Mu opioid receptor efficacy and potency of morphine-6-glucuronide in neonatal guinea pig brainstem membranes: Comparison with transfected CHO cells

The major side effect of morphine and its active metabolite, morphine-6-glu curonide (M6G), is respiratory depression, which is mediated by mu opioid r eceptors in the medulla and pens. Although the effect of morphine on coupli ng between CL opioid receptors and G proteins has been studied, the effect of M6G on this coupling has not. Therefore, stimulation of guanylyl-5'-0-([ gamma S-35]-thio)-triphosphate ([S-35]-GTP gammaS) binding by these two nar cotic analgesic drugs was compared to the mu -specific synthetic opioid pep tide [D-Ala(2), N-MePhe(4), Glyol(5)]enkephalin in Chinese hamster ovarian cells stably transfected with the murine mu opioid receptor and in brainste m membranes prepared from 3-, 7-, and 14-day-old guinea pigs. All three ago nists stimulated [S-35]-GTP gammaS binding in transfected cells and neural tissue, and the stimulation was antagonized by naloxone. In brainstem membr anes, but not transfected cells, M6G was less efficacious but more potent t han morphine, which may be due to differences between murine and guinea pig mu opioid receptors or in the G proteins in these two tissues. Efficacy of the agonists did not change during development, but overall potency decrea sed between 3 and 14 days after birth. In vivo potency differences for resp iratory depression between morphine and M6G are qualitatively similar to in vitro potency differences of these drugs to stimulate [S-35]-GTP gammaS bi nding in neonatal guinea pig brainstem membranes. Tolerance to opioid effec ts on [S-35]-GTP gammaS binding developed in transfected cells incubated wi th morphine with the maximum decrease in potency occurring 18 h later than the maximum decline in efficacy. (C) 2001 Elsevier Science Inc.