A novel electrochemical sensor based on multi-walled carbon nanotubes doped with vanadium pentoxide/telluride (MWCNTs@V2O5/Te) was developed for the detection and quantification of morphine sulfate in real biological samples. MWCNTs@V2O5/Te nanocomposite was functionalized with cysteamine as a linker, to create thiol interaction with the -OH group of the MWCNTs@V2O5/Te nanocomposite at one end, and free -NH2 group interaction with the -OH group on morphine sulfate, on the other end. This modification enhances the conjugation capability of morphine sulfate with the fabricated biosensor.(MWCNTs@V2O5/Te-Cys/GCE). MWCNTs@V2O5/Te nanocomposite morphological and structural analysis is carried out by SEM, TEM, EDX, FTIR, and UV-Vis spectroscopy. At varying concentrations and pH levels, the electrochemical sensor response of the modified electrode is investigated using cyclic voltammetry (CV). To validate the findings, differential pulse voltammetry (DPV), electrochemical impedance spectroscopy (EIS), and chronoamperometry are employed to investigate morphine sulfate detection, yielding excellent results in real biological samples. The fabricated sensor, as indicated by the calibration curve, exhibits a wide linear range of 10-60 µM and a limit of detection (LOD) of 0.01µM by DPV. These results reveal that this novel sensor is highly stable, sensitive, and reproducible for detecting morphine sulfate. Therefore, this developed sensing platform can be used in clinical diagnostics, narcotics detection, and forensic analysis.

Ankle fractures are common, and cryotherapy is routinely used to reduce pain, swelling and local skin complications, both before and after surgery. The aim of this study is to report the results with the use of pre-operative third-generation cryotherapy (Z-One®, Zamar, Italy) in the management of patients with ankle fractures. We investigated the time to surgery, pain, opioid intake, and local skin complications. 169 patients with ankle fracture were randomised into two groups, the cryotherapy group (89 patients) and the control group (C: 80 patients). The time-to-surgery, Visual Analogue Scale (VAS) and the analgesic drug demands (Morphine Sulfate 10mg/ml solution for injection) were recorded. The development of skin complications was assessed on a daily basis. BMI and the number of cigarettes smoked were also recorded. The mean time-to-surgery was shorter in patients treated with cryotherapy compared to the control group (34.78h vs. 91.44h, p < 0.001). Significant differences between treatments and controls were found for VAS, morphine intake (number of vials), and skin complications. The mean preoperatory VAS and morphine consumption were lower in the cryotherapy group compared to controls (mean VAS 2.04 vs. 5.9, mean morphine consumption 0.1mg vs. 0.83mg). In the cryotherapy group, 4.5% of patients developed a skin complication compared to 28.7% of the control group; 85% of skin-related problems occurred in the non-cryotherapy group (p < 0.001). Preoperative third-generation cryotherapy is effective in reducing time to surgery, preoperative pain, and opioid intake in patients hospitalised for ankle fractures. It is also effective in reducing the occurrence of skin complications. No major complications related to the use of the device were reported. Third-generation cryotherapy is useful in the perioperative management of patients necessitating surgery for ankle fractures. Clinical Trial Registration NCT06396364. Level of evidence I (RCT).

Purpose: Patients with end-stage knee osteoarthritis typically undergo total knee arthroplasty (TKA), a surgical procedure that has long been considered a cost-effective treatment. However, moderate to severe postoperative pain is a common problem following TKA. Therefore, in this study, we aimed to compare the effects of postoperative pain management using conventional periarticular infiltration (conventional periarticular infiltration [PA]) versus modified periarticular infiltration (modified PA). Methods: This study was designed as a randomized controlled non-inferiority clinical trial conducted from April 2024 to April 2025. A total of 58 patients undergoing primary unilateral TKA were enrolled and randomly assigned to receive either modified PA or conventional PA. The primary outcome was postoperative pain within the first 24 h after surgery, measured using the visual analog scale. Secondary outcomes included time to first morphine hydrochloride rescue, total morphine consumption during the first 24 postoperative hours, and length of hospital stay (LOS). Results: Modified PA was non-inferior to conventional PA for postoperative pain control at rest and during movement within 24 h after TKA. Time to first morphine rescue, 24 h morphine consumption, and LOS did not differ significantly between the groups. All mean differences and corresponding 95% confidence intervals remained within the predefined non-inferiority margin of 0.5. Conclusions: Modified PA and conventional PA provided comparable pain relief during the first 24 h after TKA and showed similar times to first morphine rescue. Morphine consumption and LOS were similar between the groups. These findings may inform the selection of intraoperative analgesic infiltration techniques.

Development and application of hair matrix reference materials for the determination of morphine, cocaine, 3,4-methylenedioxymethamphetamine, methamphetamine, and their metabolites.

Agarose-loaded mesoporous silica nanocomposite embedded in a polyether sulfone substrate for thin film solid-phase microextraction: An approach for narcotic drugs extraction from eye tears in a multi-channel microfluidic device prior to liquid chromatography-tandem mass spectrometry.

GPRASP1 deletion suppresses antinociceptive tolerance during chronic activation of delta opioid receptor in persistent pain.

Five novel platinum(II) complexes C1–C5 were synthesized in the reaction of the appropriate substituted 4-nitroisothiazoles with K2PtCl4 and characterized with elemental analysis, ESI MS spectrometry, NMR spectroscopy, and IR spectroscopy. Also, a new methyl 3-methyl-4-nitroisothiazole-5-carboxylate (L2) was obtained. The structures of trans complex C4 and the new isothiazole derivative L2 were additionally confirmed by X-ray diffraction (XRD) method. The cytotoxicity of the investigated complexes was examined in vitro on three human cancer cell lines (MCF-7 breast, ES-2 ovarian, and A549 lung adenocarcinomas) in both normoxic and hypoxic conditions. The tested complexes, except for the most polar cisC5, which appeared to be the least active, showed cytotoxic activity comparable to that of the reference cisplatin. cis-complex C1, transC2, and transC3 showed slightly better cytotoxic activity than cisplatin against the MCF-7 cell line. The complexes had the weakest effect on the A549 cell line. No differences in the cytotoxic activity of the complexes were observed between normoxic and hypoxic conditions, except for the A549 cell line, where all the complexes, except for C2, were inactive in hypoxia. However, most complexes, including the reference cisplatin, were equally toxic to healthy BALB/3T3 cells and cancer cells. The trans complex C2 (isomeric to cisC1) showed even greater toxicity to healthy cells than to MCF-7 and A549 cancer cells. Some complexes were tested for stability against glutathione (GSH) solution to gain additional information that may facilitate the explanation of the pharmacological activity of the tested compounds. Additionally, some theoretical calculations on the thermochemistry of the complexation process were performed using quantum density functional theory (DFT), which indicate that complexation should occur through the coordination of the platinum cation by the nitrogen rather than the sulfur atom of the isothiazole ring.

Adults who are critically ill frequently require multiple intravenous infusions through limited vascular access, making Y-site co-infusion unavoidable. However, much of the primary compatibility literature uses concentrations, diluents and visual-only methods that do not reflect contemporary intensive care unit (ICU) practice, risking false reassurance at the bedside. To create an ICU-specific, concentration-matched Y-site compatibility chart aligned to standardised infusion concentrations and to identify compatible, conditional, incompatible and no-data drug-pairs. We performed a PRISMA (preferred reporting items for systematic reviews and meta-analyses) guided, method-stratified synthesis (1970-2025) of in-vitro Y-site evidence from PubMed, Trissel's and Micromedex. Classifications privileged instrumented endpoints (pH, turbidimetry, sub-visible particles, high-performance liquid chromatography) over visual inspection. Drug-drug pairs were mapped to our tertiary adult ICU formulary; medicines with an established ward standard were deemed ICU standardised. compatible (C), compatible in saline only (Csf), conditional (concentration/diluent dependent; applied only when at least one medicine was ICU standardised), incompatible-physical (Ie/Ip/It) or chemical (Iq)-or no data (ND). Among 4465 mapped drug-pairs, 43.94% were compatible (C 42.37%, Csf 1.57%); 2.53% were conditional; 8.24% were incompatible-predominantly physical; and 45.29% lacked eligible evidence. High-risk clusters included lipid emulsions (eg, propofol, clevidipine), extreme-pH agents (eg, amiodarone, furosemide), phenytoin and calcium salts. For morphine hydrochloride, evidence was sparse (76% ND, 21% compatible, 1% conditional, 2% incompatible). Amiodarone exemplified concentration non-concordance; with an ICU concentration of 15 mg/mL, 34% of amiodarone drug-pairs had compatibility that was concentration dependent. At standardised ICU concentrations, fewer than half of potential Y-site pairings are unequivocally compatible and nearly half have no concentration-matched data. A conservative, method-stratified framework anchored to exact concentration and diluent mitigates risk and exposes evidence gaps. Applying a conservative, method-stratified framework anchored to exact concentration and diluent mitigates risk while revealing priority evidence gaps-especially for lipid emulsions, calcium-containing solutions, extreme-pH drugs and opioids. Embedding the chart within the electronic prescribing and medicines administration (EPMA) system can deliver checks, standardise line allocation, reduce uncertain Y-site mixing and prioritise dedicated lumens for high-risk agents.

The Wistar-Kyoto rat strain (WKY) is a model for treatment-resistant depression, exhibiting behaviors indicative of anhedonia. Although anhedonia is measured using the sucrose preference test (SPT), 50-kHz ultrasonic vocalizations (USVs) hold promise as a complementary assessment tool. This study aimed to detect whether 50-kHz USVs differ in the WKY rats compared to control Wistar (W) rats. First, WKY and W rats were compared for their basal 50-kHz calls. Then, rats were repeatedly treated with four administrations of either amphetamine (AMPH) or morphine (MORPH), and 50-kHz calls were recorded. In addition, the drug-evoked locomotor activity, sucrose consumption in the SPT, and the time spent in the drug- vs. saline-paired compartment in the conditioned place preference (CPP) test were collected. WKY rats emitted fewer basal calls and fewer calls following the first and the fourth AMPH administration. Contrary to controls, AMPH did not affect the number of calls in WKY rats following the first administration. WKY also displayed reduced AMPH-induced locomotor activity and sucrose consumption in the SPT. MORPH did not affect USVs or locomotion in either strain. The results highlight the benefits of 50-kHz calls as a complementary behavioral marker for assessing anhedonia in preclinical models of depression.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-27298-x.

To describe the pattern of contacts with the healthcare system associated with drug use in Spain in the years 2022 and 2023. For the period 2016-23, data derived from a registry of activity in specialized care, included in the clinical-administrative database of Spanish hospitals (Registro de Atención Especializada-Conjunto Mínimo Básico de Datos), were extracted. Contacts with the healthcare system associated with alcohol, cannabis, cocaine, morphine derivatives, and sedative-hypnotics use were analyzed. The methodology of endemic corridors was applied for each drug category based on data from 2016-21. The series of contacts in 2022 and 2023 were then represented in the corridors to compare their expected and observed pattern. A total of 193433 contacts associated with the use of alcohol (90735), cannabis (39730), cocaine (23485), morphine derivatives (4888), and sedative-hypnotics (34595) were analyzed for the period 2016-23. Of the contacts, 70.3% corresponded to men and 23.4% corresponded to people aged 45-54. The number of contacts increased for all categories of drugs in 2022 and 2023. This increase was reflected in the corridors, where contacts were mainly located in alert zones, and sometimes in epidemic zones. The results of this study show that endemic corridors allow the surveillance of the pattern of contacts with the healthcare system associated with drug use and, indirectly, of drug use itself. This methodology should be further studied as a complement in epidemiological surveillance of addictive behaviors at a population level.

The lack of suitable medical adsorbents that exhibita quick responseat the time of an overdose is challenging. In this work, we focusedon morphine (MORPH) adsorbents that efficiently abate MORPH duringthe acute overdose and provide, in a controlled, gradual manner, MORPHantagonistnaloxone (NAL) to effectively and safely reverseoverdose and its side effects by using, as sorbent, zirconium metal–organicframeworks (MOFs). Three model MOFs, including UiO-66, UiO-67, andNU-1000, were characterized in terms of their ability to adsorb MORPHas well as NAL release in water and a simulated body fluid (SBF).Single MORPH adsorption on NU-1000 was 100% in water and 90 wt % inSBF solution. At the same time, in a single NAL release in SBF fromthe prepared NAL@UiO-67 composite was equal to 76%. Additionally,in the simultaneous experiment of MORPH adsorption and NAL release,a designed mixture of NU-1000/NAL@UiO-67 has shown maximum adsorption/releasevalues in SBF solution of 89 and 8%, respectively. The in vivo andin vitro experiments confirmed the exceptional effect of preparedmaterials on the locomotor activity of mice and the low cytotoxicityof MOFs. In vivo fluorescent imaging has confirmed that the nano-MOFsobtained are mostly accumulated in the liver when administered intravenously.

Illicit drug abuse poses a significant global threat to public health and social security, highlighting the urgent need for rapid, sensitive, and versatile detection technologies. To address the limitations of traditional chromatographic techniques-such as high costs and slow response times-and the drawbacks of conventional immunochromatographic sensors (ICS), including low sensitivity and non-intuitive signal outputs, a fluorescence-quenching ICS (FQICS) was developed. This sensor leverages fluorescence resonance energy transfer (FRET) between aggregation-induced emission fluorescent microspheres (AIEFMs) and gold nanoparticles (AuNPs). The ICS operates on a positive signal-readout mechanism and is integrated with a smartphone-based portable reader, enabling rapid quantitative detection of methamphetamine (MET), morphine (MOR), and ketamine (KET). Detection limits of 0.041, 0.072, and 0.059ngmL-1 were determined for MET, MOR, and KET, respectively. Recovery rates ranged from 73% to 134% across urine, hair, saliva, and sewage samples, with intra-assay precision consistently below 15%, indicating robust performance in complex matrices. Furthermore, we developed a multiplexed AIEFM-FQICS, enabling the simultaneous detection of three illicit drugs, thereby enhancing detection efficiency and reducing the cost. Generally, this work presents a highly sensitive, field-deployable platform for real-time monitoring in drug interdiction and public safety emergencies, offering substantial potential for practical anti-drug applications.

Disclosure: E. Klindtworth: None. J. Bryant: None. B. Procaccini: None. Z. Khan: None. S.B. Stephens: None.Adolescence is a developmental period between 10 and 24 years old that causes behavioral, psychological, and emotional changes, causing an increased susceptibility to drug and alcohol usage. It is also a time of hormonal changes, including the onset of puberty. During adolescence, sex specific changes occur in neural development, including in response to opioids like morphine. These changes are most pronounced during the adolescent critical period when development and behavior are thought to be permanently altered. Previous studies have shown that morphine exposure during puberty can have lasting effects on behavior and hormone levels. This study aims to determine the effects of morphine exposure just prior to puberty (PND 23-27) on body weight and the timing of puberty onset. We hypothesized that morphine exposure prior to puberty would delay puberty onset in both sexes. Male and female adult Sprague Dawley Rats were obtained and bred. Litters were weaned on PND21 and pair-housed with open access to food and water. All rats (n=14-16/sex/treatment) were handled on PND 21 and PND 22 to acclimate them to injection procedures. Rats were subcutaneously injected with either Morphine Sulfate (3mg/kg-6mg/kg) or Sterile Saline, twice daily from PND 23-27, which is prior to puberty, as well as weighed once daily. Starting on PND 28, male and female rats were checked daily for puberty onset which was determined by Vaginal Opening (females) and Preputial Separation (males). Following Vaginal Opening, vaginal lavage was performed on females daily. We found no significant difference in age of vaginal opening (VO), first estrus, or preputial separation (PPS) between saline and morphine groups. Additionally, prepubertal body weight increased daily for both morphine and saline treated males and did not differ between treatment groups. Our study shows morphine exposure just prior to puberty did not have a significant impact on the age of vaginal opening or first estrus in females, and preputial separation in males, which does not support our hypothesis. Although the morphine treatment occurred prior to the presence of VO, first estrus, and PPS, it is possible that the cascade of events in the brain that triggers puberty onset was already started and thus, would not be affected by morphine exposure. Future studies should repeat the study during earlier age points as well as later ages (i.e. during puberty) to better understand how morphine interacts with the reproductive axis. Morphine exposure during this prepubertal time period may still have lasting effects on adult fertility and reproduction, despite having no effects on pubertal timing, and future studies are needed to determine the long-term consequences of adolescent morphine exposure.Presentation: Saturday, July 12, 2025

Abstract Background and Aims The management of medications in hemodialysis (HD) patients with cancer requires meticulous evaluation of the metabolic pathways. Consequently, in practice of palliative care for advanced cancer, HD patients may have difficulty in controlling renal metabolic drugs, leading to suboptimal pain control. Nonetheless, the specific status of palliative care for advanced cancer in HD patients have been documented only through limited case reports and remain insufficiently elucidated. The aim of this study is to elucidate real-world palliative care strategies for advanced cancer in HD patients by comparing with those implemented in non-HD patients. Method In our study, patients diagnosed with stage III or IV cancer were identified from the cancer registry data collected from 69 hospitals in Osaka Prefecture, Japan, between January 2019 and December 2021. To obtain more detailed information on treatment and pharmaceutical intervention, we integrated these data with Japan's Diagnosis Procedure Combination (DPC) data, resulting in the creation of a consolidated dataset. From this dataset, information on maintenance HD, the practice of palliative care, and the use of opioid analgesics—such as morphine sulfate, morphine hydrochloride, hydromorphone, oxycodone, fentanyl, and tramadol hydrochloride—was extracted. The patient characteristics, cancer types, the practice of palliative care, and the use of opioid analgesics were analyzed and compared between patients on maintenance HD and the non-HD. Results Among 57,917 patients diagnosed with stage Ⅲ or Ⅳ cancer, 377 patients (0.7%) were identified as receiving maintenance HD. The median age was 73 years (interquartile range: 68–79) for HD patients and 73 years (66–80) for non-HD patients, with no significant difference (P = 0.411). A higher proportion of HD patients were male compared to non-HD patients (78.8% vs. 61.2%, P &amp;lt; 0.001). There was no significant difference of cancer type between the two groups. HD patients had a higher prevalence of the practice of palliative care compared to non-HD patients (14,3% vs 10.4, P = 0.020). There was no significant difference in use of opioid analgesics (76.1% vs 72.7%, P = 0.462). However, regarding the opioid types, HD patients had a higher prevalence of fentanyl (65.3% vs 59.1%, P = 0.024) and tramadol hydrochloride (23.6% vs 14.2%, P &amp;lt; 0.001) use, and a lower prevalence of morphine hydrochloride (4.2% vs 8.2%, P = 0.004) and hydromorphone (1.9% vs 3.9%, P = 0.043) use compared to non-HD patients. There was no significant difference in use of morphine sulfate (0% vs 0.9%, P = 0.054) and oxycodone (13.3% vs 14.0%, P = 0.766). Conclusion In cancer patients with stage Ⅲ or Ⅳ, HD patients received a greater implementation of palliative care practices compared to non-HD patients. Although the use of opioid was comparable, the selection of drug types differed. Our findings indicate that HD patients received comprehensive palliative care through the use of pharmacological drugs targeting non-renal metabolic pathways.

Necroptosis, a form of programmed cell death, has emerged as a promising therapeutic target. Although several RIPK1 inhibitors have demonstrated favorable safety profiles in clinical trials, clinical translation of necroptosis-targeted therapies remains limited by modest efficacy, limited specificity, and species-specific activity of compounds such as necrosulfonamide (NSA). To resolve these challenges, this study identified a potential necroptosis inhibitor from a clinical drug library. Apomorphine (APO), a non-addictive morphine derivative used to treat Parkinson’s disease, was found to inhibit necroptosis by sterically blocking key residues involved in mixed lineage kinase domain-like protein (MLKL) activation and oligomerization, as confirmed by nuclear magnetic resonance analysis. APO is redox sensitive and prone to auto-oxidation. The oxidized form of APO (Ox-APO) showed stronger binding to MLKL than the reduced form of APO (Re-APO), as demonstrated by surface plasmon resonance analysis. Ox-APO significantly ameliorated tissue damage in two murine necroptosis models: dextran sulfate sodium (DSS)-induced colitis and acetaminophen (APAP)-induced liver injury. Collectively, these data highlight the therapeutic potential of APO as a necroptosis-specific inhibitor in necroptosis-related diseases in both humans and mice.

PurposeOur aim is to investigate whether an intra‐articular injection of tranexamic acid (TXA), administered alongside a standard multimodal analgesic cocktail, improves postoperative pain control and functional recovery.MethodsThis was a randomised, triple‐blind, placebo‐controlled clinical trial conducted from April 2022 to October 2023 at a tertiary care center. One hundred patients with isolated, unilateral, chronic ACL tears were randomised 1:1 to receive either an intra‐articular injection containing TXA (1 g), morphine sulphate, ketorolac, lidocaine and normal saline (intervention group) or an identical injection without TXA (control group). All surgeries were performed using hamstring autografts and standardised surgical and postoperative protocols. All patients received 15 mg/kg intravenous TXA in addition to intra‐articular TXA. The primary outcomes were pain scores (Visual Analogue Scale, VAS) at predefined time points up to 3 months. The secondary outcomes were Knee Injury and Osteoarthritis Outcome Score (KOOS), Lysholm scores, range of motion, swelling and morphine consumption.ResultsPostoperative pain scores did not differ significantly between groups at any time point (p > 0.05). Both groups demonstrated significant within‐group improvements over time in KOOS subscores (p < 0.001) and Lysholm scores (p < 0.001). Postoperative morphine consumption was similar in both groups (p > 0.05). The TXA group had better Lysholm scores at 1 month (85.8 ± 9.1 vs. 79.6 ± 13.9; p < 0.01). The TXA group had significantly better KOOS subscores and Lysholm scores at 3 months with moderate effect size (p < 0.01). No serious complications were observed in either group.ConclusionIntra‐articular TXA did not significantly reduce early postoperative pain or opioid use when added to a multimodal analgesic regimen and intravenous TXA in arthroscopic ACL reconstruction. However, it was associated with modest improvements in functional recovery at 1 and 3 months postoperatively, as measured by KOOS and Lysholm scores.Level of EvidenceLevel I.

INTRODUCTION: Prolonged morphine use can trigger dependence and addiction leading to severe withdrawal symptoms upon cessation. Oxidative stress is a key factor in its pathogenesis. Olea europaea (olive) oil, rich in polyphenols and oleuropein, exhibits antioxidant, anti-inflammatory and neuroprotective properties. Thus, this study aimed to evaluate the effects of Olea europaea oil in alleviating morphine withdrawal symptoms in morphine-dependent rats. MATERIALS AND METHODS: A total of eighteen rats were randomly divided into three groups. The control group received normal saline, while the positive control group received intraperitoneal injections of morphine sulphate (2.5 mg/kg to 50 mg/kg) for seven days. The treatment group received the same morphine doses followed by oral administration of 250 mg/kg Olea Europaea oil for twenty-one days during morphine withdrawal period. Spontaneous morphine withdrawal behaviours of rats were observed. Subsequently the rats were sacrificed and the brain tissue was stained with H&amp;E for histological markers. Blood serum and brain tissue were collected for Glutathione (GSH) level measurement using an ELISA kit. The findings were analysed using GraphPad Prism. RESULTS: The administration of Olea Europaea oil significantly reduced (p&lt;0.05) spontaneous withdrawal symptoms. Findings show that Olea Europaea oil ameliorated histological brain signs of morphine toxicity and GSH levels in the brain tissue of the treated group were significantly higher (p&lt;0.05) compared to the no treatment group. CONCLUSION: This study demonstrates that Olea Europaea oil supplementation significantly alleviates morphine withdrawal symptoms and restores antioxidant capacity likely due to its potent antioxidant and neuroprotective properties.

BackgroundEffective analgesia is crucial for patients with blunt thoracic trauma, yet the optimal analgesic approach remains controversial. This study aimed to evaluate the efficacy of opioids combined with Sodium Aescinate in blunt thoracic trauma management.MethodsFifty patients with blunt thoracic trauma were randomly assigned to receive either opioids alone (morphine hydrochloride sustained-release tablets (MHST), Group A) or opioids combined with Sodium Aescinate (Group B). Pain scores, respiratory parameters, complications, and hospitalization metrics were assessed.ResultsWhen pain number rating scale (NRS) scores reached ≤4, Group B required significantly lower opioid doses throughout therapy. Group B demonstrated significantly higher FEV1, FVC, and arterial PO2, and lower PCO2 compared to Group A, while respiratory rates remained similar between groups. Opioid-related complications (nausea, constipation) were significantly reduced in Group B, which also experienced shorter hospital stays and lower costs.ConclusionThis study demonstrated synergism between opioids and Sodium Aescinate in providing effective analgesia. The combination therapy offers an efficient and economical approach for pain management in blunt thoracic trauma, with improved respiratory function and reduced opioid-related complications.

Background Microglia are brain resident cells that control neural network maintenance, damage healing, and brain development. Microglia undergo apoptosis, cytokine production, and reactive free radicals of oxygen (ROS) in response to lipopolysaccharide (LPS) stimulation. TRPM2 is activated by LPS-induced oxidative stress, but it is inhibited by carvacrol (CARV) and N-(p-amylcinnamoyl)anthranilic acid (ACA). Morphine (MRP), an opioid ligand, has the potential to be both an anesthetic and an antioxidant. Objective We investigated how MRP changed the TRPM2 signaling pathways to protect murine BV-2 microglia cells from LPS-induced ROS, cytokine production, and death. Materials and Methods We generated five primary groups in the cultured BV-2 cells: Control, MRP (50 μM for 24h), LPS (1 μg/ml for 24h), LPS + MRP, and LPS + TRPM2 blockers (ACA or CARV). Results The incubation of LPS increased the amounts of apoptosis, cell death (propidium iodide positive cell number), oxidants (ROS and lipid peroxidation), mitochondrial dysfunction, apoptotic markers (caspase −3, −8, and −9), cytokines (TNF-α, IL-1β, and IL-6), death cell waste (debris), cytosolic free Ca2+, Zn2+, and ADP-ribose-induced TRPM2 current densities, while the treatments of MRP and TRPM2 blockers reduced their amounts. The LPS-induced reductions in BV-2 viability percentage, BV-2 number, glutathione peroxidase activity, and glutathione levels were increased by the treatments. Conclusions MRP reduced the levels of LPS-induced oxidative stress, inflammatory cytokines, and apoptosis via inhibiting TRPM2 in the BV-2 cells. One possible treatment option for oxidative microglia damage and neurological disorders induced by LPS could be the MRP.

ABSTRACTThe current investigation was designed to explore the chemical composition, antioxidant capacity, enzyme inhibitory activity, and cytotoxic potential of four different extracts (Ethyl Acetate, Ethanol, Ethanol/Water (70%) and Water) derived from the aerial parts of Eschscholzia californica. In vitro, assessments were performed utilizing diverse antioxidant assays, along with evaluations of neuroprotective enzyme inhibition targeting acetylcholine and butyl choline enzymes, as well as antidiabetic activities against α‐amylase and α‐glucosidase and a potential candidate for a tyrosinase inhibitor. LC‐ESI‐QTOF‐MS identification provided a total of 70 compounds in the extracted samples of E. californica, including kaempferol 3‐(deoxyhexosyl‐hexoside)‐7‐hexoside, rutin, quercetin dideoxyhexoside, caffeic acid hexoside, quinoline alkaloids, morphine derivatives, and scoulerine. Moreover, the ethanol extract exhibited the highest anti‐AChE (2.39 mg GALAE/g), while ethyl acetate exhibited anti‐BChE (3.31 mg GALAE/g), Ethanol/Water (70%) anti‐tyrosinase (53.09 mg KAE/g) and anti‐glucosidase (1.09 mmol ACAE/g) activities. Additionally, the ethyl acetate extract effectively inhibited carbonic anhydrase I and II isoenzymes. Furthermore, the ethanol and ethanol/water extracts demonstrated significant cytotoxicity against A549 lung cancer cells. However, E. californica partially/weakly triggers the apoptosis of cancer cells. Furthermore, the investigation identified 885 target genes for E. californica's phytochemicals, 31 of which were familiar to insomnia. In silico studies demonstrated that protopine, rutin, eschscholtzidine, boldine, and (S)‐scoulerine exhibited notable inhibitory effects on insomnia‐related DRD5, DRD4, and SERT proteins. These findings highlight the potential pharmacological applications of the aerial parts of E. californica as a source for developing novel phytopharmaceuticals targeting various oxidative stress‐related conditions, including diabetes, cancer, Alzheimer's disease, and insomnia.