RT Journal Article
SR Electronic
T1 <strong> </strong><strong>A comparison of breathing stimulants for reversal of synthetic opioid-induced respiratory depression in conscious rats </strong>
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2021-000675
DO 10.1124/jpet.121.000675
A1 Kaye Elizabeth Dandrea
A1 Joseph Frank Cotten
YR 2021
UL http://jpet.aspetjournals.org/content/early/2021/05/21/jpet.121.000675.abstract
AB 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. METHODS: 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 IV), PKTHPP (5 mg/kg IV), CX717 (30 mg/kg IV), BIMU8 (1 mg/kg IV), A85380 (30 mcg/kg IV), 8-OH-DPAT (150 mcg/kg IV/IM), and used sufentanil (10 mcg/kg IV). RESULTS: By plethysmography (in % baseline, mean{plus minus}SEM), taltirelin restored ventilation in sufentanil-treated rats (from 50{plus minus}5 to 102{plus minus}8%) by increased breathing rates (from 80{plus minus}4 to 160{plus minus}12%). By arterial blood analysis, however, taltirelin did not correct hypoxia, decreased hypercarbia only after 45 min, and worsened metabolic acidosis (base excess from +0{plus minus}1 to -7{plus minus}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{plus minus}8 to 92{plus minus}10%), reversed hypercarbia (from 64{plus minus}6 to 47{plus minus}2 mmHg) and shortened time-to-righting from 43{plus minus}4 to 15{plus minus}1 min in sufentanil-treated rats placed supine. CONCLUSION: 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-induce respiratory depression; 8-OH-DPAT, however, warrants further study. Significance Statement Respiratory depression is an important cause of death following potent synthetic opioid overdose. 8-OH-DPAT or related compounds may be useful in treating respiratory depression as caused by potent synthetic opioids.