Morphine-3-Glucuronide Has a Minor Effect on Morphine Antinociception. Pharmacodynamic Modeling

Gårdmark, Marie; Karlsson, Mats O.; Jönsson, Fredrik; Hammarlund‐Udenaes, Margareta

doi:10.1021/js980056f

Cited by 32 publications

(15 citation statements)

References 51 publications

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“…On the other hand, female rats are reported to have a higher morphine-3-glucuronide (M3G)/morphine ratio after subcutaneous injection of morphine (7). Given that M3G could act as a functional antagonist to the actions of morphine (32,36,72), sex differences in plasma M3G/morphine ratio after systemic injection may play a role in sex differences in morphine antinociception.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated

Murphy²,

Traub³

2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Increasing evidence suggests there is a sex difference in opioid analgesia of pain arising from somatic tissue. However, the existence of a sex difference in visceral pain and opioid analgesia is unclear. This was examined in the colorectal distention (CRD) model of visceral pain in the current study. The visceromotor response (vmr) to noxious CRD was recorded in gonadally intact male and female rats. Subcutaneous injection of morphine dose-dependently decreased the vmr in both groups without affecting colonic compliance. However, morphine was significantly more potent in male rats than females. Because systemic morphine can act at peripheral tissue and in the central nervous system (CNS), the source of the sex difference in morphine analgesia was determined. The peripherally restricted mu-opioid receptor (MOR) antagonist naloxone methiodide dose-dependently attenuated the effects of systemic morphine. Systemic administration of the peripherally restricted MOR agonist loperamide confirmed peripherally mediated morphine analgesia and revealed greater potency in males compared with females. Spinal administration of morphine dose-dependently attenuated the vmr, but there was no sex difference. Intracerebroventricular administration of morphine also dose-dependently attenuated the vmr with significantly greater potency in male rats. The present study documents a sex difference in morphine analgesia of visceral pain that is both peripherally and supraspinally mediated.

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Section: Discussionmentioning

confidence: 99%

Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated

Murphy²,

Traub³

2006

American Journal of Physiology-Regulatory, Integrative and Comp

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“…For example, Smith and Smith (22) observed an inverse relationship between morphine-associated antinociception and M3G concentrations. However, careful examination of the influence of M3G pretreatment on morphine antinociception in rats revealed that acute M3G exposure, at concentrations similar to those produced by pharmacologically-relevant doses of morphine, does not attenuate antinociception to a significant extent (23,24). In contrast, M3G concentrations that are far in excess of those produced by pharmacologic doses of the parent drug can evoke neuro-excitatory behavioral responses that oppose the analgesic effects mediated by morphine binding to opioid receptors.…”

Section: Metabolite Contributions To Opioid Response and Tolerancementioning

confidence: 99%

Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective

Dumas

Pollack

2008

AAPS J

231

164

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Abstract. The opioids are commonly used to treat acute and severe pain. Long-term opioid administration eventually reaches a dose ceiling that is attributable to the rapid onset of analgesic tolerance coupled with the slow development of tolerance to the untoward side effects of respiratory depression, nausea and decreased gastrointestinal motility. The need for effective-long term analgesia remains. In order to develop new therapeutics and novel strategies for use of current analgesics, the processes that mediate tolerance must be understood. This review highlights potential pharmacokinetic (changes in metabolite production, metabolizing enzyme expression, and transporter function) and pharmacodynamic (receptor type, location and functionality; alterations in signaling pathways and crosstolerance) aspects of opioid tolerance development, and presents several pharmacodynamic modeling strategies that have been used to characterize time-dependent attenuation of opioid analgesia.

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“…However, M6G is a more potent µ opioid agonist [1] and a number of studies have shown its contribution to analgesia, particularly after a high dose or during chronic morphine therapy [2,3,51,52]. In contrast, several animal studies have shown that M3G attenuates the opioid effects of morphine [5,6,53,54], although this has yet to be well demonstrated in humans. Thus, decreased M6G formation combined with an increase in the M3G/M6G ratio may result in decreased analgesia and an increase in excitatory effects.…”

Section: Tablementioning

confidence: 99%

“…M6G is a potent µ -opioid agonist [1] with clinical studies suggesting it contributes to analgesia after the administration of morphine [2,3]. M3G has no anal-gesic activity, but has been shown to cause excitation and attenuation of opioid effects in rats [4][5][6]. Sjögren and coworkers [7] proposed that reduced morphine efficacy in chronically treated cancer patients may be due to increased plasma M3G concentrations, or an increase in the M3G/M6G plasma concentration ratio.…”

Section: Introductionmentioning

confidence: 99%

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

Morrish

Foster

Somogyi

2005

Brit J Clinical Pharma

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Differential in vitro inhibition of M3G and M6G formation from morphine by (R)-and (S)-methadone and structurally related opioids Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia AimsTo determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. MethodsM3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 µ M ) and the mechanism of inhibition determined for (R)-and (S)-methadone (70-500 µ M ) using three microsomal samples. ResultsGlucuronide formation displayed single enzyme kinetics. The M3G V max (mean ± SD) was 4.8-fold greater than M6G V max (555 ± 110 vs. 115 ± 19 nmol mg − 1 protein h − 1 ; P = 0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg − 1 protein h − 1 ). K m values for M3G and M6G formation were not significantly different (1.12 ± 0.37 vs. 1.11 ± 0.31 m M ; P = 0.89, 0.02; − 0.29, 0.32 m M ). M3G and M6G formation was inhibited ( P < 0.01) with a significant increase in the M3G/M6G ratio ( P < 0.01) for all compounds tested. Detailed analysis with (R)-and (S)-methadone revealed noncompetitive inhibition with (R)-methadone K i of 320 ± 42 µ M and 192 ± 12 µ M for M3G and M6G, respectively, and (S)-methadone K i of 226 ± 30 µ M and 152 ± 20 µ M for M3G and M6G, respectively. K i values for M3G inhibition were significantly greater than for M6G for (R)-methadone ( P = 0.017, 128; 55, 202 µ M ) and (S)-methadone ( P = 0.026, 75; 22, 128 µ M ). ConclusionsBoth methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadonemaintained patients and reduced relative formation of the opioid active M6G compared with M3G. IntroductionMorphine is the gold standard opioid for the treatment of moderate to severe acute and chronic pain. Morphine is primarily cleared via glucuronidation to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M6G is a potent µ -opioid agonist [1] with clinical studies suggesting it contributes to analgesia after the administration of morphine [2,3]. M3G has no anal- [11,12,14]. Investigations with expressed recombinant human UDPglucuronosyltransferase (UGT) enzymes have shown UGT1A1, 1A3, 1A6, 1A8, 1A9, 1A10 and 2B7 all metabolize morphine to M3G [15][16][17]. However, only UGT2B7 has been shown to form M6G [17,18]. The relative contribution of these isoforms to the overall glucuronidation of morphine is still unknown. Only one investigation using human liver microsomes has shown the possible involvement of more than one UGT isoform in M3G formation, with the suggested involvement of a high-affinity, low-capacity enzyme (with a mean K m and V max of 5.3 µ M and 18 nmol mg − 1 protein h...

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Morphine-3-Glucuronide Has a Minor Effect on Morphine Antinociception. Pharmacodynamic Modeling

Cited by 32 publications

References 51 publications

Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated

Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated

Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective

Differential in vitro inhibition of M3G and M6G formation from morphine by (R)‐ and (S)‐methadone and structurally related opioids

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