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Cell Nov 2022Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of...
Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of μ-opioid receptor (μOR). Here, we report structures of the human μOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of μOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of μOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of μOR, which may facilitate rational design of next-generation analgesics.
Topics: Humans; Analgesics, Opioid; Arrestin; Fentanyl; GTP-Binding Proteins; Morphine; Receptors, Opioid, mu
PubMed: 36368306
DOI: 10.1016/j.cell.2022.09.041 -
The Alkaloids. Chemistry and Biology 2021This chapter provides a short overview of the history of morphine since it's isolation by Sertürner in 1805. The biosynthesis of the title alkaloid as well as all total... (Review)
Review
This chapter provides a short overview of the history of morphine since it's isolation by Sertürner in 1805. The biosynthesis of the title alkaloid as well as all total and formal syntheses of morphine and codeine published after 1996 are discussed in detail. The last section of this chapter provides a detailed overview of medicinally relevant derivatives of the title alkaloid.
Topics: Alkaloids; Biology; Codeine; Morphine
PubMed: 34565506
DOI: 10.1016/bs.alkal.2021.04.001 -
Anesthesiology Jun 2020Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia is well established, and the use of intrathecal hydromorphone is growing. No prospective studies have compared the effectiveness of equipotent doses of intrathecal morphine versus intrathecal hydromorphone as part of a multimodal analgesic regimen for postcesarean analgesia. The authors hypothesized that intrathecal morphine would result in superior analgesia compared with intrathecal hydromorphone 24 h after delivery.
METHODS
In this single-center, double-blinded, randomized trial, 138 parturients undergoing scheduled cesarean delivery were randomized to receive 150 µg of intrathecal morphine or 75 µg of intrathecal hydromorphone as part of a primary spinal anesthetic and multimodal analgesic regimen; 134 parturients were included in the analysis. The primary outcome was the numerical rating scale score for pain with movement 24 h after delivery. Static and dynamic pain scores, nausea, pruritus, degree of sedation, and patient satisfaction were assessed every 6 h for 36 h postpartum. Total opioid consumption was recorded.
RESULTS
There was no significant difference in pain scores with movement at 24 h (intrathecal hydromorphone median [25th, 75th] 4 [3, 5] and intrathecal morphine 3 [2, 4.5]) or at any time point (estimated difference, 0.5; 95% CI, 0 to 1; P = 0.139). Opioid received in the first 24 h did not differ between groups (median [25th, 75th] oral morphine milligram equivalents for intrathecal hydromorphone 30 [7.5, 45.06] vs. intrathecal morphine 22.5 [14.0, 37.5], P = 0.769). From Kaplan-Meier analysis, the median time to first opioid request was 5.4 h for hydromorphone and 12.1 h for morphine (log-rank test P = 0.200).
CONCLUSIONS
Although the hypothesis was that intrathecal morphine would provide superior analgesia to intrathecal hydromorphone, the results did not confirm this. At the doses studied, both intrathecal morphine and intrathecal hydromorphone provide effective postcesarean analgesia when combined with a multimodal analgesia regimen.
Topics: Adult; Analgesia, Epidural; Analgesia, Obstetrical; Analgesics, Opioid; Cesarean Section; Double-Blind Method; Female; Humans; Hydromorphone; Male; Morphine; Pain, Postoperative; Treatment Outcome
PubMed: 32251031
DOI: 10.1097/ALN.0000000000003283 -
Anaesthesia and Intensive Care Mar 2022
Topics: Humans; Methadone; Morphine
PubMed: 35112583
DOI: 10.1177/0310057X211070686 -
Small (Weinheim An Der Bergstrasse,... Mar 2022Rapid, accessible, and highly accurate biosensors for the detection of addictive and abused drugs are needed to reduce the adverse personal and societal impacts of... (Review)
Review
Rapid, accessible, and highly accurate biosensors for the detection of addictive and abused drugs are needed to reduce the adverse personal and societal impacts of addiction. Modern sensors that utilize next-generation technologies, e.g., nanobiotechnology and nanoarchitectonics, have triggered revolutionary progress in the field as they allow accurate detection and tracking of trace levels of major classes of drugs. This paper reviews advances in the field of biosensors for the detection of commonly abused drugs, both prescribed such as codeine and morphine, and illegal narcotics like cocaine.
Topics: Biosensing Techniques; Cocaine; Illicit Drugs; Morphine
PubMed: 34882957
DOI: 10.1002/smll.202104847 -
Nature Reviews. Neuroscience Nov 2022
Topics: Humans; Astrocytes; Reward; Morphine
PubMed: 36175497
DOI: 10.1038/s41583-022-00638-w -
ACS Chemical Neuroscience Oct 2018As the major psychoactive agent in opium and direct precursor for heroin, morphine is a historically critical molecule in chemical neuroscience. A structurally complex... (Review)
Review
As the major psychoactive agent in opium and direct precursor for heroin, morphine is a historically critical molecule in chemical neuroscience. A structurally complex phenanthrene alkaloid produced by Papaver somniferum, morphine has fascinated chemists seeking to disentangle pharmacologically beneficial analgesic effects from addiction, tolerance, and dependence liabilities. In this review, we will detail the history of morphine, from the first extraction and isolation by Sertürner in 1804 to the illicit use of morphine and proliferation of opioid use and abuse disorders currently ravaging the United States. Morphine is a molecule of great cultural relevance, as the agent that single-handedly transformed our understanding of pharmacognosy, receptor dynamics, and substance abuse and dependence disorders.
Topics: Analgesics, Opioid; Drug Tolerance; History, 16th Century; History, 17th Century; History, 18th Century; History, 19th Century; History, 20th Century; History, 21st Century; History, Ancient; Morphine; Opioid-Related Disorders; Pain; Papaver; Receptors, Opioid; United States
PubMed: 29757600
DOI: 10.1021/acschemneuro.8b00150 -
MMW Fortschritte Der Medizin May 2021
Review
Topics: Delayed-Action Preparations; Dyspnea; Health Status; Humans; Morphine; Pulmonary Disease, Chronic Obstructive
PubMed: 34033036
DOI: 10.1007/s15006-021-9986-4 -
Clinics (Sao Paulo, Brazil) Aug 2016Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief,... (Review)
Review
Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords "morphine metabolism neonate" and "morphine pharmacokinetics neonate". The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.
Topics: Age Factors; Analgesics, Opioid; Birth Weight; Central Nervous System Stimulants; Extracorporeal Membrane Oxygenation; Gestational Age; Humans; Infant, Newborn; Morphine; Morphine Derivatives; Respiration, Artificial; Time Factors
PubMed: 27626479
DOI: 10.6061/clinics/2016(08)11 -
Journal of Anesthesia History Apr 2017
Topics: History, 19th Century; Humans; Morphine
PubMed: 28641830
DOI: 10.1016/j.janh.2017.03.001