Cardiorespiratory effects and kinetics of intrathecally injected D-Ala2-D-Leu5-enkephalin and morphine in unanesthetized dogs

Abstract

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 [V̇(E)] 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 Pa(O2) during the 3 h postinjection. In contrast, Pa(CO2) was significantly elevated and pH significantly decreased (P < 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 )α was 13.8 ± 3.6 min for DADL and 9.4 ± 1.6 min for morphine (mean ± SE). The t( 1/2 )β was 101.3 ± 17.7 min for DADL and 116.7 ± 27.9 min for morphine. The volume of distribution at steady state (Vd(ss)) was 1.6 ± 0.88 ml/m2 for DADL and 3.4 ± 2.1 ml/m2 for morphine. The clearance was 29.6 ± 1.7 μl·min-1·m-2 for DADL and 41.6 ± 12.7 μl·min-1·m-2 for morphine. DADL may present an alternative to morphine for IT administration, especially in morphine-tolerant patients.