Further Evidence that Morphine-6-Glucuronide is a More Patent Opioid Agonist than Morphine

1 The pharmacological properties of the active morphine metabolite, morphine-6b-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 responses 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 di erence in the relative e cacy of the agonists. 4 3-O-methoxynaltrexone, which has been reported to behave as a selective antagonist of a M6G preferring receptor, was equally e ective at blocking currents produced by M6G and the selective mu-opioid receptor agonist DAMGO. 5 M6G currents were occluded by a prior application of morphine, and were reduced when muopioid receptors were desensitized by using [Met 5 ]-enkephalin. 6 Morphine-3b-D-glucuronide did not a ect action potential ®ring or membrane currents in locus coeruleus neurons and had no e ect on currents produced by M6G. 7 These results show that the relative e cacy of M6G is higher than morphine in locus coeruleus neurons, contrary to what has been shown using mu-opioid receptors expressed in cell clones.

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Osborne

Chieng

Christie

2000

“…M6G appears to be active and more potent than morphine in several systems. Thus, it has been shown to produce analgesia in man (Osborne et al, 1988;Hanna et al, 1990) and in rodent (Shimomura et al, 1971;Yoshimura et al, 1973;Pasternak et al, 1987;Abbott & Palmour et al, 1988;Paul et al, 1989;Sullivan et al, 1989;Gong et al, 1991;1992;Frances et al, 1992). It also possesses a respiratory depressant action in guinea-pigs (Murphey & Olsen, 1994).…”

Section: Introductionmentioning

confidence: 99%

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Barjavel

Scherrmann

Bhargava

1995

1 The effect of morphine (10 mg kg-', s.c.) on the analgesic response measured by the tail-flick method was determined in male Sprague-Dawley rats. The analgesic response to morphine was correlated with the levels of morphine and its metabolites collected by microdialysis from the cortical extracellular fluid (ECF).2 The analgesic response to morphine lasted for 4 h. The concentration of morphine during a 4 h collection period was significantly higher than the metabolites concentration. The relative concentration of morphine and its metabolites during the 4 h period was 70 and 30% respectively. 3 The analgesic response during the first 2.25 h period accounted for more than 82% of the total analgesia as determined by the area under the time-response curve (AUC). The concentration of morphine and its metabolites during the same period were 78 and 22%, respectively, but they did not differ during the 2.25-4.0 h period (52 and 48%). 4 The half-life for morphine and its metabolites were similar, the maximal achievable concentration Cma, and AUCO4 h were lower for metabolites but the time to reach maximum concentration was higher for morphine metabolites than for morphine. The ratio of the concentration of metabolites to the concentration of morphine in the cortical ECF increased with time whereas the analgesic response to morphine decreased with time. 5 At several time points following morphine injection even though the levels of morphine were the same, the concentration of metabolites (mainly M3G) differed and thus the ratio [metabolite/morphine]. A plot of [metabolite]/[morphine] vs. analgesia gave a high correlation coefficient. Since M3G has been shown to be antianalgesic and is the only metabolite of morphine in the rat, it is concluded that the levels of this metabolite may regulate the analgesic effect of morphine in the rat.

“…This value is considerably lower than that for somatosensory antinociception as judged by tail-flick and/or hot-plate tests via the i.c.v. route (20-360 times;Pastemak et al, 1987;Paul et al, 1989;Gong et al, 1991;Frances et al, 1992) and via the i.t. route (650 times; Paul et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Effects of morphine metabolites on micturition in normal, unanaesthetized rats

Igawa

Westerling

Mattiasson

et al. 1993

1 By means of continuous cystometry in normal, unanaesthetized rats, the effects on micturition of intrathecally (i.t.) administered morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the two main metabolites of morphine, were studied and compared with those of i.t. morphine.2 Both M6G (0.01, 0.1, and 0.5 lg) and M3G (5 pg) were found to have significant effects on micturition. Like morphine (0.1, 0.5, and 10pg), M6G was able to inhibit the micturition reflex, and produce urinary retention and dribbling incontinence in a dose-dependent manner. The potency of M6G for inhibiting micturition was approximately 10 times higher than that of morphine, and the duration of its effect was longer. All effects of M6G could be reversed by naloxone.3 M3G (5 jig) facilitated the micturition reflex, resulting in decreases in bladder capacity and micturition volume, and an increase in spontaneous contractile activity. Pretreatment with naloxone (10 fig), which by itself had no effect on micturition, enhanced the facilitatory effects of M3G. In addition, M3G tended to counteract the inhibitory effects of both morphine and M6G on micturition. M3G (5 jg) also produced an excitatory behavioural syndrome. 4 It is concluded that in rats, i.t. M3G has excitatory effects on micturition and behaviour, probably not mediated via opioid receptors. I.t M6G has a potent inhibitory effect on micturition mediated by stimulation of opioid receptors. It may have effects on somatosensory afferent input in lower doses than those required for effects on micturition.