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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 -
Pharmacogenomics Apr 2021Oxycodone is a semisynthetic μ- and κ-opioid receptor with agonist with a broad scope of use including postoperative analgesia as well as control of neuropathic and... (Review)
Review
Oxycodone is a semisynthetic μ- and κ-opioid receptor with agonist with a broad scope of use including postoperative analgesia as well as control of neuropathic and cancer pain. Advantages over other opioids include prolonged duration of action, greater potency than morphine and lack of histamine release or ceiling effect. Individual responses to oxycodone can vary due to genetic differences. This review article aims to summarize the oxycodone literature and provide context on its pharmacogenomics and pharmacokinetics. The evidence for clinical effect of genetic polymorphisms on oxycodone is conflicting. There is stronger evidence linking polymorphic genetic enzymes CYP2D6 and CYP3A with therapeutic outcomes. Further, research is needed to discern all of oxycodone's metabolites and their contribution to the overall analgesic effect.
Topics: Analgesics, Opioid; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Humans; Morphine; Oxycodone; Pharmacogenetics; Polymorphism, Genetic
PubMed: 33728947
DOI: 10.2217/pgs-2020-0143 -
Clinics in Perinatology Mar 2022Chronic pain and agitation in neonatal life impact the developing brain. Oral sweet-tasting solutions should be used judiciously to mitigate behavioral responses to mild... (Review)
Review
Chronic pain and agitation in neonatal life impact the developing brain. Oral sweet-tasting solutions should be used judiciously to mitigate behavioral responses to mild painful procedures, keeping in mind that the long-term impact is unknown. Rapidly acting opioids should be used as part of premedication cocktails for nonemergent endotracheal intubations. Continuous low-dose morphine or dexmedetomidine may be considered for preterm or term neonates exhibiting signs of stress during mechanical ventilation and therapeutic hypothermia, respectively. Further research is required regarding the pharmacokinetics, pharmacodynamics, safety, and efficacy of pharmacologic agents used to mitigate mild, moderate, and chronic pain and stress in neonates.
Topics: Analgesia; Analgesics, Opioid; Chronic Pain; Humans; Infant, Newborn; Morphine; Pain Management
PubMed: 35210004
DOI: 10.1016/j.clp.2021.11.014 -
Pharmacological Reviews Nov 2023Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used... (Review)
Review
Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence of convulsions at higher doses, it has been converted to a number of other widely used compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite the early identification of oxycodone, it was not until the 1990s that clinical studies began to explore its analgesic efficacy. These studies were followed by the pursuit of several preclinical studies to examine the analgesic effects and abuse liability of oxycodone in laboratory animals and the subjective effects in human volunteers. For a number of years oxycodone was at the forefront of the opioid crisis, playing a significant role in contributing to opioid misuse and abuse, with suggestions that it led to transitioning to other opioids. Several concerns were expressed as early as the 1940s that oxycodone had significant abuse potential similar to heroin and morphine. Both animal and human abuse liability studies have confirmed, and in some cases amplified, these early warnings. Despite sharing a similar structure with morphine and pharmacological actions also mediated by the -opioid receptor, there are several differences in the pharmacology and neurobiology of oxycodone. The data that have emerged from the many efforts to analyze the pharmacological and molecular mechanism of oxycodone have generated considerable insight into its many actions, reviewed here, which, in turn, have provided new information on opioid receptor pharmacology. SIGNIFICANCE STATEMENT: Oxycodone, a -opioid receptor agonist, was synthesized in 1916 and introduced into clinical use in Germany in 1917. It has been studied extensively as a therapeutic analgesic for acute and chronic neuropathic pain as an alternative to morphine. Oxycodone emerged as a drug with widespread abuse. This article brings together an integrated, detailed review of the pharmacology of oxycodone, preclinical and clinical studies of pain and abuse, and recent advances to identify potential opioid analgesics without abuse liability.
Topics: Animals; Humans; Oxycodone; Thebaine; Analgesics, Opioid; Opioid-Related Disorders; Morphine; Receptors, Opioid
PubMed: 37321860
DOI: 10.1124/pharmrev.121.000506 -
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 -
Inflammopharmacology Feb 2024There is documentation of the use of opium derived products in the ancient history of the Assyrians: the Egyptians; in the sixth century AD by the Roman Dioscorides; and... (Review)
Review
There is documentation of the use of opium derived products in the ancient history of the Assyrians: the Egyptians; in the sixth century AD by the Roman Dioscorides; and by Avicenna (980-1037). Reference to opium like products is made by Paracelsus and by Shakespeare. Charles Louis Derosne and Fredrich Wilhelm Adam Serturner isolated morphine from raw opium in 1802 and 1806 respectively, and it was Sertürner who named the substance morphine, after Morpheus, the Greek God of dreams. By the middle 1800s, Opium and related opioid derived products were the source of a major addiction in USA, and to some extent in the United Kingdom. Opioid products are of major therapeutic value in the treatment of pain from injury, post surgery, intractable pain conditions, and some forms of terminal cancer.
Topics: Humans; Analgesics, Opioid; Morphine; Narcotics; Opium
PubMed: 37515654
DOI: 10.1007/s10787-023-01304-y -
Nature Reviews. Neuroscience Nov 2022
Topics: Humans; Astrocytes; Reward; Morphine
PubMed: 36175497
DOI: 10.1038/s41583-022-00638-w