Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts
J Pharmacol Exp Ther. 2021 Aug;378(2):146-156. doi: 10.1124/jpet.121.000675. Epub 2021 May 21.
Potent synthetic opioids are an important cause of death in the United States' opioid epidemic, and a breathing stimulant may have utility in treating opioid overdose. We hypothesized that sufentanil-induced respiratory depression may be reversed by breathing stimulant administration. Using nose-only plethysmography and arterial blood analysis, we compared effects of several breathing stimulants in reversing sufentanil-induced respiratory depression in conscious rats. We studied taltirelin (1 mg/kg i.v.), PKTHPP (5 mg/kg i.v.), CX717 (30 mg/kg i.v.), BIMU8 (1 mg/kg i.v.), A85380 (30 μg/kg i.v.), and 8-hydroxy-2-(di-propylamino)tetralin (8-OH-DPAT) (150 μg/kg i.v./i.m.) and used sufentanil (10 μg/kg i.v.). By plethysmography (in % baseline, mean ± S.E.M.), taltirelin restored ventilation in sufentanil-treated rats (from 50 ± 5% to 102 ± 8%) by increased breathing rates (from 80 ± 4% to 160 ± 12%). By arterial blood analysis, however, taltirelin did not correct hypoxia, decreased hypercarbia only after 45 minutes, and worsened metabolic acidosis (base excess from +0 ± 1 to -7 ± 1 mEq/l). Additionally, taltirelin increased exhaled carbon dioxide, an estimate of oxygen consumption, by up to 64%. PKTHPP, CX717, BIMU8, and A85380 failed to significantly change ventilation or arterial blood values in sufentanil-treated rats. 8-OH-DPAT, however, improved ventilation (from 54 ± 8% to 92 ± 10%), reversed hypercarbia (from 64 ± 6 to 47 ± 2 mmHg), and shortened time to righting from 43 ± 4 to 15 ± 1 minutes in sufentanil-treated rats placed supine. Taltirelin has limited therapeutic potential, as its ventilatory effects are offset by metabolic acidosis, possibly from increased oxygen consumption. At the doses studied, PKTHPP, CX717, BIMU8, and A85380 have limited effects in reversing sufentanil-induced respiratory depression; 8-OH-DPAT, however, warrants further study. SIGNIFICANCE STATEMENT: Respiratory depression is an important cause of death after potent synthetic opioid overdose. 8-Hydroxy-2-(di-propylamino)tetralin or related compounds may be useful in treating respiratory depression as caused by potent synthetic opioids.
强效合成阿片类药物是美国阿片类药物流行中的一个重要死亡原因，呼吸兴奋剂可能在治疗阿片类药物过量方面具有一定效用。我们假设呼吸兴奋剂的使用可能会逆转舒芬太尼引起的呼吸抑制。我们使用鼻腔气流描记法和动脉血气分析，比较了几种呼吸兴奋剂在逆转清醒大鼠舒芬太尼引起的呼吸抑制中的作用。我们研究了他替瑞林（1mg/kg，静脉注射）、PKTHPP（5mg/kg，静脉注射）、CX717（30mg/kg，静脉注射）、BIMU8（1mg/kg，静脉注射）、A85380（30μg/kg，静脉注射）和 8-羟基-2-（二丙基氨基）四氢萘（8-OH-DPAT）（150μg/kg，静脉注射/肌肉注射），并使用舒芬太尼（10μg/kg，静脉注射）。通过气流描记法（以%基线为单位，平均值±S.E.M.），他替瑞林通过增加呼吸频率（从 80±4%到 160±12%）使舒芬太尼处理过的大鼠的通气得到恢复（从 50±5%到 102±8%）。然而，通过动脉血气分析，他替瑞林并未纠正低氧血症，仅在 45 分钟后才降低高碳酸血症，并使代谢性酸中毒恶化（碱剩余从+0±1 到-7±1mEq/L）。此外，他替瑞林使呼出的二氧化碳增加了 64%，这是氧气消耗的一个估算值。PKTHPP、CX717、BIMU8 和 A85380 未能显著改变舒芬太尼处理过的大鼠的通气或动脉血气值。然而，8-OH-DPAT 改善了通气（从 54±8%到 92±10%），逆转了高碳酸血症（从 64±6 到 47±2mmHg），并缩短了仰卧位舒芬太尼处理大鼠的翻正时间（从 43±4 到 15±1 分钟）。他替瑞林的治疗潜力有限，因为其通气作用被代谢性酸中毒抵消，这可能是由于耗氧量增加所致。在所研究的剂量下，PKTHPP、CX717、BIMU8 和 A85380 在逆转舒芬太尼引起的呼吸抑制方面作用有限；然而，8-OH-DPAT 值得进一步研究。意义声明：呼吸抑制是强力合成阿片类药物过量后的一个重要死亡原因。8-羟基-2-（二丙基氨基）四氢萘或相关化合物可能在治疗由强力合成阿片类药物引起的呼吸抑制方面具有一定作用。
