Cardiorespiratory effects and kinetics of intrathecally injected D-Ala2-D-Leu5-enkephalin and morphine in unanesthetized dogs.
In unanesthetized dogs prepared with chronic tracheostomies and chronically implanted intrathecal (IT) catheters having openings in the cisterna magna and lumbar region, lumbar IT injection of D-Ala2-D-Leu5-enkephalin (DADL, 1-10 mg) and morphine (3-30 mg) produced a dose-dependent depression of the slope of the CO2 response function (minute expired volume [VE] vs. end-tidal [ET] CO2) as investigated by a modified Read rebreathing technique. The maximum depression occurred less than 3 h after IT injection of either agent and lasted as long as 12 h. The depression was totally reversed by naloxone (0.4 mg/kg, iv). Naloxone alone had no effect on ventilatory function. After 10 mg DADL, there was no significant change in heart rate (HR), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), cardiac output (CO), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), or PaO2 during the 3 h postinjection. In contrast, PaCO2 was significantly elevated and pH significantly decreased (P less than 0.05). Naloxone administration after high-dose IT DADL resulted in a doubling of MABP, MPBP, CO, and SVR that lasted approximately 20 min. In concurrently measured cisternal cerebrospinal fluid (CSF) levels, both morphine and DADL displayed peak levels by 30-60 min. The lumbar CSF clearance curves for both agents were fitted with a two-compartment intravenous bolus model. The t 1/2 alpha was 13.8 +/- 3.6 min for DADL and 9.4 +/- 1.6 min for morphine (mean +/- SE). The t 1/2 beta was 101.3 +/- 17.7 min for DADL and 116.7 +/- 27.9 min for morphine.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002245:Carbon Dioxide / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects*; D004285:Dogs; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D007278:Injections, Spinal; D007700:Kinetics; D008297:Male; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D012119:Respiration / Q000187:drug effects*
D002245:Carbon Dioxide; D009270:Naloxone; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine