Morphine-6 beta-glucuronide has a higher efficacy than morphine as a mu-opioid receptor agonist in the rat locus coeruleus

1 The pharmacological properties of the active morphine metabolite, morphin e-6 beta -D-glucuronide (M6G), and the parent compound were compared in rat locus coeruleus neurons by electrophysiological recording in brain slices. 2 M6G and morphine activated potassium currents in voltage clamped neurons, which were blocked by the opioid receptor antagonist naloxone. 3 Both M6G and morphine behaved as partial agonists that produced maximal r esponses smaller than the system maximum. which was measured using [Met(5)] -enkephalin. M6G produced a larger maximal response (78%) than morphine (62 %), which we estimated was due to a 2-4 fold difference in the relative eff icacy of the agonists. 4 3-O-methoxynaltrexone, which has been reported to behave as a selective a ntagonist of a M6G preferring receptor, was equally effective at blocking c urrents produced by M6G and the selective mu-opioid receptor agonist DAMGO. 5 M6G currents were occluded by a prior application of morphine, and were r educed when mu-opioid receptors were desensitized by using [Met(5)]-enkepha lin. 6 Morphine-3 beta -D-glucuronide did not affect action potential firing or membrane currents in locus coeruleus neurons and had no effect on currents produced by M6G. 7 These results show that the relative efficacy of M6G is higher than morph ine in locus coeruleus neurons, contrary to what has been shown using mu-op ioid receptors expressed in cell clones.