Characteristics and comparative severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine in rats.
Opioids are known to induce respiratory depression. We aimed to characterize in rats the effects of four opioids on arterial blood gases and plethysmography after intraperitoneal administration at 80% of their LD(50) in order to identify opioid molecule-specific patterns and classify response severity. Opioid-receptor (OR) antagonists, including intravenous 10 mg kg(-1)-naloxonazine at 5 min [mu-OR antagonist], subcutaneous 30 mg kg(-1)-naloxonazine at 24 h [mu1-OR antagonist], subcutaneous 3 mg kg(-1)-naltrindole at 45 min [delta-OR antagonist], and subcutaneous 5 mg kg(-1)-Nor-binaltorphimine at 6 h [kappa-OR antagonist] were pre-administered to test the role of each OR. Methadone, morphine, and fentanyl significantly decreased PaO(2) (P<0.001) and increased PaCO(2) (P<0.05), while buprenorphine only decreased PaO(2) (P<0.05). While all opioids significantly increased inspiratory time (T(I), P<0.001), methadone and fentanyl also increased expiratory time (T(E), P<0.05). Intravenous 10 mg kg(-1)-naloxonazine at 5 min completely reversed opioid-related effects on PaO(2) (P<0.05), PaCO(2) (P<0.001), T(I) (P<0.05), and T(E) (P<0.01) except in buprenorphine. Subcutaneous 30 mg kg(-1)-naloxonazine at 24 h completely reversed effects on PaCO(2) (P<0.01) and T(E) (P<0.001), partially reversed effects on T(I) (P<0.001), and did not reverse effects on PaO(2). Naltrindole reversed methadone-induced T(E) increases (P<0.01) but worsened fentanyl's effect on PaCO(2) (P<0.05) and T(I) (P<0.05). Nor-binaltorphimine reversed morphine- and buprenorphine-induced T(I) increases (P<0.001) but worsened methadone's effect on PaO(2) (P<0.05) and morphine (P<0.001) and buprenorphine's (P<0.01) effects on pH. In conclusion, opioid-related respiratory patterns are not uniform. Opioid-induced hypoxemia as well as increases in T(I) and T(E) are caused by mu-OR, while delta and kappa-OR roles appear limited, depending on the specific opioid. Regarding severity of opioid-induced respiratory effects at 80% of their LD(50), all drugs increased T(I). Methadone and fentanyl induced hypoxemia, hypercapnia, and T(E) increases, morphine caused both hypoxemia and hypercapnia while buprenorphine caused only hypoxemia.
Chevillard
Lucie
L
Université Paris-Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157, 75010 Paris, France.
Mégarbane
Bruno
B
Risède
Patricia
P
Baud
Frédéric J
FJ
D000818:Animals; D001784:Blood Gas Analysis; D002047:Buprenorphine / Q000037:antagonists & inhibitors / Q000633:toxicity; D002404:Catheterization; D005283:Fentanyl / Q000037:antagonists & inhibitors / Q000633:toxicity; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008691:Methadone / Q000037:antagonists & inhibitors / Q000633:toxicity; D009020:Morphine / Q000037:antagonists & inhibitors / Q000633:toxicity; D009022:Morphine Derivatives / Q000633:toxicity; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000633:toxicity*; D010993:Plethysmography, Whole Body; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology; D015656:Respiratory Mechanics / Q000187:drug effects
D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D009294:Narcotics; D011957:Receptors, Opioid; D019344:Lactic Acid; C051844:norbinaltorphimine; D002047:Buprenorphine; D009271:Naltrexone; C035349:morphine-6-glucuronide; D009020:Morphine; C026979:6-O-monoacetylmorphine; D008691:Methadone; D005283:Fentanyl