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Brain and Behavior Dec 2021Morphine is the predominantly used drug for postoperative and cancer pain management. However, the abuse potential of morphine is the primary disadvantage of using...
PURPOSE
Morphine is the predominantly used drug for postoperative and cancer pain management. However, the abuse potential of morphine is the primary disadvantage of using opioids in pain management. Melatonin is a neurohormone synthesized in the pineal gland and is involved in circadian rhythms in mammals, as well as other physiological functions. Melatonin provenly attenuates alcohol-seeking and relapse behaviors in rats. Therefore, we aimed to investigate the involvement of the melatonergic system in attenuating morphine dependence.
MATERIALS AND METHODS
Male Wistar rats were divided into three groups: control, morphine, and morphine + melatonin. Animals were habituated for 3 days, and the initial preference was evaluated. Following the initial preference, the control group received the vehicle and was placed for a 45-min session in the assigned chamber every day, alternating between the two chambers, for 8 days. The morphine group received a morphine injection (5 mg/kg, IP) and was placed for a 45-min session in the white chamber, for a total of four sessions. The morphine + melatonin group received the morphine injection (5 mg/kg, IP) for a total of four sessions over an 8-day period. In the posttest session, the control and morphine groups received a vehicle injection 30 min before placement in the conditioned place preference (CPP). The morphine + melatonin group received a single injection of melatonin (50 mg/kg, IP) 30 min before the preference test.
RESULTS
Statistical analysis revealed that repeated administration of morphine for four sessions produced a significant increase in the CPP score in the morphine group compared to the control group. However, a single melatonin injection administered 30 min before the posttest attenuated morphine-seeking behavior and reduced morphine-induced place preference.
CONCLUSION
These findings provide novel evidence for the role of the melatonergic system as a potential target in modulating morphine-seeking behavior.
Topics: Analgesics, Opioid; Animals; Conditioning, Classical; Male; Melatonin; Morphine; Rats; Rats, Wistar
PubMed: 34710287
DOI: 10.1002/brb3.2397 -
BMC Pharmacology & Toxicology Dec 2022Patients with cancer rely on morphine for analgesia, while studies have indicated morphine can induce immunosuppression in cancer. Therefore, investigating the...
BACKGROUND
Patients with cancer rely on morphine for analgesia, while studies have indicated morphine can induce immunosuppression in cancer. Therefore, investigating the immunosuppressive roles and molecular mechanism of morphine on lung cancer progression is imperative.
METHODS
Lactate dehydrogenase (LDH) release assay was used to determine the cytotoxicity of morphine to lung cancer cells. The percentage of CD4 and CD8 T cells was detected by flow cytometry. In addition, Maelstrom (MAEL), Nrf2, and PTEN were determined by western blot and RT-qPCR. Immune factors programmed death-ligand 1 (PD-L1), transforming growth factor (TGF-β), interleukin (IL)-10, and IL-2 were determined by western blot and ELISA assay.
RESULTS
Morphine increased the levels of PD-L1, TGF-β, and IL-10, while decreased IL-2 level. Morphine enhanced MAEL expression in A549 cells and H460 cells. Morphine up-regulated Nrf2 and down-regulated PTEN, and morphine-induced MAEL up-regulation was reversed by PTEN. However, MAEL silencing inhibited the enhanced effects of morphine on cell viability and proliferation of A549 cells. Furthermore, morphine treatment reduced the LDH release and the percentage of CD8 T cells, and increased the ratio of CD4/CD8 T cells and tumor weight. Meanwhile, MAEL silencing reversed the effects of morphine on immune factors (PD-L1, TGF-β, IL-10, and IL-2), the percentage of CD8 T cells, and the ratio of CD4/CD8 T cells.
CONCLUSION
Morphine activated MAEL in lung cancer cells by Nrf2/PTEN pathway and regulated the immune factors, thereby promoting tumor immune escape.
Topics: Humans; B7-H1 Antigen; Morphine; Interleukin-10; CD8-Positive T-Lymphocytes; Interleukin-2; Lung Neoplasms; Transforming Growth Factor beta; Immunity
PubMed: 36476246
DOI: 10.1186/s40360-022-00632-z -
Basic & Clinical Pharmacology &... Jul 2022Tramadol is a commonly used opioid with a potential of addiction and abuse. Using Danish nationwide registers, we aimed to (1) characterise opioid poisonings; (2) assess...
Tramadol is a commonly used opioid with a potential of addiction and abuse. Using Danish nationwide registers, we aimed to (1) characterise opioid poisonings; (2) assess the 30-day mortality following morphine, oxycodone, and mixed poisonings compared to tramadol poisonings; and (3) assess the development in tramadol poisonings during a 12-year period. Poisonings were identified from 2006 to 2017. A Cox proportional hazards regression model was used to estimate adjusted hazard ratios (aHRs) along with 95% confidence intervals (CIs) for 30-day mortality following morphine, oxycodone or mixed poisonings compared to tramadol poisonings. We identified 7718 opioid poisonings among 6365 patients. The patients with a tramadol poisoning were younger and had less comorbidities than the patients with a morphine, oxycodone or mixed poisoning. Within 30 days, a total of 205 patients died. The 30-day mortality risk was higher following morphine (aHR 3.2, 95% CI 2.0-5.1), oxycodone (aHR 2.1, 95% CI 1.2-3.6) and mixed poisonings (aHR 1.6, 95% CI 1.0-2.7) compared to tramadol poisonings. The annual number of tramadol poisonings increased from 233 in 2006 to 501 in 2013 and declined to 348 in 2017. In conclusion, despite a lower mortality risk compared to other opioid poisonings, physicians should consider the poisoning and abuse risks when prescribing tramadol.
Topics: Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Denmark; Humans; Morphine; Oxycodone; Tramadol
PubMed: 35538919
DOI: 10.1111/bcpt.13741 -
Indian Journal of Pharmacology 2023
Topics: Ketamine; Morphine; Analgesics, Opioid
PubMed: 38174540
DOI: 10.4103/ijp.ijp_230_23 -
The International Journal of... Jul 2023Evidence has accumulated demonstrating the existence of opioid receptor heteromers, and recent data suggest that targeting these heteromers could reduce opioid side...
BACKGROUND
Evidence has accumulated demonstrating the existence of opioid receptor heteromers, and recent data suggest that targeting these heteromers could reduce opioid side effects while retaining therapeutic effects. Indeed, CYM51010 characterized as a MOR (mu opioid receptor)/DOR (delta opioid receptor) heteromer-preferring agonist promoted antinociception comparable with morphine but with less tolerance. In the perspective of developing these new classes of pharmacological agents, data on their putative side effects are mandatory.
METHODS
Therefore, in this study, we investigated the effects of CYM51010 in different models related to drug addiction in mice, including behavioral sensitization, conditioned place preference and withdrawal.
RESULTS
We found that, like morphine, CYM51010 promoted acute locomotor activity as well as psychomotor sensitization and rewarding effect. However, it induced less physical dependence than morphine. We also investigated the ability of CYM51010 to modulate some morphine-induced behavior. Whereas CYM51010 was unable to block morphine-induced physical dependence, it blocked reinstatement of an extinguished morphine induced-conditioned place preference.
CONCLUSIONS
Altogether, our results reveal that targeting MOR-DOR heteromers could represent a promising strategy to block morphine reward.
Topics: Mice; Animals; Morphine; Receptors, Opioid, delta; Receptors, Opioid, mu; Analgesics, Opioid; Reward
PubMed: 37343217
DOI: 10.1093/ijnp/pyad032 -
Behavioural Pharmacology Dec 2021Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types...
Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types of pain and in humans is unclear. Because a majority of chronic pain patients are women, and sex differences in morphine and THC potencies have been observed in rodents, the present study examined sex-specific effects of morphine and THC given alone and in combination, in rats with persistent inflammatory pain. On day 1, baseline mechanical and thermal response thresholds, hindpaw weight-bearing, locomotor activity, and hindpaw thickness were determined. Inflammation was then induced via hindpaw injection of complete Freund's adjuvant (CFA). Three days later, morphine (s.c.), THC (i.p) or a morphine-THC combination (1:1, 3:1 and 1:3 dose ratios) was administered, and behavioral testing was conducted at 30-240 min postinjection. Morphine alone was antiallodynic and antihyperalgesic, with no sex differences, but at some doses increased weight-bearing on the CFA-treated paw more in males than females. THC alone reduced mechanical allodynia with similar potency in both sexes, but reduced thermal hyperalgesia and locomotor activity with greater potency in females than males. All morphine-THC combinations reduced allodynia and hyperalgesia, but isobolographic analysis of mechanical allodynia data showed no significant morphine-THC synergy in either sex. Additionally, whereas morphine alone was antinociceptive at doses that did not suppress locomotion, morphine-THC combinations suppressed locomotion and did not increase weight-bearing on the inflamed paw. These results suggest that THC is unlikely to be a beneficial adjuvant when given in combination with morphine for reducing established inflammatory pain.
Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Female; Freund's Adjuvant; Hyperalgesia; Inflammation; Locomotion; Male; Morphine; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley; Sex Factors
PubMed: 34561365
DOI: 10.1097/FBP.0000000000000657 -
BMC Anesthesiology Oct 2021Angiogenesis, the formation of blood vessel from pre-existing ones, plays an important role in many pathophysiological diseases, such as cancer. Opioids are often used... (Comparative Study)
Comparative Study
BACKGROUND
Angiogenesis, the formation of blood vessel from pre-existing ones, plays an important role in many pathophysiological diseases, such as cancer. Opioids are often used in clinic for the management of chronic pain in cancer patients at terminal phases. Here, we investigated and compared the effects and mechanisms of four opioids on angiogenesis.
METHODS
We performed angiogenesis assays on human umbilical vein endothelial cells (HUVEC) that represent an in vitro model to assess the toxicity of drugs to endothelium.
RESULTS
Morphine and oxycodone at 0.1 μM to 100 μM dose-dependently increased endothelial cell tube formation and proliferation. We observed the same in endothelial cells exposed to fentanyl at 0.1 μM to 10 μM but there was a gradual loss of stimulation by fentanyl at 100 μM and 1000 μM. Morphine and fentanyl reduced endothelial cell apoptosis-induced by serum withdrawal whereas oxycodone did not display anti-apoptotic effect, via decreasing Bax level. Oxycodone at the same concentrations was less potent than morphine and fentanyl. Different from other three opioids, codeine at all tested concentrations did not affect endothelial cell tube formation, proliferation and survival. Mechanism studies demonstrated that opioids acted on endothelial cells via μ-opioid receptor-independent pathway. Although we observed the increased phosphorylation of mitogen-activated protein kinase (MAPK) in cells exposed to morphine, fentanyl and oxycodone, the rescue studies demonstrated that the stimulatory effects of morphine but not fentanyl nor oxycodone were reversed by a specific MAPK inhibitor.
CONCLUSION
Our work demonstrates the differential effects and mechanisms of opioids on angiogenesis.
Topics: Analgesics, Opioid; Cell Proliferation; Cells, Cultured; Endothelial Cells; Fentanyl; Humans; Mitogen-Activated Protein Kinases; Morphine; Neovascularization, Physiologic; Oxycodone; Phosphorylation; Umbilical Veins
PubMed: 34702181
DOI: 10.1186/s12871-021-01475-7 -
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 -
Addiction Biology Feb 2024Humans demonstrate significant behavioural advantages with particular perceptual dimensions (such as colour or shape) and when the relevant dimension is repeated in...
Humans demonstrate significant behavioural advantages with particular perceptual dimensions (such as colour or shape) and when the relevant dimension is repeated in consecutive trials. These dimension-related behavioural modulations are significantly altered in neuropsychological and addiction disorders; however, their underlying mechanisms remain unclear. Here, we studied whether these behavioural modulations exist in other trichromatic primate species and whether repeated exposure to opioids influences them. In a target detection task where the target-defining dimension (colour or shape) changed trial by trial, humans exhibited shorter response time (RT) and smaller event-related electrodermal activity with colour dimension; however, macaque monkeys had shorter RT with shape dimension. Although the dimensional biases were in the opposite directions, both species were faster when the relevant dimension was repeated, compared with conditions when it changed, across consecutive trials. These indicate that both species formed dimensional sets and that resulted in a significant 'switch cost'. Scheduled and repeated exposures to morphine, which is analogous to its clinical and recreational use, significantly augmented the dimensional bias in monkeys and also changed the switch cost depending on the relevant dimension. These cognitive effects occurred when monkeys were in abstinence periods (not under acute morphine effects) but expressing significant morphine-induced conditioned place preference. These findings indicate that significant dimensional biases and set formation are evolutionarily preserved in humans' and monkeys' cognition and that repeated exposure to morphine interacts with their manifestation. Shared neural mechanisms might be involved in the long-lasting effects of morphine and expression of dimensional biases and set formation in anthropoids.
Topics: Humans; Animals; Morphine; Haplorhini; Analgesics, Opioid; Conditioning, Classical; Cognition
PubMed: 38333998
DOI: 10.1111/adb.13380 -
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