title: Characteristics and comparative severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine in rats.
abstract: 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.
authors.affiliation: Université Paris-Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157, 75010 Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Chevillard
authors.forename: Bruno
authors.initials: B
authors.lastname: Mégarbane
authors.forename: Patricia
authors.initials: P
authors.lastname: Risède
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Baud
mesh_terms: 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
chemical_list: 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