芬太尼丸剂产生呼吸暂停降低了约 50% 的基线呼吸频率，并研究了将纳洛酮微量注射（1 mM，700 nl）到 Köllliker-Fuse 核、臂旁核和预Bötzinger 情结。在另一组动物中，仅将纳洛酮注射到 pre-Bötzinger 复合物中以确定先前的臂旁核/Kölliker-Fuse 复合物注射是否影响纳洛酮效应。最后，将μ-阿片受体激动剂 [d-Ala,2N-MePhe,4Gly-ol]-脑啡肽 (100 μM, 700 nl) 注射到臂旁核/Kölliker-Fuse 复合物中。数据表示为中位数（25% 至 75%）。结果 瑞芬太尼输注将呼吸频率从 36 次（31 至 40 次）降至 16 次（15 至 21 次/分钟）。纳洛酮显微注射到双侧 Köllliker-Fuse 核、臂旁核和 pre-Bötzinger 复合体中的比率增加到 17（16 至 22，n = 19，P = 0.005）、23（19 至 29，n = 19，P < 0.001 ) 和 25 (22 至 28) 次呼吸/分钟 (n = 11, P < 0.001)。将纳洛酮注射入臂旁核/Kölliker-Fuse 复合体可预防 17 只动物中的 12 只呼吸暂停，将呼吸频率提高到 10（0 至 12）次/分钟（P < 0.001）；随后的 pre-Bötzinger 复合物注射预防了所有动物的呼吸暂停（13 [10 至 19] 次呼吸/分钟，n = 12，P = 0.002）。在镇痛药浓度期间（n = 10，P = 0.008），仅将纳洛酮注射到 pre-Bötzinger 复合物中，呼吸频率增加到 21（15 到 26）次呼吸/分钟，但在呼吸暂停期间（0 [0 到 0] 次呼吸/分钟， n = 9，P = 0.500）。[d-Ala,2N-MePhe,4Gly-ol]-脑啡肽注入臂旁核/Köllliker-Fuse 复合物后，呼吸频率降至 3（2 至 6）次/分钟。结论 臂旁核/Köllliker-Fuse 复合物加 pre-Bötzinger 复合物中的阿片类药物逆转仅部分逆转了镇痛药引起的呼吸抑制，而“呼吸暂停”阿片类药物剂量则更少。缺乏恢复表明阿片类药物引起的呼吸驱动抑制决定了这些区域的活动。编辑观点