Morphine-3-glucuronide - a potent antagonist of morphine analgesia

doi:10.1016/0024-3205(90)90619-3

Life Sciences

Volume 47, Issue 6, 1990, Pages 579-585

https://doi.org/10.1016/0024-3205(90)90619-3 Get rights and content

Abstract

In this study, morphine-3-glucuronide (M3G), the major plasma and urinary metabolite of morphine, was shown to be a potent antagonist of morphine analgesia when administered to rats by the intra-cerebroventricular (i.c.v.) route. The antagonism of morphine analgesia was observed irrespective of whether i.c.v. M3G (2.5 or 3.0μg) was administered 15 mins prior to or 15 mins after i.c.v. morphine (20μg). When M3G (10mg) was administered intraperitoneally (i.p.) to rats 30–40 mins prior to morphine (1.5mg i.p.), the analgesic response was significantly reduced compared to administration of morphine (1.5mg i.p.) alone. It was further demonstrated that i.c.v. M3G (2.0μg) antagonized the analgesic effects of subsequently administered i.c.v. morphine-6-glucuronide (0.25μg).

References (11)

H. Yoshimura et al.
Biochem. Pharmacol.
(1973)
G.W. Pasternak et al.
Life Sci.
(1987)
C.J. Woolf
Brain Research
(1981)
F.S. Labella et al.
Brain Research
(1979)
K. Oguri et al.
Life Sci
(1987)

There are more references available in the full text version of this article.

Cited by (318)

Pharmacological data science perspective on fatal incidents of morphine treatment
2023, Pharmacology and Therapeutics
Citation Excerpt :
The effects of M3G have been reviewed previously (e.g. (Skarke, Geisslinger, & Lötsch, 2005)). Of note, the excitatory effects of M3G have been systematically studied in rodents (Bartlett, Cramond, & Smith, 1994; Gong, Hedner, Bjorkman, & Hedner, 1992; Halliday, Bartlett, Colditz, & Smith, 1999; M.T. Smith, Watt, & Cramond, 1990). In humans, only two studies have examined effects following injection of M3G, one of which was conducted without a control (R. T. Penson, Joel, Clark, Gloyne, & Slevin, 2001), while in a controlled study with injection of morphine, M3G, M6G and placebo, including combinations of two or three medications (R.T. Penson et al., 2000) M3G showed no significant effect on experimentally induced pain and on ventilation while M6G produced less respiratory depression than morphine.
Morphine prescribed for analgesia has caused drug-related deaths at an estimated incidence of 0.3% to 4%. Morphine has pharmacological properties that make it particularly difficult to assess the causality of morphine administration with a patient's death, such as its slow transfer between plasma and central nervous sites of action and the existence of the active metabolite morphine-6-glucuronide with opioid agonistic effects, Furthermore, there is no well-defined toxic dose or plasma/blood concentration for morphine. Dosing is often adjusted for adequate pain relief. Here, we summarize reported deaths associated with morphine therapy, including associated morphine exposure and modulating patient factors such as pharmacogenetics, concomitant medications, or comorbidities. In addition, we systematically analyzed published numerical information on the stability of concentrations of morphine and its relevant metabolites in biological samples collected postmortem. A medicolegal case is presented in which the causality of morphine administration with death was in dispute and pharmacokinetic modeling was applied to infer the administered dose. The results of this analytical review suggest that (i) inference from postmortem blood concentrations to the morphine dose administered has low validity and (ii) causality between a patient's death and the morphine dose administered remains a highly context-dependent and collaborative assessment among experts from different medical specialties.
Characterization of the pharmacokinetics, behavioral effects and effects on thermal nociception of morphine 6-glucuronide and morphine 3-glucuronide in horses
2022, Veterinary Anaesthesia and Analgesia
To describe the pharmacokinetics, behavioral and physiologic effects and effects on thermal thresholds of morphine, morphine 6-glucuronide (M6G) and morphine 3-glucuronide (M3G) following administration to horses.
Randomized balanced crossover study.
A total of seven University-owned horses, five mares and two geldings, aged 3–6 years.
Horses were treated with a single intravenous dosage of saline, morphine (0.2 mg kg^–1), M6G (0.01 mg kg^–1) and M3G (0.03 mg kg^–1). Blood was collected prior to (baseline) and at several times post administration. Drug and metabolite concentrations were determined by liquid chromatography–mass spectrometry, and plasma pharmacokinetics were calculated. Behavioral observations and physiologic variables (heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were determined at baseline and for up to 6 hours. The effects on thermal nociception were determined and thermal excursion was calculated.
The volumes of distribution were 4.75–10.5, 0.244–0.295 and 0.215–0.356 L kg^–1 for morphine, M6G and M3G, respectively. Systemic clearances were 26.8–39.6, 3.16–3.88 and 1.46–2.13 mL minute⁻¹ kg⁻¹ for morphine, M6G and M3G, respectively. Morphine administration resulted in signs of excitation as evidenced by an increase in step counts and subjective behavioral observations, whereas M6G and M3G, based on the same criteria, appeared to cause sedative-like effects. Significant effects on thermal nociception were observed until 4 hours post morphine administration, 1 hour post M6G administration and at various times post M3G administration.
Results of this study provide additional information regarding the use of morphine in horses. Less locomotor excitation and gastrointestinal adverse effects, compared with morphine, coupled with favorable effects on thermal nociception are encouraging for further study of the pharmacodynamics of both M6G and M3G in horses.
Review of addiction risk potential associated with adolescent opioid use
2020, Pharmacology Biochemistry and Behavior
Adolescence is a critical period of development with robust behavioral, morphological, hormonal, and neurochemical changes including changes in brain regions implicated in the reinforcing effects of drugs such as opioids. Here we examine the preclinical and, where appropriate complementary clinical literature, for the behavioral and neurological changes induced by adolescent opioid exposure/use and their long-term consequences during adulthood. Adolescent opioid exposure results in a widened biphasic shift in reinforcement with increased impact of positive rewarding aspects during initial use and profound negative reinforcement during adulthood. Females may have enhanced vulnerability due to fast onset of antinociceptive tolerance and reduced severity of somatic withdrawal symptoms during adolescence. Overall, adolescent opioid exposure, be it legally prescribed protracted intake or illicit consumption, results in significant and prolonged consequences of increased opioid reward concomitant with reduced analgesic efficacy and exacerbated somatic withdrawal severity during opioid use/exposure in adulthood. These findings are highly relevant to physicians, parents, law makers, and the general public as adolescent opioid exposure/misuse results in heightened risk for substance use disorders.
Morphine-3-glucuronide causes antinociceptive cross-tolerance to morphine and increases spinal substance P expression
2020, European Journal of Pharmacology
Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord. This study shows that chronic intrathecal M3G sensitises animals to mechanical stimulation and elevates substance P levels in the nociceptive laminae of the spinal cord. Chronic M3G also induces antinociceptive cross-tolerance to morphine. Thus, chronic M3G exposure might contribute to morphine-induced tolerance and opioid-induced hyperalgesia.
Opioid Prescribing Behavior in Long-Term Geriatric Care in the Netherlands
2018, Journal of the American Medical Directors Association
Pain is a highly prevalent problem in older adults and dying patients. Opioids are the main analgesic for moderate to severe pain in these patients. Different properties of various opioids can make them more or less suitable for this specific population. We therefore aim to explore opioid prescribing behavior in a group of physicians specialized in long-term geriatric care and to identify factors that are taken into account when selecting a specific opioid for treatment of pain in older patients and patients in the dying phase.
A cross-sectional study using an online questionnaire.
All members of the Dutch Association of Elderly Care Physicians and Social Geriatricians (Verenso) on the mailing list of the weekly digital newsletter were invited to participate between November and December 2017.
Preferences in opioids for the treatment of pain in nondying and dying older patients were recorded, as were the factors that were considered for these preferences.
142 members completed the questionnaire (9%). Opioids of first choice were oxycodone (61%) for nondying and morphine (90%) for dying older patients. The second choice in both cases was fentanyl (56% for nondying and 31% in dying older patients). Personal experience was the main consideration in opioid prescribing (74%-98%). In daily practice, recommendations in guidelines are only considered by 8% to 9% and renal function by 0% to 1% of the respondents.
Oxycodone is the opioid of first choice for physicians in long-term geriatric care in the Netherlands when prescribing for nondying older patients. In contrast, morphine is preferred for dying patients. Fentanyl as a second choice is mainly reserved for situations of stable pain. Prescribers base their choices almost exclusively on personal experience and are barely influenced by guidelines. Further research should therefore focus on clinical relevance for, and implementation in, daily practice.
Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression
2018, European Journal of Pharmacology
Opioid-induced respiratory depression (OIRD) involves decreased sensitivity of ventilatory control systems to decreased blood levels of oxygen (hypoxia) and elevated levels of carbon dioxide (hypercapnia). Understanding the sites and mechanisms by which opioids elicit respiratory depression is pivotal for finding novel therapeutics to prevent and/or reverse OIRD. To examine the contribution of carotid body chemoreceptors OIRD, we used whole-body plethysmography to evaluate hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses including changes in frequency of breathing, tidal volume, minute ventilation and inspiratory drive, after intravenous injection of morphine (10 mg/kg) in sham-operated (SHAM) and in bilateral carotid sinus nerve transected (CSNX) Sprague-Dawley rats. In SHAM rats, morphine produced sustained respiratory depression (e.g., decreases in tidal volume, minute ventilation and inspiratory drive) and reduced the HVR and HCVR responses. Unexpectedly, morphine-induced suppression of HVR and HCVR were substantially greater in CSNX rats than in SHAM rats. This suggests that morphine did not compromise the function of the carotid body-chemoafferent complex and indeed, that the carotid body acts to defend against morphine-induced respiratory depression. These data are the first in vivo evidence that carotid body chemoreceptor afferents defend against rather than participate in OIRD in conscious rats. As such, drugs that stimulate ventilation by targeting primary glomus cells and/or chemoafferent terminals in the carotid bodies may help to alleviate OIRD.

View all citing articles on Scopus

View full text

Morphine-3-glucuronide - a potent antagonist of morphine analgesia

Abstract

Biochem. Pharmacol.

Life Sci.

Brain Research

Brain Research

Life Sci