Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide

Hucks, D.; Thompson, P.I.; McLoughlin, L.; Joel, Sp P.; Patel, Naina; Grossman, Aaron; Rees, Linford; Slevin, M. L.

doi:10.1038/bjc.1992.23

Cited by 45 publications

(27 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Such receptors may be involved in the regulation of bladder function, and it may be speculated that the subtype of it receptor involved in spinal and/or supraspinal modulation of bladder motility is different from that involved in somatosensory antinociception. Supporting such a view, Hucks et al (1992) found that M6G had a 4 to 5 fold lower binding affinity for the t2 receptor subtype than morphine. The ,.2 receptor is believed to mediate, e.g., respiratory depression (Ling et al, 1985).…”

Section: Discussionsupporting

confidence: 54%

Effects of morphine metabolites on micturition in normal, unanaesthetized rats

Igawa

Westerling

Mattiasson

et al. 1993

British J Pharmacology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 54%

Effects of morphine metabolites on micturition in normal, unanaesthetized rats

Igawa

Westerling

Mattiasson

et al. 1993

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…[85][86][87][88] In one study, M6G had a fourfold lower affinity for m 2 -receptors than did morphine (IC 50 values of 17 nM (morphine) and 82 nM (M6G)). 72 In this study, there were no significant differences in the receptor binding affinities of morphine and M6G at m 1 -receptors. It was suggested that this differential affinity might explain the lesser effects of M6G compared to morphine on respiratory depression.…”

Section: Receptor Subtypes and Splice Variantsmentioning

confidence: 80%

Morphine‐6‐glucuronide: Actions and mechanisms

Kilpatrick¹,

Smith²

2005

Medicinal Research Reviews

131

View full text Add to dashboard Cite

Morphine-6-glucuronide (M6G) appears to show equivalent analgesia to morphine but to have a superior side-effect profile in terms of reduced liability to induce nausea and vomiting and respiratory depression. The purpose of this review is to examine the evidence behind this statement and to identify the possible reasons that may contribute to the profile of M6G. The vast majority of available data supports the notion that both M6G and morphine mediate their effects by activating the micro-opioid receptor. The differences for which there is a reasonable consensus in the literature can be summarized as: (1) Morphine has a slightly higher affinity for the micro-opioid receptor than M6G, (2) M6G shows a slightly higher efficacy at the micro-opioid receptor, (3) M6G has a lower affinity for the kappa-opioid receptor than morphine, and (4) M6G has a very different absorption, distribution, metabolism, and excretion (ADME) profile from morphine. However, none of these are adequate alone to explain the clinical differences between M6G and morphine. The ADME differences are perhaps most likely to explain some of the differences but seem unlikely to be the whole story. Further work is required to examine further the profile of M6G, notably whether M6G penetrates differentially to areas of the brain involved in pain and those involved in nausea, vomiting, and respiratory control or whether micro-opioid receptors in these brain areas differ in either their regulation or pharmacology.

show abstract

“…M6G is also more potent than morphine (146 : 1) at producing rewarding e ects measured with place preference testing following intracerebral administration (Abbott & Franklin, 1991). Binding studies show that M6G has an equal or lower a nity for the muopioid receptor than morphine (Abbott & Palmour, 1988;Chen et al, 1991;Hucks et al, 1992;Lambert et al, 1993;Mignat et al, 1995;LoÈ ser et al 1996;Brown et al, 1997b;Pan et al, 1999). In order to explain these di erences in the potencies of M6G and morphine, it has recently been hypothesized that M6G has selective antinociceptive and other behavioural agonist e ects at a receptor that is not activated by morphine (reviewed by Pasternak & Standifer, 1995).…”

Section: Introductionmentioning

confidence: 99%

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

Osborne

Chieng

Christie

2000

British J Pharmacology

View full text Add to dashboard Cite

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.

show abstract

Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide

Cited by 45 publications

References 27 publications

Effects of morphine metabolites on micturition in normal, unanaesthetized rats

Effects of morphine metabolites on micturition in normal, unanaesthetized rats

Morphine‐6‐glucuronide: Actions and mechanisms

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

Contact Info

Product

Resources

About