Search Results (742)

Background/Objectives: Umami peptides enhance flavor and contribute to appetite regulation (satiety) and metabolic health. By signaling to the orbitofrontal cortex, umami has been shown to improve cognitive function in Alzheimer’s disease dementia. This taste boosts the immune system and induces saliva secretion. However, the molecular mechanisms linking umami peptides to systemic physiology remain poorly understood. This study provides the first integrated analysis of neurological, immunological, and endocrinological pathways activated by umami peptides. Methods: Novel umami peptides were identified using machine-learning and deep-learning analyses from a library of marine-derived bioactive peptides. T1R1-T1R3 heterodimer is the dominant receptor for umami taste transmission in humans, expressed on taste cells, intestinal cells, and hypothalamic tanycytes. Molecular docking confirmed the binding of novel ligands to the T1R1-T1R3 receptor complex. New candidates and experimentally validated umami peptides, identified by sensomics approaches from tauco, chicken soup, pufferfish, and dry-cured ham, were analyzed using gene ontology. Results: The functional enrichment analysis revealed crosstalk among key signaling processes, including glutamatergic and opioidergic pathways. In addition to the role of µ1 opioid receptor (OPRM1), hub gene intersections highlight cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and the anorexigenic pro-opiomelanocortin (POMC) neurons as potential regulators of the gut–brain axis in satiety signaling. Chemokine-encoding genes, melanin-concentrating hormone (MCH), oxytocin (OXT), and neurotensin (NTS) were other key target genes. Conclusions: The identified targets reveal the coordinated crosstalk between peripheral and central umami signaling that may contribute to the regulation of feeding behavior, satiety, cognition, memory, learning, and immune function. These network-based insights generate hypotheses and guide the design of nutritional and drug-like effectors for metabolic and cognitive health. Full article

Opioid analgesics are essential in the management of severe and chronic pain; however, their prolonged use is limited by the onset of analgesic tolerance and opioid-induced hyperalgesia (OIH). Recent studies increasingly implicate both synaptic functional and structural plasticity within nociceptive pathways as crucial mechanisms in OIH and tolerance. This review integrates current mechanistic understanding of how opioids alter synaptic transmission throughout the dorsal root ganglia (DRG), spinal dorsal horn, and supraspinal nociceptive networks. Peripherally, μ-opioid receptor (MOR) activation on TRPV1-positive nociceptors initiates presynaptic long-term potentiation (LTP), forming an early substrate for central sensitization. In the spinal dorsal horn, chronic opioid exposure drives NMDAR-dependent LTP, TRPC-mediated calcium influx, and actin cytoskeleton remodeling, leading to persistent increases in synaptic strength and excitatory connectivity. In supraspinal regions—including the ventral hippocampus, prefrontal cortex, and amygdala—opioids promote experience-dependent plasticity and predictive coding, which link environmental cues to reduced analgesic effectiveness. In addition to synaptic functional plasticity, opioid-induced synaptic structural plasticity within nociceptive pathways has been shown to underlie the long-term nature of opioid analgesic tolerance. Collectively, these data define a distributed network of opioid-responsive synapses whose pathological potentiation underpins the development of tolerance and hyperalgesia. Elucidating these mechanisms underlying OIH and tolerance paves the way for targeted therapeutic strategies that maintain analgesic efficacy while minimizing adverse synaptic remodeling and negative outcomes. Full article

Background: Magnesium sulfate (MgSO₄) has been investigated as an adjuvant in perioperative analgesia because of its antagonistic effects on the N-methyl-D-aspartate receptor (NMDA receptor) and its potential to attenuate central sensitization. However, clinical findings regarding its analgesic efficacy remain inconsistent across surgical procedures. Lumbar microdiscectomy is a common spinal procedure in which effective early postoperative pain control is important for patient comfort and early mobilization. This study aimed to evaluate the effect of intraoperative MgSO₄ administration on early postoperative analgesia and perioperative outcomes in patients undergoing lumbar microdiscectomy. Methods: This retrospective single-center cohort study included thirty-eight patients with American Society of Anesthesiologists (ASA) physical status I–II who underwent elective single-level lumbar microdiscectomy under general anesthesia. Patients were divided into two groups according to intraoperative magnesium administration: a control group receiving standard anesthesia without MgSO₄ (n = 19) and an MgSO₄ group receiving an intravenous MgSO₄ bolus of 30 mg/kg followed by a continuous infusion of 10 mg/kg/h until skin closure (n = 19). Postoperative pain intensity was assessed using the Numeric Rating Scale (NRS) at 0, 5, 10, 15, and 30 min after admission to the post-anesthesia care unit. Secondary outcomes included intraoperative remifentanil consumption, extubation time, and time to first mobilization. Complementary in silico analyses included molecular docking and protein–protein interaction (PPI) network analysis. Results: Postoperative NRS scores were numerically lower in the MgSO₄ group; however, between-group differences were not statistically significant. Mean intraoperative remifentanil consumption was numerically lower in the MgSO₄ group (236 ± 166 µg) compared with the control group (319 ± 298 µg), without statistical significance (p = 0.27). Repeated-measures analysis demonstrated the significant effect of time on postoperative NRS scores, whereas the overall group effect was not significant. Molecular analyses indicated stable morphine binding to opioid receptors and highlighted glutamatergic signaling components as central nodes within the interaction network. Conclusions: Intraoperative MgSO₄ administration was not associated with significant improvements in early postoperative pain scores or perioperative recovery parameters following lumbar microdiscectomy. Molecular analyses provide exploratory in silico insights and should be interpreted cautiously given the retrospective design and the in silico nature of these findings. Full article

Ixora chinensis Lam. has traditionally been used to treat conditions such as acne, high blood pressure, bleeding, tuberculosis, and rheumatism. This study aimed to investigate the methanolic extract of I. chinensis leaves to determine their bioactive compounds and evaluate their effects on both central and peripheral pain using in vivo and in silico approaches. The GC-MS analysis revealed 41 phytochemicals, including 14 phenolics, 4 esters, 12 terpenoids, 8 alkaloids, and 3 sulfur-containing compounds. In the glucose tolerance test, both the chloroform-soluble fraction (CF) and n-hexane fraction (NHF) exhibited p < 0.05 reductions in blood glucose levels at a dosage of 400 mg/kg with decreases of 51.94% and 46.63%, respectively, compared to the positive control (64.02%). The central analgesic evaluation showed significant (p < 0.001) enhancements in tail-flick latency for the fraction (184.94%) and CF (170.51%) following 90 min. In the pain relief assay, NHF showed inhibition (64.33%, p < 0.001) followed by an aqueous fraction (57.35%). These pharmacological findings were supported by in silico analysis. Concerning activity, 5-(dimethylamino)-1- acid phenyl ester (−8.9 kcal/mol) and 9,9-dimethyl-9H-fluoren-3-ol (−8.4 kcal/mol) displayed the strongest binding affinity to AMPK. Additionally, 2,3-diphenyl-2-cyclopropen-1-one exhibited favorable interactions with α-amylase (−8.0 kcal/mol) and α-glucosidase (−8.3 kcal/mol). Similarly, the central analgesic effect correlated with the strong μ-opioid receptor affinity of s-Triazine, 2-amino-4-(piperidinomethyl)-4-piperidino (−8.8 kcal/mol). N-Methyl-N-(4-toluenesulfonyl)-benzamide (−8.6 kcal/mol) and s-Triazine derivative (−8.9 kcal/mol) demonstrated notable COX-1 and COX-2 inhibition potential. Overall, the findings indicate I. chinensis leaves as a promising source of bioactive compounds with significant antihyperglycemic and analgesic properties. Full article

Tramadol acts via μ-opioid receptor agonism and monoamine reuptake inhibition but is clinically limited by metabolic dependence, interindividual variability, and addiction risks. Structural modification aims to resolve these limitations. This review systematically summarizes tramadol’s structure–activity relationships and mechanisms, focusing on key strategies for structural optimization. Major advances include: (i) synergistic strategies, such as tramadol–celecoxib cocrystals (tramadol and celecoxib coexist in the supramolecular crystal network at a 1:1 molar ratio), achieving multimodal analgesia at lower doses; (ii) mechanism-balancing strategies such as tapentadol (derivatives of tramadol with a dual mechanism of action), which enhance μ-opioid agonism and norepinephrine reuptake inhibition while attenuating serotonergic effects to improve efficacy; (iii) metabolic optimization utilizing M1 analogues to circumvent CYP2D6 polymorphisms (tramadol is metabolized by this enzyme into the active metabolite M1 to exert analgesic effects); and (iv) pharmacophore optimization leveraging tramadol–morphine homology and “message–address” concepts to design selective ligands. Novel derivatives demonstrate improved potency and metabolic stability but continue to face challenges regarding opioid risks and clinical translation. Future research should integrate rational drug design, delivery systems, and personalized medicine to facilitate the development of safer next-generation analgesics. Full article

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article

Fentanyl is a potent analgesic widely used in clinical practice. Fentanyl and its analogues are seriously abused and are emerging in the illegal drug market, leading to numerous intoxication cases. However, assessment of the potency of the pharmacological effect of these novel fentanyl analogues remains limited and inconsistent across studies. The development of novel analgesics has largely relied on the assessment of mu opioid receptor (MOR) binding affinity, with insufficient verification through the assessment of antinociceptive effects. This study evaluated the antinociceptive effects of 25 fentanyl analogues to investigate the relationship between chemical structure and antinociceptive effect. In this study, hot plate tests were conducted in mice to generate time–effect and dose–effect curves for the evaluation of the antinociceptive effect of fentanyl and its analogues. The results demonstrated that the antinociceptive effects of fentanyl analogues were dose- and time-dependent. The potency of the antinociceptive effect observed in this study generally aligned with the corresponding MOR binding affinities reported in the literature, although several analogues exhibited discrepancies. Structural modifications in different regions of the fentanyl scaffold affect the antinociceptive potency to different degrees, and the duration of action also varied across fentanyl analogues. Furthermore, opioid-induced hyperalgesia (OIH) was observed following administration of several fentanyl analogues, raising potential concerns regarding their abuse liability and development for analgesic purposes. Taken together, this study systematically evaluated and compared the antinociceptive effects of fentanyl analogues. The findings clarify the relationship between chemical structure and the antinociceptive effect, providing valuable insights for drug regulation and the development of novel analgesics. Full article

Background/Objectives: Postoperative pain pharmacology is complex. We investigated the sensitivity of analgesic-like effects induced by morphine, ibuprofen, and their combination to peripheral opioid antagonism in a mouse laparotomy model. Methods: Mechanical hypersensitivity was assessed using von Frey filaments, and ongoing pain (abdominal licking and facial expressions) was evaluated using artificial intelligence algorithms. We tested the sensitivity of the analgesic treatments to the opioid antagonist naloxone or its peripherally restricted analog, naloxone methiodide. We also tested the effects of neutrophil depletion using an anti-Ly6G antibody. Gastrointestinal transit and pupillary diameter were measured to assess non-analgesic opioid effects. Results: Morphine reversed all pain-related behaviors; its effect on mechanical hypersensitivity was reversed by peripheral opioid antagonism, whereas its effects on ongoing pain were not. Ibuprofen reduced mechanical hypersensitivity and facial expressions but failed to alter licking. Interestingly, the ibuprofen effect on mechanical hypersensitivity depended on peripheral opioid receptors and neutrophils at the injury site. The morphine–ibuprofen combination produced synergistic analgesia across all endpoints without enhancing opioid-induced gastrointestinal inhibition or mydriasis. Peripheral opioid antagonism reversed the effect of the combination on mechanical hypersensitivity and facial expressions but not on licking. Conclusions: Our results replicate the key clinical phenomena relevant to the postoperative pain context, including the potentiation of morphine analgesia by ibuprofen without the exacerbation of adverse effects. Our results suggest that drug effects on different postoperative pain measures rely on distinct neurobiological mechanisms and are not interchangeable. Therefore, the use of a battery of complementary pain endpoints in preclinical pharmacology studies is advisable. Full article

Major depressive disorder (MDD) is a highly prevalent psychiatric illness for which rapid-acting antidepressants such as ketamine provide only transient benefit. Because κ-opioid receptor (KOR) signaling contributes to stress-related dysphoria and impaired neuroplasticity, we examined whether KOR antagonism could prolong ketamine’s antidepressant-like effects in a mouse model of adolescent chronic unpredictable stress (CUS). Male C57BL/6J mice (n = 10 per group for behavioral analyses) were exposed to CUS during adolescence and developed persistent depression-like behavior in adulthood. Mice with depressive-like behavior received a single injection of ketamine, the selective KOR antagonist norbinaltorphimine (nBNI), or their combination. Behavioral testing showed that all treatments reduced immobility in the tail suspension test (TST) 24 h post-administration; however, only the combined ketamine/nBNI treatment maintained antidepressant-like effects one week post-treatment. Molecular analyses (n = 4–8 per group) were conducted at this single time point, one week post-treatment, to characterize region-specific signaling states in the prefrontal cortex, hippocampus, and striatum, focusing on ERK, AKT, JNK, mTOR, and BDNF pathways. These molecular findings represent correlates of sustained behavioral effects rather than evidence of causal mechanisms. Together, the data indicate that concurrent KOR antagonism is associated with prolonged antidepressant response to ketamine in stress-exposed male mice and with distinct region-dependent signaling profiles at one week post-treatment. Further studies are needed to establish mechanistic causality and confirm the possible applicability of these findings. Full article

Background/Objectives: Opioid-induced constipation (OIC) is a frequent adverse effect of opioid therapy. In contrast to other opioid-related side effects, OIC usually does not improve over time and significantly impairs the quality of life of affected patients. Despite its high prevalence, OIC remains underdiagnosed and undertreated in clinical practice, which has been demonstrated in several European countries. Healthcare data indicates that approximately 2.3 million people in Germany received potentially OIC-inducing opioids in 2023, the majority being patients with chronic non-cancer pain. Methods: An interdisciplinary board of experts in gastroenterology, pain medicine, neurology, oncology, and palliative care developed consensus-based recommendations to improve the diagnosis and management of OIC. Fifteen statements were drafted according to current national German and international guidelines and literature and subsequently discussed. Out of the fifteen statements, twelve statements remained, which achieved consensus with at least 90% agreement. Results: The consensus statements address key aspects of OIC management, including pathophysiology, patient education, diagnosis, prevention, treatment and structured follow-up. Following the statements, a practical treatment algorithm was developed to facilitate clinical implementation. Use of validated tools such as the Bowel Function Index (BFI) for diagnosis and monitoring, early initiation of laxative therapy and timely escalation to mechanism-oriented therapy with peripherally acting μ-opioid receptor antagonists (PAMORAs) in cases of inadequate response have been recommended by the panel. Accordingly, treatment should follow an approach with the following steps: (1) Laxative, (2) switch to PAMORA, (3) rotation of PAMORA, and (4) combination of PAMORA with laxative. In Europe, the PAMORAs methylnaltrexone, naloxegol and naldemedine are approved for the treatment of OIC. Conclusions: This consensus paper provides both evidence-based and practice-oriented recommendations for the systematic management of OIC. By promoting patient education, early recognition, structured evaluation and stepwise treatment escalation, the presented statements and algorithm aim to improve patient outcomes and quality of life under opioid therapy including better adherence to opioid therapy. Full article

Background and Objective: Sickle cell disease (SCD) is an inherited blood disorder associated with recurrent painful crises. Sickle cell pain crises are a significant source of distress for patients and contribute substantially to hospital utilization among SCD populations. Many children with SCD also experience chronic pain, which is often multifactorial in nature. The management of both acute and chronic pain in SCD commonly relies on opioid medications. Acute and chronic use of opioids is associated with health risks and potential complications, which has raised interest in alternatives. Buprenorphine is a partial μ-receptor agonist with strong affinity that confers pain relief and may have an improved side-effect profile. While there is emerging evidence for its use in adult patients, the data is less developed in pediatrics. Methods: A scoping review was designed in accordance with PRISMA guidelines to systematically explore the literature on buprenorphine use in pain management for children with sickle cell disease (SCD). Results: This review shows that the published literature in this area is of low quality and extremely limited, and there is a lack of trials specifically designed to address the use of buprenorphine for this patient population. Studies are limited in their generalizability but suggest that buprenorphine may be useful in managing pain in this population. Conclusions: While promising, more data is required both retrospectively and prospectively to understand the utility of buprenorphine. The development of pediatric-specific protocols for transitioning from full µ-receptor agonist opioids to buprenorphine is also needed. Full article

Chronic pain imposes a substantial burden on global health and remains challenging to manage, despite ongoing advances in pharmacologic and interventional therapies. Recognition of chronic pain as a condition driven by central sensitization and neuroimmune dysregulation has prompted interest in therapies that target these mechanisms rather than peripheral nociception alone. Low-dose naltrexone (LDN), administered at doses substantially lower than those used for opioid or alcohol use disorders, has emerged as a repurposed treatment with potential analgesic and anti-inflammatory properties. This review summarizes the pharmacologic characteristics of LDN, with emphasis on its proposed mechanisms involving transient opioid receptor blockade, modulation of microglial activation, Toll-like receptor signaling, and central neuroimmune pathways. Available clinical evidence evaluating LDN across a range of chronic pain conditions, such as fibromyalgia, neuropathic pain syndromes, inflammatory and autoimmune disorders, headache disorders, and other centralized pain states, is critically reviewed. Although early trials, observational studies, and case series suggest potential benefit in selected populations, the overall evidence base remains limited, heterogeneous, and characterized by variability in dosing strategies and outcome measures. Safety, tolerability, and practical considerations relevant to contemporary pain practice are discussed, including interactions with opioid therapy and challenges related to off-label use. Finally, key gaps in the current evidence and priorities for future research are highlighted, underscoring the need for larger, well-designed randomized trials and mechanism-informed studies to better define LDN’s role in multimodal chronic pain management. Full article

Background: There is currently increasing interest in atypical opioid compounds capable of expanding their clinical applications beyond pain management, including the treatment of psychiatric disorders and substance abuse. In this context, the cyclotetrapeptide c[Trp-Phe-D-Pro-Phe] (CJ-15,208, 1) and its derivatives represent an unusual class of opioid peptides. This compound was found to be a mixed KOR/MOR antagonist in vitro, but it acted as an agonist in vivo. For its diverse analogues, it appeared that receptors’ affinity, selectivity, and agonist/antagonist activity greatly varied upon modifications to backbone geometry and the 3D display of pharmacophores. Methods: We utilized NMR, molecular dynamics, and molecular docking to analyze 3D structures and pharmacodynamic properties of selected representative cyclopeptide analogues of 1. Results: The simulations support that, despite its contradictory functional activity in vitro and in vivo, 1 can bind to the active conformation of receptors in an agonist-like fashion. In general, Trp appeared to be the fundamental pharmacophore in the ligand–receptor complexes. In particular, agonists showed a direct interaction between the indole ring and the carboxylate of the conserved Asp(3:32). Conclusions: These studies support a distinctive pharmacodynamic model for this class of compounds, potentially useful for the design of opioid compounds with novel binding/activity profiles and improved therapeutic effects. Full article

Background: Opioid receptors are a commonly used target for treatment of pain conditions. Most opioids used in therapy are linked to adverse effects such as tolerance, dependence, and respiratory depression. Indole alkaloids acting on opioid receptors may provide a novel molecular mechanism to confer analgesic effects. Results: Indole alkaloids such as ibogaine and mitragynine act on μ-opioid receptors as biased full or partial agonists that do not, or much less strongly, recruit β-arrestin compared to non-biased agonists. The recruitment of β-arrestin has been linked to adverse effects, most notably substantial respiratory depression. The molecular mechanism of biased activation has been proposed to be associated with accommodation of the indole structure that leads to a different spatial orientation of amino acid residues in transmembrane regions 2 and 3 of the μ-opioid receptor as well as extracellular helix 8. Conclusions: Naturally occurring indole alkaloids show biased G-protein coupled activation of opioid receptors with limited recruitment of β-arrestin, thus limiting commonly observed adverse effects. Indole alkaloids may present a feasible structure to develop new biased opioid modulators with an improved risk-to-benefit ratio. Full article

Benzylisoquinoline alkaloids (BIAs) exhibit diverse biological activities, such as neuroprotective effects. The delta-opioid receptor (DOR) has emerged as a promising therapeutic target due to its potential role in enhancing neuroprotection and regeneration. However, reports on the binding of BIAs to the DOR remain scarce. Here, neferine, a BIA from Nelumbo nucifera, as a potential DOR agonist. Molecular docking ranked neferine among the top of 15 BIAs. Initial binding was detected by cellular membrane chromatography and quantitatively confirmed by bio-layer interferometry, with a K_D value of 37.4 μM. ONE vector G protein Optical biosensor revealed that G_i2, G_i3 and G_Z signaling could be activated by neferine through DOR modulation. Consistent with the G_i/z activation, neferine dose-dependently inhibited cAMP accumulation with an EC₅₀ of 0.25 µM. Transcriptomic analysis in DOR-overexpressing HEK293T cells indicated that neferine stimulation predominantly regulates gene networks governing cell cycle and stress adaptation. However, direct transcriptional signature for neuroprotection was not predominant in our system, suggesting that DOR signaling may exhibit context-dependent effects. In conclusion, we identified the neferine as a natural DOR agonist through in silico and in vitro approach, providing a reference for further investigation into its pharmacological potential. Full article