A Comparison of Breathing Stimulants for Reversal of Synthetic Opioid-Induced Respiratory Depression in Conscious Rats

Abstract

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-n-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-n-propylamino)tetralin or related compounds may be useful in treating respiratory depression as caused by potent synthetic opioids.