and comparative severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine in rats. Toxicology letters [Toxicol Lett] Journal article | | Title | and comparative severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine in rats. | | Author(s) | Chevillard L, Mégarbane B, Risède P, Baud FJ | | Institution | Université Paris-Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR7157 and Université Paris-Diderot, Paris, France; INSERM, U705, Paris, France. | | Source | Toxicol Lett 2009 Oct 8. | | 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 10mg.kg(-1)-naloxonazine at 5min [mu-OR antagonist], subcutaneous 30mg.kg(-1)-naloxonazine at 24h [mu1-OR antagonist], subcutaneous 3mg.kg(-1)-naltrindole at 45min [delta-OR antagonist], and subcutaneous 5mg.kg(-1)-Nor-binaltorphimine at 6h [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 10mg.kg(-1)-naloxonazine at 5min 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 30mg.kg(-1)-naloxonazine at 24h 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19819313 |
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