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Journal of Trace Elements in Medicine... Jul 2020Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical... (Review)
Review
Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical dopaminergic pathways play an important role in modulation of cognitive processes and decision making and, therefore, changes in dopamine metabolism are considered the central basis for the development of dependence. Disturbances caused by excesses or deficiency of certain elements have a significant impact on the functioning of the central nervous system (CNS) both in physiological conditions and in pathology and can affect the cerebral reward system and therefore, may modulate processes associated with the development of addiction. In this paper we review the mechanisms of interactions between morphine and zinc, manganese, chromium, cadmium, lead, fluoride, their impact on neural pathways associated with addiction, and on antinociception and morphine tolerance and dependence.
Topics: Animals; Humans; Morphine; Morphine Dependence; Neural Pathways; Transition Elements
PubMed: 32179426
DOI: 10.1016/j.jtemb.2020.126495 -
American Journal of Respiratory and... Dec 2021
Topics: Analgesics, Opioid; Fentanyl; Humans; Infusions, Intravenous; Intensive Care Units; Morphine
PubMed: 34644514
DOI: 10.1164/rccm.202109-2112ED -
Respiratory Physiology & Neurobiology Aug 2022We determined whether intravenous injections of the membrane-permeable ventilatory stimulants, D-cysteine ethyl ester (ethyl (2 S)- 2-amino-3-sulfanylpropanoate)...
D-cysteine ethyl ester and D-cystine dimethyl ester reverse the deleterious effects of morphine on arterial blood-gas chemistry and Alveolar-arterial gradient in anesthetized rats.
We determined whether intravenous injections of the membrane-permeable ventilatory stimulants, D-cysteine ethyl ester (ethyl (2 S)- 2-amino-3-sulfanylpropanoate) (D-CYSee) and D-cystine dimethyl ester (methyl (2 S)- 2-amino-3-[[(2 S)- 2-amino-3-methoxy-3-oxopropyl]disulfanyl] propanoate) (D-CYSdime), could overcome the deleterious actions of intravenous morphine on arterial blood pH, pCO, pO and sO, and Alveolar-arterial (A-a) gradient (i.e., the measure of exchange of gases in the lungs) in Sprague Dawley rats anesthetized with isoflurane. Injection of morphine (2 mg/kg, IV) caused pronounced reductions in pH, pO and sO accompanied by elevations in pCO all which are suggestive of diminished ventilation, and elevations in A-a gradient, which suggests a mismatch of ventilation-perfusion. Subsequent boluses of D-cysteine ethyl ester (2 ×100 μmol/kg, IV) or D-cystine dimethyl ester (2 ×50 μmol/kg, IV) rapidly reversed of the negative actions of morphine on pH, pCO, pO and sO and A-a gradient. Similar injections of D-cysteine (2 ×100 μmol/kg, IV) were without effect, whereas injections of D-cystine (2 ×50 μmol/kg, IV) produced a modest reversal. Our data show that D-cysteine ethyl ester and D-cystine dimethyl ester readily overcome the deleterious effects of morphine on arterial blood gas (ABG) chemistry and A-a gradient by mechanisms that may depend upon their ability to rapidly enter cells. As a result of their known ability to enter the brain, lungs, muscles of the chest wall, and most likely the major peripheral chemoreceptors (i.e., carotid bodies), the effects of the thiolesters on changes in ABG chemistry and A-a gradient elicited by morphine likely involve central and peripheral mechanisms. We are employing target prediction methods to identify an array of in vitro and in vivo methods to test potential functional proteins by which D-CYSee and D-CYSdime modulate the effects of morphine on breathing.
Topics: Animals; Cysteine; Cystine; Morphine; Rats; Rats, Sprague-Dawley
PubMed: 35447347
DOI: 10.1016/j.resp.2022.103912 -
Journal of Clinical Pharmacology Jan 2022While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we... (Randomized Controlled Trial)
Randomized Controlled Trial
While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration-effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT-Behavior (COMFORT-B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up-titration). In responders to morphine up-titration, the COMFORT-B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT-B score is expected. In general, lower baseline COMFORT-B scores (2.1 points on average) in younger children (postnatal age <10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT-B score is maximized at a morphine concentration between 5 and 30 ng/mL for children aged <10 days, and between 5 and 40 ng/mL for children >10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.
Topics: Analgesics, Opioid; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Infant, Newborn; Male; Morphine; Pain, Postoperative
PubMed: 34383975
DOI: 10.1002/jcph.1952 -
Nature Communications Feb 2021Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid...
Roughly half of the drug overdose-related deaths in the United States are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, X-ray crystal structures of mOR in complex with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like opioids remains lacking. Exploiting the X-ray structure of BU72-bound mOR and several molecular simulation techniques, we elucidated the detailed binding mechanism of fentanyl. Surprisingly, in addition to the salt-bridge binding mode common to morphinan opiates, fentanyl can move deeper and form a stable hydrogen bond with the conserved His297, which has been suggested to modulate mOR's ligand affinity and pH dependence by previous mutagenesis experiments. Intriguingly, this secondary binding mode is only accessible when His297 adopts a neutral HID tautomer. Alternative binding modes may represent a general mechanism in G protein-coupled receptor-ligand recognition.
Topics: Analgesics, Opioid; Fentanyl; Ligands; Models, Molecular; Molecular Dynamics Simulation; Morphine; Receptors, Opioid, mu; Structure-Activity Relationship
PubMed: 33579956
DOI: 10.1038/s41467-021-21262-9 -
Pharmacology Research & Perspectives Aug 2023Morphine induces spinal 5-hydroxytryptamine (5-HT) release, but the role and mechanism of the spinal 5-HT release induced by morphine are not well understood. The...
Morphine induces spinal 5-hydroxytryptamine (5-HT) release, but the role and mechanism of the spinal 5-HT release induced by morphine are not well understood. The purpose of this study was to define the role and mechanism of spinal 5-HT release induced by oral morphine. We also examined whether persistent pain affected the spinal 5-HT release induced by oral morphine. Spinal 5-HT release was measured using microdialysis of lumbar cerebrospinal fluid (CSF). Two opioids, morphine and oxycodone, were orally administered and 5-HT release was measured in awake rats. Naloxone and β-funaltrexamine (β-FNA) were used to determine whether the effect of morphine on 5-HT release was mediated by opioid receptor activation. To study persistent pain, a formalin test was used. At 45 min after oral morphine administration, the formalin test was started and spinal 5-HT release was measured. Oral morphine, but not oral oxycodone, increased 5-HT release at the spinal cord to approximately 4000% of the baseline value. This effect of morphine was not antagonized by either naloxone or β-FNA at a dose that antagonized the antinociceptive effect of morphine. Formalin-induced persistent pain itself had no effect on spinal 5-HT release but enhanced the oral morphine-induced spinal 5-HT release. Oral morphine-induced spinal 5-HT release was not mediated by opioid receptor activation. Spinal 5-HT induced by oral morphine did not play a major role in the antinociceptive effect of morphine in the hot plate test. Persistent pain increased oral morphine-induced spinal 5-HT release.
Topics: Animals; Rats; Receptors, Opioid; Serotonin; Oxycodone; Morphine; Analgesics, Opioid; Naloxone; Pain
PubMed: 37488088
DOI: 10.1002/prp2.1119 -
British Journal of Clinical Pharmacology May 2016
Topics: Analgesics, Opioid; Dyspnea; Humans; Morphine; Pulmonary Disease, Chronic Obstructive; Surveys and Questionnaires
PubMed: 26632146
DOI: 10.1111/bcp.12856 -
Scientific Reports Feb 2018Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious comorbidities, such as dependence, tolerance, immunosuppression and...
Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious comorbidities, such as dependence, tolerance, immunosuppression and gastrointestinal disorders limit their long-term use. In the current study, a morphine-murine model was used to investigate the role of the gut microbiome and metabolome as a potential mechanism contributing to the negative consequences associated with opioid use. Results reveal a significant shift in the gut microbiome and metabolome within one day following morphine treatment compared to that observed after placebo. Morphine-induced gut microbial dysbiosis exhibited distinct characteristic signatures, including significant increase in communities associated with pathogenic function, decrease in communities associated with stress tolerance and significant impairment in bile acids and morphine-3-glucuronide/morphine biotransformation in the gut. Moreover, expansion of Enterococcus faecalis was strongly correlated with gut dysbiosis following morphine treatment, and alterations in deoxycholic acid (DCA) and phosphatidylethanolamines (PEs) were associated with opioid-induced metabolomic changes. Collectively, these results indicate that morphine induced distinct alterations in the gut microbiome and metabolome, contributing to negative consequences associated with opioid use. Therapeutics directed at maintaining microbiome homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management.
Topics: Analgesics, Opioid; Analysis of Variance; Animals; Deoxycholic Acid; Disease Models, Animal; Drug Tolerance; Dysbiosis; Enterococcus faecalis; Female; Gastrointestinal Microbiome; Metabolome; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Morphine Derivatives; Naltrexone; Narcotic Antagonists; Phosphatidylethanolamines; Statistics, Nonparametric
PubMed: 29483538
DOI: 10.1038/s41598-018-21915-8 -
Molecules (Basel, Switzerland) Jun 2023Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of... (Review)
Review
Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current 'opioid crisis', warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to -methylmorphinans to limit their ability to cross the blood-brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy.
Topics: Humans; Analgesics, Opioid; Morphinans; Pain; Analgesics; Morphine; Receptors, Opioid, mu
PubMed: 37375318
DOI: 10.3390/molecules28124761 -
Reviews in Cardiovascular Medicine Sep 2021Intravenous morphine is a controversial treatment for acute heart failure (AHF). This study aimed to evaluate and compare the efficacy of intravenous morphine treatment... (Meta-Analysis)
Meta-Analysis
Intravenous morphine is a controversial treatment for acute heart failure (AHF). This study aimed to evaluate and compare the efficacy of intravenous morphine treatment vs. no morphine treatment in AHF patients. Relevant research conducted before June 2020 was retrieved from electronic databases. One unpublished study of our own was also included. Studies were eligible for inclusion if they compared AHF patients treated with intravenous morphine and patients who did not receive morphine. This meta-analysis included three propensity-matched cohorts and two retrospective analyses, involving a total of 149,967 patients (intravenous-morphine group, n = 22,072; no-morphine group, n = 127,895). There was a non-significant increase in the in-hospital mortality in the morphine group (combined odds ratio [OR] = 2.14, 95% confidence interval [CI]: 0.88-5.23, = 0.095, = 97.1%). However, subgroup analyse showed that the rate of in-hospital mortality with odds of 1.41 times more likely (95% CI: 1.11-1.80, = 0.005, = 0%) in those receiving vs. not receiving intravenous morphine. No significant correlation was found between intravenous morphine and invasive mechanical ventilation (OR = 2.19, 95% CI: 0.84-5.73, = 0.10, = 94.2%; subgroup analysis: OR = 2.24, 95% CI: 0.70-7.21, = 0.176, = 95.1%) or long-term mortality (hazard ratio = 1.15, 95% CI: 0.96-1.34, = 0.335; = 8.6%). The administration of intravenous morphine to patients with AHF may be related to in-hospital mortality, but not to invasive mechanical ventilation and long-term mortality.
Topics: Acute Disease; Heart Failure; Hospital Mortality; Humans; Morphine; Retrospective Studies
PubMed: 34565084
DOI: 10.31083/j.rcm2203092