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Search Results (333)

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29 pages, 3037 KiB  
Review
Methods for GC/MS Analysis of the Most Commonly Seized Drugs of Abuse and Their Metabolites in Biological Samples
by Ivan Kojić, Violeta M. Đurović, Yulia A. Smyatskaya, Nemanja Brkljača, Angi E. Skhvediani, Andrey V. Vasin, Ksenija Stojanović and Saša D. Đurović
Chemosensors 2025, 13(8), 286; https://doi.org/10.3390/chemosensors13080286 (registering DOI) - 4 Aug 2025
Viewed by 18
Abstract
Gas chromatography with mass spectrometry (GC-MS) is a common analytical technique used for identifying and quantifying drugs of abuse, as well as their metabolites, extracted from biological samples. Depending on the properties of the analyzed compounds, particularly in the case of metabolites, derivatization [...] Read more.
Gas chromatography with mass spectrometry (GC-MS) is a common analytical technique used for identifying and quantifying drugs of abuse, as well as their metabolites, extracted from biological samples. Depending on the properties of the analyzed compounds, particularly in the case of metabolites, derivatization is often necessary. In this article, we will address the definition, properties, sample preparation, and GC-MS analysis of the most common drugs of abuse in their native (seized) form and their metabolites in biological samples (urine, blood, hair, and tissue). Drugs that will be described are: amphetamines and their derivatives, cannabinoids, cocaine, opioids, lysergide (LSD), benzodiazepines, gamma-hydroxybutyric acid (GHB), phencyclidine (PCP), mescaline, psilocin, and psilocybin. The literature review showed that the analysis of the drugs of abuse requires a simple extraction procedure and analysis with or without derivatization. However, the analysis of the metabolites requires removing the interferences from the matrix (proteins, other compounds, water, and other species that may interfere with the analysis or contaminate the GC-MS). This review article will provide insights into the available procedures for sample preparation and analytical methods, helping authors gain the necessary information and select the desired procedure for analysis. Full article
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11 pages, 221 KiB  
Review
Superficial Cervical Plexus Block for Postoperative Pain Management in Occipital Craniotomies: A Narrative Review
by Shahab Ahmadzadeh, Bennett M. Ford, Alex V. Hollander, Mary Kathleen Luetkemeier, Tomasina Q. Parker-Actlis and Sahar Shekoohi
Med. Sci. 2025, 13(3), 101; https://doi.org/10.3390/medsci13030101 - 28 Jul 2025
Viewed by 388
Abstract
Post-craniotomy pain is common yet often sub-optimally managed because systemic opioids can obscure postoperative neurologic examinations. The superficial cervical plexus block (SCPB) has, therefore, emerged as a targeted regional anesthesia option for occipital craniotomies. The SCPB targets the C2–C4 nerves to anesthetize the [...] Read more.
Post-craniotomy pain is common yet often sub-optimally managed because systemic opioids can obscure postoperative neurologic examinations. The superficial cervical plexus block (SCPB) has, therefore, emerged as a targeted regional anesthesia option for occipital craniotomies. The SCPB targets the C2–C4 nerves to anesthetize the occipital scalp region, covering the lesser occipital nerve territory that lies within typical posterior scalp incisions. Clinical evidence shows the block is effective in reducing acute postoperative pain after occipital craniotomy and diminishes opioid requirements. Studies have demonstrated successful and long-lasting analgesia, reductions in 24-h opioid consumption, and a lower incidence of severe pain. Moreover, the technique exhibits a low complication rate and is safer than a deep cervical plexus block because the injection remains superficial and avoids critical vascular and neural structures. When delivered under ultrasound guidance, major adverse events are exceedingly rare. By reducing opioid use, the SCPB can help reduce postoperative complications, allowing earlier neurological assessments and fewer opioid-related side effects. Incorporation of the SCPB into multimodal analgesia regimens can, therefore, accelerate postoperative recovery by providing regionally focused, opioid-sparing pain control without clinically significant sedation. Overall, current data support the SCPB as a dependable, well-tolerated, and clinically practical approach for managing post-craniotomy pain in patients undergoing occipital approaches. In this narrative review, we will discuss the mechanism of action and anatomy, the clinical application, safety and tolerability, patient outcomes, and emerging future directions of the superficial cervical plexus block and how it mitigates post-occipital craniotomy pain. Full article
13 pages, 1538 KiB  
Article
Respiratory and Cardiovascular Activity of LENART01, an Analgesic Dermorphin–Ranatensin Hybrid Peptide, in Anesthetized Rats
by Piotr Wojciechowski, Dominika Zając, Adrian Górski, Wojciech Kamysz, Patrycja Kleczkowska and Katarzyna Kaczyńska
Int. J. Mol. Sci. 2025, 26(15), 7188; https://doi.org/10.3390/ijms26157188 - 25 Jul 2025
Viewed by 176
Abstract
Opioids are among the most effective drugs for treating moderate to severe pain. Unfortunately, opioid use, even short-term, can lead to addiction, tolerance, overdose, and respiratory depression. Therefore, efforts to design and develop novel compounds that would retain analgesic activity while reducing side [...] Read more.
Opioids are among the most effective drugs for treating moderate to severe pain. Unfortunately, opioid use, even short-term, can lead to addiction, tolerance, overdose, and respiratory depression. Therefore, efforts to design and develop novel compounds that would retain analgesic activity while reducing side effects continue unabated. The present study was designed to investigate the respiratory and cardiovascular effects of the hybrid peptide LENART01, which has evidenced potent antinociceptive and antimicrobial activity. This hybrid peptide, composed of N-terminally located dermorphin and C-terminal modified ranatensin pharmacophore, was tested in vivo in anesthetized rats. The main effect of LENART01 was apnea in 70% of examined animals, sighing, and a significant increase in blood pressure. Interestingly, the hybrid induced sighs less frequently than ranatensin, and apnea dependent on vagus nerve mu opioid receptor activation much less frequently and less intensely than dermorphin itself. This shows that LENART01 is a safer opioid system-related agent as compared to dermorphin for its prospective use in the treatment of pain. Full article
(This article belongs to the Special Issue Recent Progress of Opioid Research, 2nd Edition)
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22 pages, 3768 KiB  
Article
MWB_Analyzer: An Automated Embedded System for Real-Time Quantitative Analysis of Morphine Withdrawal Behaviors in Rodents
by Moran Zhang, Qianqian Li, Shunhang Li, Binxian Sun, Zhuli Wu, Jinxuan Liu, Xingchao Geng and Fangyi Chen
Toxics 2025, 13(7), 586; https://doi.org/10.3390/toxics13070586 - 14 Jul 2025
Viewed by 432
Abstract
Background/Objectives: Substance use disorders, particularly opioid addiction, continue to pose a major global health and toxicological challenge. Morphine dependence represents a significant problem in both clinical practice and preclinical research, particularly in modeling the pharmacodynamics of withdrawal. Rodent models remain indispensable for investigating [...] Read more.
Background/Objectives: Substance use disorders, particularly opioid addiction, continue to pose a major global health and toxicological challenge. Morphine dependence represents a significant problem in both clinical practice and preclinical research, particularly in modeling the pharmacodynamics of withdrawal. Rodent models remain indispensable for investigating the neurotoxicological effects of chronic opioid exposure and withdrawal. However, conventional behavioral assessments rely on manual observation, limiting objectivity, reproducibility, and scalability—critical constraints in modern drug toxicity evaluation. This study introduces MWB_Analyzer, an automated and high-throughput system designed to quantitatively and objectively assess morphine withdrawal behaviors in rats. The goal is to enhance toxicological assessments of CNS-active substances through robust, scalable behavioral phenotyping. Methods: MWB_Analyzer integrates optimized multi-angle video capture, real-time signal processing, and machine learning-driven behavioral classification. An improved YOLO-based architecture was developed for the accurate detection and categorization of withdrawal-associated behaviors in video frames, while a parallel pipeline processed audio signals. The system incorporates behavior-specific duration thresholds to isolate pharmacologically and toxicologically relevant behavioral events. Experimental animals were assigned to high-dose, low-dose, and control groups. Withdrawal was induced and monitored under standardized toxicological protocols. Results: MWB_Analyzer achieved over 95% reduction in redundant frame processing, markedly improving computational efficiency. It demonstrated high classification accuracy: >94% for video-based behaviors (93% on edge devices) and >92% for audio-based events. The use of behavioral thresholds enabled sensitive differentiation between dosage groups, revealing clear dose–response relationships and supporting its application in neuropharmacological and neurotoxicological profiling. Conclusions: MWB_Analyzer offers a robust, reproducible, and objective platform for the automated evaluation of opioid withdrawal syndromes in rodent models. It enhances throughput, precision, and standardization in addiction research. Importantly, this tool supports toxicological investigations of CNS drug effects, preclinical pharmacokinetic and pharmacodynamic evaluations, drug safety profiling, and regulatory assessment of novel opioid and CNS-active therapeutics. Full article
(This article belongs to the Section Drugs Toxicity)
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25 pages, 1374 KiB  
Article
Investigation into Safety Profiles of Antiepileptic Drugs and Identification of Predictors for Serious Adverse Events: Insights from National Pharmacovigilance Data
by Soo Hyeon Lee, Dae Hyeon Sung, Euna Cho, Jeongah Min, Sooyoung Shin and Yeo Jin Choi
Pharmaceuticals 2025, 18(7), 1013; https://doi.org/10.3390/ph18071013 - 7 Jul 2025
Viewed by 396
Abstract
Backgrounds/Objectives: This study aims to comprehensively characterize the prevalence and severity of antiepileptic drug (AED)-induced adverse drug events (ADEs) and to identify predictors strongly associated with serious adverse events (SAEs) in both general and geriatric populations. Methods: This cross-sectional study investigated AED-related ADEs [...] Read more.
Backgrounds/Objectives: This study aims to comprehensively characterize the prevalence and severity of antiepileptic drug (AED)-induced adverse drug events (ADEs) and to identify predictors strongly associated with serious adverse events (SAEs) in both general and geriatric populations. Methods: This cross-sectional study investigated AED-related ADEs reported to the KIDS KAERS DB from January 2014 to December 2023. Disproportionality analysis was performed to detect the association between reported SAEs, and multiple logistic regression was conducted to identify predictors associated with SAEs. Cox’s proportional hazard model was utilized to assess ADE duration in elderly patients aged 60 years and older. Results: More than 50% of 36,809 AED-related ADEs were reported in elderly patients aged 60 years and older, and the prevalence of SAEs was 3.78%. ADEs associated with endocrine disorders had the highest likelihood of SAEs being reported (ROR 15.30), followed by hematological disorders. The predictors associated with elevated SAE risks in the elderly were male sex (OR 1.91; 95% CI 1.62–2.27), aging (OR 1.17; 95% CI 1.04–1.31), and certain AEDs. However, the concomitant administration of acid-suppressive therapy (AST) and opioids was associated with a lower risk of SAEs in the elderly population. Elderly patients not receiving concomitant AST were less likely to experience prolonged ADE duration (HR 0.28, 95% CI 0.07–1.15); however, no substantial differences in ADE duration were observed with the concomitant use of opioids. Conclusions: This study implies significant variability in the frequency, severity, and duration of ADEs depending on the type of AEDs, patient demographics, and concomitant medication use. Full article
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25 pages, 2976 KiB  
Article
Dual Opioid–Neuropeptide FF Small Molecule Ligands Demonstrate Analgesia with Reduced Tolerance Liabilities
by Marco Mottinelli, V. Blair Journigan, Samuel Obeng, Victoria L. C. Pallares, Christophe Mѐsangeau, Coco N. Kapanda, Stephen J. Cutler, Janet A. Lambert, Shainnel O. Eans, Michelle L. Ganno, Wanhui Sheng, Tamara King, Abhisheak Sharma, Catherine Mollereau, Bonnie A. Avery, Jay P. McLaughlin and Christopher R. McCurdy
Molecules 2025, 30(13), 2851; https://doi.org/10.3390/molecules30132851 - 3 Jul 2025
Viewed by 381
Abstract
Neuropeptide FF (NPFF) receptor antagonists prevent morphine-mediated antinociceptive tolerance, and compounds with dual mu opioid receptor (MOR) agonist and NPFF antagonist activity produce antinociception without tolerance. Compounds synthesized showed affinities in radioligand competition binding assays in the nM and µM range at the [...] Read more.
Neuropeptide FF (NPFF) receptor antagonists prevent morphine-mediated antinociceptive tolerance, and compounds with dual mu opioid receptor (MOR) agonist and NPFF antagonist activity produce antinociception without tolerance. Compounds synthesized showed affinities in radioligand competition binding assays in the nM and µM range at the opioid and NPFF receptors, respectively, and displayed substitution-dependent functional profiles in the [35S]GTPγS functional assay. From six compounds screened in vivo for antinociception and ability to prevent NPFF-induced hyperalgesia in mouse warm water tail withdrawal tests, compound 22b produced dose-dependent MOR-mediated antinociception with an ED50 value (and 95% confidence interval) of 6.88 (4.71–9.47) nmol, i.c.v., and also prevented NPFF-induced hyperalgesia. Meanwhile, 22b did not demonstrate the respiratory depression, hyperlocomotion, or impaired intestinal transit of morphine. Moreover, repeated treatment with 22b produced a 1.6-fold rightward shift in antinociceptive dose response, significantly less acute antinociceptive tolerance than morphine. Evaluated for microsomal stability in vitro and in vivo pharmacokinetic profile, 22b showed suitable microsomal stability paired in vivo with a large apparent volume of distribution and a clearance smaller than the hepatic flow in rats, suggesting no extra-hepatic metabolism. In conclusion, the present study confirms that dual-action opioid–NPFF ligands may offer therapeutic promise as analgesics with fewer liabilities of use. Full article
(This article belongs to the Special Issue New Strategies for Drug Development)
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27 pages, 8911 KiB  
Article
Unidirectional Crosstalk Between NTRK1 and IGF2 Drives ER Stress in Chronic Pain
by Caixia Zhang, Kaiwen Zhang, Wencui Zhang, Bo Jiao, Xueqin Cao, Shangchen Yu, Mi Zhang and Xianwei Zhang
Biomedicines 2025, 13(7), 1632; https://doi.org/10.3390/biomedicines13071632 - 3 Jul 2025
Viewed by 541
Abstract
Background: Chronic postsurgical pain (CPSP) poses a major clinical challenge due to unresolved links between neurotrophic pathways and endoplasmic reticulum (ER) stress. While Neurotrophic Tyrosine Kinase Receptor Type 1 (NTRK1) modulates ER stress in neuropathic pain, its interaction with Insulin-Like Growth Factor [...] Read more.
Background: Chronic postsurgical pain (CPSP) poses a major clinical challenge due to unresolved links between neurotrophic pathways and endoplasmic reticulum (ER) stress. While Neurotrophic Tyrosine Kinase Receptor Type 1 (NTRK1) modulates ER stress in neuropathic pain, its interaction with Insulin-Like Growth Factor II (IGF2) in CPSP remains uncharacterized, impeding targeted therapy. This study defined the spinal NTRK1-IGF2-ER stress axis in CPSP. Methods: Using a skin/muscle incision–retraction (SMIR) rat model, we integrated molecular analyses and intrathecal targeting of NTRK1 (GW441756) or IGF2 (siRNA). Results: SMIR surgery upregulated spinal NTRK1, IGF2, and ER stress mediators. NTRK1 inhibition reduced both NTRK1/IGF2 expression and ER stress, reversing mechanical allodynia. IGF2 silencing attenuated ER stress and pain but did not affect NTRK1, revealing a unidirectional signaling cascade where NTRK1 drives IGF2-dependent ER stress amplification. These findings expand understanding of stress-response networks in chronic pain. Conclusions: We show that spinal NTRK1 drives IGF2-mediated ER stress to sustain CPSP. The NTRK1-IGF2-ER stress axis represents a novel therapeutic target; NTRK1 inhibitors and IGF2 biologics offer non-opioid strategies for precision analgesia. This work advances CPSP management and demonstrates how decoding unidirectional signaling hierarchies can transform neurological disorder interventions. Full article
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12 pages, 675 KiB  
Article
Cannabis Use in Opioid Maintenance Therapy: Prevalence, Clinical Correlates and Reasons for Use
by Markus Backmund, Greta G. Zámbó, Susanne Schöfl and Michael Soyka
Brain Sci. 2025, 15(7), 699; https://doi.org/10.3390/brainsci15070699 - 29 Jun 2025
Viewed by 437
Abstract
Background and aims: Opioid maintenance therapy (OMT) is the first-line treatment for opioid use disorder (OUD), reducing opioid use and mortality while improving physical and mental health. However, concomitant substance use remains common, with cannabis being the most frequently used substance. This study [...] Read more.
Background and aims: Opioid maintenance therapy (OMT) is the first-line treatment for opioid use disorder (OUD), reducing opioid use and mortality while improving physical and mental health. However, concomitant substance use remains common, with cannabis being the most frequently used substance. This study assessed the prevalence and clinical correlates of cannabis use in OMT patients, as well as individual motivations. Methods: In this cross-sectional, single-center study, 128 OUD patients (96 male, 32 female) receiving OMT were assessed using standardized questionnaires: the Marijuana Smoking History Questionnaire (MSHQ), Cannabis Problems Questionnaire (CPQ) and the Severity of Dependence Scale (SDS). Cannabis users and non-users were compared regarding type (methadone vs. buprenorphine) and dosage of maintenance medication. Results: Cannabis use was reported by 41% of patients, 73% met criteria for cannabis dependence, 30% of the full sample. Of the patients, 85% reported cannabis-related legal issues. Common reasons for use included recreational motives (mood change, enhancement) and reduction in cravings for other substances. Cannabis dependence was significantly more common in patients receiving buprenorphine than methadone. Higher methadone doses were also associated with increased cannabis use. These results suggest a clinically relevant pattern. Conclusions: Cannabis use is highly prevalent and appears to be influenced by type and dosage of substitution medication. These findings highlight a complex interaction between opioid treatment and cannabis use, possibly involving behavioral coping or regulatory processes. Further longitudinal and placebo-controlled trials are needed to investigate the clinical and pharmacological interactions between cannabis and OMT, including effects on craving, withdrawal, and overall treatment outcomes. Full article
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19 pages, 336 KiB  
Review
Pain Neuroscience Education on Reducing Opioid Dependency in African American and Caucasian Populations: A Narrative Review
by Austin Granger and Ersilia Mirabelli
J. Clin. Med. 2025, 14(12), 4360; https://doi.org/10.3390/jcm14124360 - 19 Jun 2025
Viewed by 1949
Abstract
This review explores pain neuroscience education (PNE) in the context of opioid dependence among Caucasian and African American populations, addressing disparities and sociocultural influences in the opioid epidemic. Von Bertalanffy’s general systems theory and Bronfenbrenner’s ecological systems theory comprise the underlying theoretical frameworks [...] Read more.
This review explores pain neuroscience education (PNE) in the context of opioid dependence among Caucasian and African American populations, addressing disparities and sociocultural influences in the opioid epidemic. Von Bertalanffy’s general systems theory and Bronfenbrenner’s ecological systems theory comprise the underlying theoretical frameworks behind the review, emphasizing the importance of biopsychosocial perspectives of chronic pain and ecological systems on individual development. Within these frameworks, the study objective is to summarize relevant and contemporary literature among African American and Caucasian populations regarding opioid dependency, neuroplasticity in chronic pain, and PNE. Peer-reviewed articles published within the last 10 years were reviewed for relevance. Limitations include a lack of research on the intersection of ethnicity and PNE, a lack of studies investigating interdisciplinary input regarding PNE, and a focus on only two ethnic groups. This narrative review finds that African Americans face systemic barriers to effective treatment for pain and opioid use disorder (OUD), while Caucasians are more likely to be overprescribed with higher rates of OUD. From a systems and ecological perspective, maladaptive neuroplasticity in chronic pain (biologic subsystem) intersects with ethnic disparities in prescribing access and pain beliefs (psychosocial subsystem) to influence opioid use and the chronic pain experience. PNE shows promise as an adjunct to traditional physical therapy in reducing nociplastic pain, potentially affecting opioid dependency. Future research should incorporate readiness-to-change models, generational and ethnocultural perspectives, and neuroimaging with PNE to optimize the delivery of PNE to individuals of different backgrounds. Full article
(This article belongs to the Section Clinical Rehabilitation)
20 pages, 5381 KiB  
Article
Role of Central Inflammatory and Oxidative Pathways in the Morphine Exacerbation of Cardiovascular Effects of Sepsis in Rats
by Mohamed Abdelnaby, Marwa Y. Sallam, Mai M. Helmy, Hanan M. El-Gowelli and Mahmoud M. El-Mas
Pharmaceuticals 2025, 18(6), 882; https://doi.org/10.3390/ph18060882 - 12 Jun 2025
Viewed by 599
Abstract
Background/Objectives: Sepsis remains one of the most serious and possibly fatal complications encountered in intensive care units. Considering the frequent use of narcotic analgesics in this setting, we investigated whether the cardiovascular and peripheral and central inflammatory features of sepsis could be modified [...] Read more.
Background/Objectives: Sepsis remains one of the most serious and possibly fatal complications encountered in intensive care units. Considering the frequent use of narcotic analgesics in this setting, we investigated whether the cardiovascular and peripheral and central inflammatory features of sepsis could be modified by morphine. Methods: Rats were instrumented with femoral and intracisternal (i.c.) indwelling catheters and sepsis was induced by cecal ligation and puncture (CLP). Results: The i.v. administration of morphine (3 and 10 mg/kg) significantly and dose-dependently aggravated septic manifestations of hypotension and impaired cardiac autonomic activity, as reflected by the reductions in indices of heart rate variability (HRV). Cardiac contractility (dP/dtmax) was also reduced by morphine in septic rats. The morphine effects were mostly eliminated following (i) blockade of μ-opioid receptors by i.v. naloxone and (ii) inhibition of central PI3K, MAPK-ERK, MAPK-JNK, NADPH oxidase (NADPHox), or Rho-kinase (ROCK) by i.c. wortmannin, PD98059, SP600125, diphenyleneiodonium, and fasudil, respectively. Further, these pharmacologic interventions significantly reduced the heightened protein expression of toll-like receptor 4 (TLR4) and monocyte chemoattractant protein-1 (MCP1) in brainstem rostral ventrolateral medullary (RVLM), but not cardiac, tissues of CLP/morphine-treated rats. Conclusions: Morphine worsens cardiovascular and autonomic disturbances caused by sepsis through a mechanism mediated via μ-opioid receptors and upregulated central inflammatory, chemotactic, and oxidative signals. Clinical studies are warranted to re-affirm the adverse cardiovascular interaction between opioids and the septic challenge. Full article
(This article belongs to the Special Issue Pharmacology and Toxicology of Opioids)
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34 pages, 7701 KiB  
Article
Docking Simulations of G-Protein Coupled Receptors Uncover Crossover Binding Patterns of Diverse Ligands to Angiotensin, Alpha-Adrenergic and Opioid Receptors: Implications for Cardiovascular Disease and Addiction
by Harry Ridgway, Graham J. Moore, Laura Kate Gadanec and John M. Matsoukas
Biomolecules 2025, 15(6), 855; https://doi.org/10.3390/biom15060855 - 11 Jun 2025
Viewed by 1664
Abstract
Recent bioassay studies have unexpectedly supported the high (computationally predicted) binding affinities of angiotensin receptor blockers (ARBs) at α-adrenergic receptors (αARs) in isolated smooth muscle. Computational predictions from ligand docking studies are consistent with very low concentrations of ARBs (e.g., sartans or bisartans) [...] Read more.
Recent bioassay studies have unexpectedly supported the high (computationally predicted) binding affinities of angiotensin receptor blockers (ARBs) at α-adrenergic receptors (αARs) in isolated smooth muscle. Computational predictions from ligand docking studies are consistent with very low concentrations of ARBs (e.g., sartans or bisartans) that partially reduce (20–50%) the contractile response to phenylephrine, suggesting that some ARBs may function as partial inverse agonists at αARs. Virtual ligand screening (docking) and molecular dynamics (MD) simulations were carried out to explore the binding affinities and stabilities of selected non-peptide ligands (e.g., ARBs and small-molecule opioids) for several G-protein coupled receptor (GPCR) types, including angiotensin II (AngII) type 1 receptor (AT1R), α1AR, α2AR, and μ-(µOR) and ժ-opioid receptors (ժOR). Results: All ligands docked preferentially to the binding pocket on the cell surface domain of the GPCR types investigated. Drug binding was characterized by weak interactions (hydrophobic, hydrogen bonding, pi-pi) and stronger ionic and salt-bridge interactions (cation-pi and cation-anion interactions). Ligands specific to each GPCR category showed considerable cross-binding with alternative GPCRs, with small-molecule medications appearing less selective than their peptide or ARB functional equivalents. ARBs that exhibit higher affinities for AT1R also demonstrate higher affinities for µORs and ժORs than opiate ligands, such as fentanyl and naltrexone. Moreover, ARBs had a higher affinity for αARs than either alpha agonists (epinephrine and phenylephrine) or inhibitors (prazosin and doxazosin). MD simulations of membrane-embedded ARB-GPCR complexes proved stable over nanosecond time scales and suggested that some ARBs may behave as agonists or antagonists depending on the GPCR type. Based on the results presented in this and related investigations, we propose that agonists bind to the resting A-site of GPCRs, while inverse agonists occupy the desensitizing D-site, which partial agonists like morphine and fentanyl share, contributing to addiction. ARBs block both AngII and alpha receptors, suggesting that they are more potent antihypertensive drugs than ACE inhibitors. ARBs have the potential to inhibit morphine tolerance and appear to disrupt receptor desensitization processes, potentially by competing at the D-site. Our results suggest the possible therapeutic potential of ARBs in treating methamphetamine and opiate addictions. Full article
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14 pages, 608 KiB  
Article
Sodium Oxybate (SMO) as Part of Agonist Opioid Treatment in Alcohol–Heroin-Addicted Patients
by Angelo G. I. Maremmani, Filippo Della Rocca, Matteo Pacini, Silvia Bacciardi, Silvia Cimino, Luca Cerniglia, Mario Miccoli and Icro Maremmani
J. Clin. Med. 2025, 14(12), 4016; https://doi.org/10.3390/jcm14124016 - 6 Jun 2025
Viewed by 737
Abstract
Background: Alcohol use disorder in the context of heroin addiction presents a significant challenge for clinicians, particularly in selecting the most appropriate pharmacological treatment. Methods: The present study aimed to retrospectively evaluate the efficacy of a six-month methadone maintenance (MM)/sodium oxybate (SMO) combination [...] Read more.
Background: Alcohol use disorder in the context of heroin addiction presents a significant challenge for clinicians, particularly in selecting the most appropriate pharmacological treatment. Methods: The present study aimed to retrospectively evaluate the efficacy of a six-month methadone maintenance (MM)/sodium oxybate (SMO) combination treatment in reducing ethanol intake among chronic alcohol-dependent patients with heroin use disorder (HUD). Specifically, we compared outcomes between those who continued SMO treatment after alcohol detoxification (MM/SMO-Maintained) and those who discontinued it (MM/SMO-Detoxified). Data were recruited using the ‘Pisa Addiction Database’ through a retrospective, naturalistic, cross-sectional comparative design involving a single patient assessment. Results: Our results indicate that treatment retention was higher in the MM/SMO-Maintained group. Conversely, discontinuing SMO treatment after alcohol detoxification was associated with a higher likelihood of dropout. At the endpoint, the MM/SMO-Maintained group showed significant improvement and was considered less severely ill. Conclusions: Long-term SMO treatment has proven to be well tolerated and effective in preventing relapse in individuals with both alcohol and HUD undergoing agonist opioid treatment. SMO may be considered the closest pharmacological option to substitution therapy for alcohol use disorder, and ongoing agonist opioid treatment should not preclude its co-administration. Full article
(This article belongs to the Section Mental Health)
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14 pages, 384 KiB  
Article
Opioid Dependence Increases Complications and Costs Following Lumbar Spinal Fusion: Insights from a Nationwide Database
by Assil Mahamid, Lior Laver, Liad Alfandari, Hamza Jabareen, Noa Martonovich, Amit Keren and Eyal Behrbalk
J. Clin. Med. 2025, 14(11), 3929; https://doi.org/10.3390/jcm14113929 - 3 Jun 2025
Viewed by 525
Abstract
Background: Opioid dependence is prevalent among patients undergoing lumbar spinal fusion and has been linked to poor postoperative outcomes. However, its specific impact on surgical complications and hospital resource utilization remains unclear. This study evaluates the association between opioid dependence and postoperative complications, [...] Read more.
Background: Opioid dependence is prevalent among patients undergoing lumbar spinal fusion and has been linked to poor postoperative outcomes. However, its specific impact on surgical complications and hospital resource utilization remains unclear. This study evaluates the association between opioid dependence and postoperative complications, length of stay (LOS), and hospital charges in lumbar fusion patients. Methods: A retrospective analysis was conducted using the National Inpatient Sample (NIS) database from 2016 to 2021. Adult patients (aged > 18 years) who underwent lumbar fusion surgery were identified and categorized based on opioid dependence using ICD-10 codes. Propensity score weighting (PSW) was employed to balance baseline characteristics. Primary outcomes included inpatient mortality, LOS, hospital charges, and postoperative complications. Statistical analyses were performed using survey-weighted generalized linear models. Results: Among 597,455 lumbar fusion patients, 7715 (1.3%) had documented opioid dependence. After PSW, opioid-dependent patients had significantly increased odds of blood loss anemia (OR 1.79, p < 0.001), respiratory complications (OR 2.17, p < 0.001), surgical site infections (OR 3.94, p = 0.001), and cardiac complications (OR 1.53, p = 0.002). They also had higher hospital charges (mean difference USD 17,739.2, p < 0.001) and prolonged LOS (mean difference 0.83 days, p < 0.001). Differences in urinary tract infections, acute renal failure, and stroke were not statistically significant after PSW. Conclusions: Opioid dependence is associated with increased postoperative complications, longer hospital stays, and higher healthcare costs in lumbar fusion patients. These findings highlight the need for improved perioperative pain management and opioid stewardship strategies to optimize surgical outcomes. Full article
(This article belongs to the Section Orthopedics)
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17 pages, 1679 KiB  
Article
Peripheral Antinociception Induced by Carvacrol in the Formalin Test Involves the Opioid Receptor-NO-cGMP-K+ Channel Pathway
by Mario I. Ortiz, Raquel Cariño-Cortés, Eduardo Fernández-Martínez, Victor Manuel Muñoz-Pérez, Gilberto Castañeda-Hernández and Martha Patricia González-García
Metabolites 2025, 15(5), 314; https://doi.org/10.3390/metabo15050314 - 7 May 2025
Viewed by 529
Abstract
Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the main constituents of the essential oils of oregano (Origanum vulgare) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. Carvacrol can activate and inhibit several second messengers and [...] Read more.
Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the main constituents of the essential oils of oregano (Origanum vulgare) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. Carvacrol can activate and inhibit several second messengers and ionic channels at the systemic level. However, there is no evidence of the peripheral antinociception of carvacrol and its mechanism of action. This study was designed to determine whether the opioid receptor-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-K+ channel pathway is involved in the local antinociception of carvacrol. Methods: Wistar rats were injected with 1% formalin subcutaneously on the dorsal surface of the right hind paw with the vehicle or carvacrol (100–300 µg/paw). To determine whether the opioid receptor-NO-cGMP-K+ channel pathway and a biguanide-dependent mechanism are responsible for the local antinociception induced by carvacrol, the effect of the injection (10 min before the 1% formalin injection) with the corresponding vehicles, metformin, naltrexone, NG-L-nitro-arginine methyl ester (L-NAME), 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ), and K+ channel blockers on the antinociception induced by local carvacrol (300 µg/paw) was determined. Results: In both phases of the formalin test, carvacrol produced antinociception. Naltrexone, metformin, L-NAME, ODQ, glibenclamide and glipizide (both ATP-sensitive K+ channel blockers), tetraethylammonium and 4-aminopyridine (voltage-gated K+ channel blockers), and apamin and charybdotoxin (Ca2+-activated K+ channel blockers) reversed the carvacrol-induced peripheral antinociception. Conclusions: The local peripheral administration of carvacrol produced significant antinociception and activated the opioid receptor-NO-cGMP-K+ channel pathway. Full article
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16 pages, 2141 KiB  
Article
Exploring Nepicastat Activity: Beyond DβH
by Rafal Jas, Marta Bauer, Błażej Grodner, Weronika Kończak, Karolina Frączek, Anna K. Laskowska, Małgorzata Milczarek, Wojciech Kamysz and Patrycja Kleczkowska
Int. J. Mol. Sci. 2025, 26(9), 4356; https://doi.org/10.3390/ijms26094356 - 3 May 2025
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Abstract
Recently, an old drug, disulfiram, has been shown to reduce cocaine intake by inhibiting dopamine beta (β)-hydroxylase. Its effectiveness was also reported in opioid treatment, as disulfiram attenuated morphine-induced tolerance and dependence. A similar mechanism of action was evident in a selective inhibitor [...] Read more.
Recently, an old drug, disulfiram, has been shown to reduce cocaine intake by inhibiting dopamine beta (β)-hydroxylase. Its effectiveness was also reported in opioid treatment, as disulfiram attenuated morphine-induced tolerance and dependence. A similar mechanism of action was evident in a selective inhibitor of DβH, nepicastat, particularly in the aspect of cocaine-seeking behavior. Hence, the objective of this study was to verify whether or not nepicastat reproduces disulfiram activity in pain reduction. Moreover, determination of its likely biological effects resulting from interactions with targets other than DβH has been given, in particular acetylcholinesterase. As was found, nepicastat was characterized by the absence of desired antinociceptive activity, though its co-administration with morphine resulted in a dose- and time-dependent enhancement of morphine-induced analgesic effect and attenuation of tolerance. Similarly, nepicastat was found to manifest antimicrobial potency against selected bacterial strains, although the effect was found to be weak. Intriguingly, this compound interacted with acetylcholinesterase through inhibition of its activity. These results clearly indicate nepicastat as a potent molecule that exhibits various biological effects. This, in turn, suggests its possible application in pathological conditions that still require effective treatment. Full article
(This article belongs to the Special Issue Drug Repurposing: Emerging Approaches to Drug Discovery)
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