Differential Effect of Morphine and Morphine-6-glucuronide on the Control of Breathing in the Anesthetized Cat

Abstract

Morphine's metabolite, morphine-6-glucuronide (M6G), activates the mu-opioid receptor. Previous data suggest that M6G activates a unique M6G receptor that is selectively antagonized by 3-methoxynaltrexome (3mNTX). The authors compared the effects of M6G and morphine on breathing in the anesthetized cat and assessed whether 3mNTX reversal was selective for M6G. Step changes in end-tidal carbon dioxide concentration were applied in cats anesthetized with alpha-chloralose-urethane. In study 1, the effect of the 0.15 mg/kg morphine followed by 0.2 mg/kg 3mNTX and next 0.8 mg/kg M6G was assessed in six cats. In study 2, the effect of 0.8 mg/kg M6G followed by 0.2 mg/kg 3mNTX and 0.15 mg/kg morphine was tested in another six cats. The ventilatory carbon dioxide responses were analyzed with a two-compartment model of the ventilatory controller, which consists of a fast peripheral and a slow central component. Both opioids shifted the ventilatory carbon dioxide responses to higher end-tidal carbon dioxide levels. Morphine had a preferential depressant effect within the central chemoreflex loop. In contrast, M6G had a preferential depressant effect within the peripheral chemoreflex loop. Irrespective of the opioid, 3mNTX caused full reversal of and prevented respiratory depression. In anesthetized cats, the mu-opioids morphine and M6G induce respiratory depression at different sites within the ventilatory control system. Because 3mNTX caused full reversal of the respiratory depressant effects of both opioids, it is unlikely that a 3mNTX-sensitive unique M6G receptor is the cause of the differential respiratory behavior of morphine and M6G.