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Progress in Neuro-psychopharmacology &... Jan 2024Few pharmacological treatments are available for substance use disorders (SUDs). Neuroplastic changes induced by increased activity of metalloproteinase (MMP) enzymes in...
Few pharmacological treatments are available for substance use disorders (SUDs). Neuroplastic changes induced by increased activity of metalloproteinase (MMP) enzymes in the brain are among the several molecular processes that may play a role in drug addiction. Doxycycline, a widely used tetracycline that crosses the blood-brain barrier, inhibits MMPs and has been investigated as a potential treatment for brain disorders. However, the effects of doxycycline on rewarding properties of drugs of abuse remain not investigated. Here, we tested the effects of low doses of doxycycline on the rewarding effects of morphine and cocaine in conditioned place preference (CPP) and locomotor sensitization in mice. Acute doxycycline (10 mg/kg) attenuated the cocaine-induced CPP and hyperlocomotion. Repeated doxycycline (10 mg/kg) blocked hyperlocomotion and attenuated the locomotor sensitization induced by cocaine. It also decreased the rewarding effects in the CPP induced by morphine and cocaine. Our results suggest that doxycycline could be repurposed for treating SUDs.
Topics: Mice; Animals; Morphine; Cocaine; Doxycycline; Substance-Related Disorders; Reward
PubMed: 37793480
DOI: 10.1016/j.pnpbp.2023.110870 -
Journal of Equine Veterinary Science Jul 2021The study aim is to compare the effects of epidural administration of two different doses of romifidine combined with morphine in horses. A prospective crossover blinded...
The study aim is to compare the effects of epidural administration of two different doses of romifidine combined with morphine in horses. A prospective crossover blinded experimental design was used. Five adult healthy horses two males and three females with a mean body weight of 380 ± 45 Kg (335-425 kg), were studied. Treatments consisted of romifidine 30 μg/kg (R30) or 60 μg/kg (R60) combined with morphine 0.1 mg/kg with a washout interval of 72 hours, administered through an epidural catheter placed at the first intercoccygeal space. Heart rate (HR) and respiratory rate (f), pH, blood gases, arterial blood pressures (mmHg), and threshold for electrical noxious stimulation was evaluated for 120 minutes and after 240 minutes of epidural injection. Data were collected before injections and every 15 minutes for 120 minutes, and at 240 minutes of epidural administration. Significant sedation occurred in both treatments with no statistically significant difference between them. There were significant changes in f and HR from baseline but no difference between treatments. Arterial blood pressures were significantly lower in R60 treatment from 75 up to 120 minutes post epidural injection. Analgesia was considered moderate for both treatments lasting longer with romifidine at 60 μg/kg. Epidurally administered romifidine and morphine combination in horses produces dose-dependent sedation, arterial hypotension, and antinociceptive effects.
Topics: Analgesics; Animals; Female; Horses; Imidazoles; Male; Morphine; Prospective Studies
PubMed: 34119202
DOI: 10.1016/j.jevs.2021.103459 -
Acta Neurobiologiae Experimentalis 2021Morphine and tramadol are the opioid analgesic drugs acting via activation of μ‑opioid receptors. It is important to understand which mechanism (synergistic or...
Morphine and tramadol are the opioid analgesic drugs acting via activation of μ‑opioid receptors. It is important to understand which mechanism (synergistic or additive anti‑nociceptive activity) induced potent anti‑nociceptive effect by co‑administration of morphine and tramadol. Identification of new strategies that can potentiate analgesic effects of opioids will be good therapeutic approaches for pain relief. To this aim, male mice were cannulated in the left ventricle by a stereotaxic instrument. A tail‑flick test was used to record the pain threshold. The results revealed that intracerebroventricularly injection of morphine induced an anti‑nociceptive effect in non‑sensitized and morphine‑sensitized mice. We found that infusion of tramadol produced an anti‑nociceptive response in non‑sensitized mice, whereas tramadol in doses of 0.5 and 1 μg/mouse induced analgesia in morphine‑sensitized mice. Co‑injection of a non‑effective dose of tramadol or morphine (0.25 μg/mouse) with different doses of morphine or tramadol (0.25, 0.5, and 1 μg/mouse) respectively potentiated the analgesic effect of the previous drug. An isobolographic analysis of data was performed, indicating a synergistic interaction between morphine and tramadol in non‑sensitized and morphine‑sensitized mice. Our data indicated that both morphine and tramadol elicit more anti‑nociceptive response in morphine sensitized mice; there is a synergistic effect between morphine and tramadol upon induction of analgesic effect in non‑sensitized and morphine‑sensitized mice.
Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Male; Mice; Morphine; Pain; Pain Measurement; Tramadol
PubMed: 35014984
DOI: No ID Found -
British Journal of Anaesthesia Oct 2021Intrathecal morphine in combination with fentanyl is an effective and safe alternative to diamorphine for Caesarean delivery analgesia. Evidence suggests minimal... (Comparative Study)
Comparative Study
Intrathecal morphine in combination with fentanyl is an effective and safe alternative to diamorphine for Caesarean delivery analgesia. Evidence suggests minimal differences in clinical efficacy and side-effects between intrathecal morphine and diamorphine. Recommended intrathecal morphine doses for Caesarean delivery analgesia are 100-150 ug.
Topics: Analgesia, Obstetrical; Analgesics, Opioid; Cesarean Section; Dose-Response Relationship, Drug; Evidence-Based Medicine; Female; Fentanyl; Heroin; Humans; Injections, Spinal; Morphine; Pregnancy
PubMed: 34362559
DOI: 10.1016/j.bja.2021.06.023 -
Pharmacology Research & Perspectives Oct 2022Morphine is frequently applied in cancer patients for pain management. However, its effects on cancer are not well understood but observed to be specific to certain...
Morphine is frequently applied in cancer patients for pain management. However, its effects on cancer are not well understood but observed to be specific to certain cancer types. We previously revealed the stimulatory properties of morphine in esophageal carcinoma. This work addressed the effects of morphine and its underlying mechanisms in cervical cancer. Proliferation, apoptosis, and migration assays were performed to examine the effects of morphine alone and its combinatory effects with chemotherapeutic drugs. Immunoblotting and biochemical analysis were performed to determine the underlying mechanisms of morphine's action. Morphine promoted proliferation in opioid receptor-dependent manner and stimulated migration in opioid receptor-independent manner. However, morphine did not affect cervical cancer cell survival. Morphine also interfered with all tested chemotherapeutic drugs (e.g., cisplatin, 5-FU, and paclitaxel) and alleviates their efficacy. Mechanistically, morphine-stimulated growth via activating EGFR-mediated signaling pathways and is opioid-receptor-dependent; morphine-stimulated migration via activating RhoA-mediated signaling pathways and this is opioid receptor-independent. Our work suggests a strong correlation of this opioid receptor on growth factor signaling to stimulate growth and opioid receptor-independent activation of RhoA and consequent migration. Our findings have the potential to guide the clinical use of morphine for patients with cervical cancer.
Topics: Analgesics, Opioid; Cisplatin; ErbB Receptors; Female; Fluorouracil; Humans; Morphine; Paclitaxel; Receptors, Opioid; Uterine Cervical Neoplasms
PubMed: 36200813
DOI: 10.1002/prp2.1016 -
Drug Development Research Sep 2021Morphine-6-O-sulfate (M6S), a polar, zwitterionic sulfate ester of morphine, is a powerful and safe analgesic in several rat models of pain. A sensitive liquid...
Morphine-6-O-sulfate (M6S), a polar, zwitterionic sulfate ester of morphine, is a powerful and safe analgesic in several rat models of pain. A sensitive liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated for the simultaneous determination of M6S and morphine (MOR) in rat plasma and brain after M6S administration. Morphine-d was used as internal standard. Multiple reaction monitoring was used for detection and quantitation of M6S, MOR, and morphine-d in the turbo ion spray positive mode. The chromatographic separation was carried out on an Alltech Altima C18 column. The analytical method was validated for linearity, precision, accuracy, specificity, and stability over a concentration range of 3-8000 ng/ml in rat plasma and 10-10,000 ng/ml in brain samples for both M6S and MOR. The validated method was applied to determine the PK profile of M6S in plasma after i.v., i.p., and oral dosing in male Sprague-Dawley rats. Rats were administered M6S by i.p. administration (5.6 and 10.0 mg/kg) or orally (10 and 30 mg/kg) and bioavailability compared to an i.v. injection (1 mg/kg) of M6S. The in vivo results indicate that M6S is not a prodrug of morphine, since M6S is not biotransformed into MOR in plasma after either i.p. or oral administration, and MOR was not detected in brain. The bioavailability of M6S was >93% and about 5% after i.p. and oral dosing, respectively. The low oral bioavailability of M6S may be due to poor permeation of the intestinal epithelial membrane. After i.p.-administration, M6S appears to reach brain tissues in low, but significant, concentrations.
Topics: Animals; Brain; Male; Morphine; Morphine Derivatives; Rats; Rats, Sprague-Dawley
PubMed: 33427316
DOI: 10.1002/ddr.21785 -
Molecular Psychiatry Apr 2021Opioids, such as morphine, are clinic analgesics which induce euphoria. Morphine exposure modifies the excitability and functional interactions between neurons, while...
Opioids, such as morphine, are clinic analgesics which induce euphoria. Morphine exposure modifies the excitability and functional interactions between neurons, while the underlying cellular and molecular mechanisms, especially how morphine assembles heterogeneous interneurons (INs) in prelimbic cortex (PrL) to mediate disinhibition and reward, are not clear. Using approaches of optogenetics, electrophysiology, and cell type-specific RNA-seq, we show that morphine attenuates the inhibitory synaptic transmission from parvalbumin (PV)-INs onto pyramidal neurons in PrL via μ-opioid receptor (MOR) in PV-INs. Meanwhile, morphine enhances the inhibitory inputs from somatostatin (SST)-INs onto PV-INs, and thus disinhibits pyramidal neurons via δ-opioid receptor (DOR)-dependent Rac1 upregulation in SST-INs. We show that MOR in PV-INs is required for morphine-induced behavioral sensitization, while DOR as well as Rac1 activity in SST-INs is required for morphine-induced conditioned place preference and hyper-locomotion. These results reveal that SST- and PV-INs, functioning in PrL as a disinhibitory architecture, are coordinated by morphine via different opioid receptors to disinhibit pyramidal neurons and enhance reward.
Topics: Interneurons; Morphine; Parvalbumins; Pyramidal Cells; Reward
PubMed: 31413370
DOI: 10.1038/s41380-019-0480-7 -
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 -
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