Search Results (236)

Cridanimod (acridoneacetic acid), the active ingredient of the immunomodulatory drug Cycloferon^®, has a well-characterized antiviral profile, but an unexplored analgesic potential. Bornane monoterpenes, notably (+)-camphor and (−)-fenchone, are established scaffolds for analgesic drug design. We therefore synthesized thirteen cridanimod–monoterpene conjugates—seven amides, three acylhydrazones, and three esters—by EDCI/DMAP-mediated coupling or CDI/DBU-promoted esterification, and evaluated them in mice at an oral dose of 10.0 mg/kg in the acetic acid writhing and hot plate tests, with diclofenac sodium (10.0 mg/kg) as the reference. Acridoneacetic acid and Cycloferon^® were themselves inactive in both assays. By contrast, six of the thirteen conjugates were significantly active (p < 0.05) in at least one test, with distinct leads in each: amide 19 matched diclofenac in the writhing test (−63.7% vs. −64.4%), whereas acylhydrazone 23 exceeded diclofenac in the hot plate test (+43.9% vs. +25.7%). The divergent profiles suggest that different structural subclasses engage peripheral and central antinociceptive mechanisms. Conjugation thus converts an analgesically inactive immunomodulator into a substance yielding analgesics that match or exceed a standard NSAID at the same oral dose, providing a promising starting point for the development of new pain-relieving agents. Full article

The voltage-gated sodium channel Nav1.7 is a strongly validated target for the development of novel, non-opioid analgesics due to its genetic link to pain signaling. To accelerate the discovery of safe Nav1.7 modulators, this study outlines an integrated computational pipeline to repurpose FDA-approved drugs. A structurally complete model of the Nav1.7 central pore was generated via homology modeling from a high-resolution cryo-EM structure (PDB: 7W9K) to ensure a physically consistent model suitable for dynamic simulations. We conducted a structure-based virtual screening of 2296 FDA-approved compounds, identifying four promising candidates (DB04868, DB00941, DB01419, and DB15982) with strong predicted affinities ranging from −11.38 to −12.57 kcal/mol. Interaction fingerprinting revealed that binding is predominantly driven by hydrophobic contacts with conserved pore-lining residues, including Phe1503, Leu1010, and Ile1500. To validate these static predictions, the top protein–ligand complexes were subjected to single-replica 250 ns molecular dynamics (MD) simulations. Comprehensive trajectory analyses, including RMSD, RMSF, and principal component analysis, revealed a notable discrepancy between static docking scores and dynamic stability. The highest-scoring docking candidate, DB04868, exhibited substantial conformational flexibility and reduced stabilization under simulated physiological conditions. Conversely, DB01419, despite a lower initial docking rank, demonstrated the highest structural stability across all metrics and uniquely formed intermittent stabilizing hydrogen bonds. These findings underscore the value of post-docking MD validation in computational drug discovery and nominate DB01419 and DB15982 as candidate scaffolds that warrant subsequent experimental validation, including electrophysiological characterization and Nav-isoform selectivity profiling. We emphasize that these are computational predictions: in silico binding stability is not equivalent to functional inhibition of Nav1.7 currents, and the lead designations reported here remain hypothesis-generating until confirmed by patch-clamp and biochemical assays. Full article

Prospero autumnale L. is a Mediterranean medicinal plant traditionally employed for inflammatory and neurological disorders. Nonetheless, its safety profile, toxicity, and application for treating inflammation and pain are yet to be comprehensively established. This investigation aimed to assess the bioactivity and toxicity of extracts derived from its aerial (AgP) and underground (UgP) parts. The phytochemical constituents of various P. autumnale extracts were analyzed using LC-MS/MS, and their phenolic content was quantified. The biological activities were evaluated through in vitro assays—including antioxidant, anti-inflammatory, acetylcholinesterase-inhibitory, and photoprotection assessments—and in vivo experiments, including evaluations of acute oral toxicity, anti-inflammatory, and analgesic effects. UgP extracts demonstrated significant antioxidant activity, with the methanolic extract exhibiting the highest reducing and superoxide scavenging capacities. Dichloromethane and ethyl acetate extracts performed exceptionally well in ABTS and DPPH assays. The aqueous extract from AgP exhibited noteworthy anti-inflammatory and analgesic effects, surpassing diclofenac in vitro and demonstrating efficacy in vivo. It also showed considerable acetylcholinesterase inhibition, while the ethyl acetate extract displayed high photoprotective potential. The acute toxicity was moderate (LD₅₀: 300–400 mg/kg), indicating dose-dependent risks. LC-MS/MS analysis revealed diverse phenolics potentially contributing to both therapeutic and adverse effects. This research enhances the medicinal prospects of P. autumnale, provides new perspectives on plant utilization, and suggests its potential as a natural anti-inflammatory agent. However, due to moderate toxicity and dose-dependent effects, cautious application is advised. These findings underscore the importance of toxicological evaluation alongside bioactivity screening in ethnopharmacology to ensure safety. Full article

Introduction: Labor pain is among the most intense forms of acute pain, mediated in part by excitatory glutamatergic neurotransmission within central nociceptive pathways. Glutamate plays a key role in spinal dorsal horn signaling and central sensitization, yet its peripheral dynamics during labor and in response to different analgesic modalities remain unclear. This exploratory study aimed to evaluate whether maternal salivary glutamate levels differ between epidural labor analgesia and systemic morphine analgesia during normal vaginal delivery. Method: In this observational comparative study, 36 women were selected to either epidural analgesia (n = 16) or systemic morphine analgesia (n = 20). Salivary samples were collected during active labor and analyzed for glutamate concentration using a validated enzymatic colorimetric assay. Clinical and demographic data were recorded. Non-parametric tests were applied due to non-normal distribution of glutamate levels. Results: Baseline maternal and perinatal characteristics were comparable between groups. Median salivary glutamate levels were higher in the epidural group than in the morphine group (5.32 nmol/µL [IQR 2.83–8.00] vs. 3.99 nmol/µL [IQR 2.26–8.03]), but the difference was not statistically significant (p = 0.599). Glutamate concentrations showed marked inter-individual variability (0.14–29.89 nmol/µL) and a right-skewed distribution. No significant associations were observed between glutamate levels and maternal age, Body Mass Index, gestational age, birth weight, or obstetric comorbidities. Conclusion: In this exploratory cohort, maternal salivary glutamate concentrations did not differ significantly between epidural labor analgesia and systemic morphine analgesia during labor. The variability observed suggests complex and heterogeneous regulation of peripheral glutamatergic activity in parturition. Further larger-scale studies integrating central and peripheral measurements are warranted. Full article

Background: Neuropathic pain remains difficult to treat because current analgesics often provide insufficient efficacy or dose-limiting adverse effects. Nav1.7 is genetically validated as a key regulator of human pain sensation, but the development of selective small-molecule Nav1.7 inhibitors has been limited by the high similarity among voltage-gated sodium channel subtypes. Methods: We generated monoclonal antibodies selectively targeting Nav1.7, humanized them for therapeutic development, and evaluated their binding, selectivity, functional channel inhibition, systemic analgesic efficacy, and effects on neuronal activity in a rat model of partial sciatic nerve ligation-induced neuropathic pain. Results: The humanized antibodies showed high-affinity and selective binding to Nav1.7 and functionally inhibited the channel in cellular assays. After systemic administration to neuropathic pain model rats, the lead antibody produced robust analgesia lasting at least 96 h. Electrophysiological analyses demonstrated reduced mechanically evoked and spontaneous neuronal activity, and immunohistochemistry showed decreased mechanical stimulus-induced phosphorylation of extracellular signal-regulated kinase in dorsal root ganglion neurons. The antibodies did not impair physiological nociception or motor function under the tested conditions. Conclusions: These findings provide preclinical proof of concept that humanized anti-Nav1.7 antibodies can act as systemically administered, long-acting biologic analgesics for neuropathic pain while preserving normal nociceptive and motor functions. The clinical advancement of S-151128 further supports the translational potential of this modality. Full article

Mori Cortex Radicis (MCR), which is abundant in resources and low in cost, is a Chinese herbal medicine with antitussive, anti-inflammatory, analgesic, and hypoglycemic effects; however, its application in the prevention and control of aquatic pathogens remains understudied. In this study, a MCR water extract (MCR-WE) was prepared, and its contents of polysaccharides, polyphenols, and proteins were found to be 0.63%, 1.17%, and 2.79%, respectively. LC-MS metabolomics revealed that L(+)-Arginine, 9,12,13-Todea, Citric acid, 1-Deoxynojirimycin, and 4-Guanidinobutanoic acid were the most abundant compounds. Subsequently, by feeding the MCR-WE to crucian carp (Carassius auratus) and challenging them with Aeromonas veronii, it was found that the MCR-WE enhanced the activities of immune factors (AKP, ACP, LZM) and the phagocytic activity of leukocytes (p < 0.05). Furthermore, the MCR-WE improved the survival rate of crucian carp (p < 0.05), reduced the bacterial load in the kidneys (p < 0.05), decreased the mRNA expression of inflammatory factors (IL-6, IL-1β, TNF-α), and lowered the expression levels of antioxidant-related factors (CAT, GSH-Px, SOD, MDA) and the mRNAs of oxidative stress pathway factors (Nrf2, HO-1, Keap1) (p < 0.05). Histopathological sections and immunofluorescence assays showed that the MCR-WE maintained the structural integrity of internal organs and reduced renal cell apoptosis and DNA damage. Therefore, MCR-WE is rich in immunologically active substances, can activate the immune response of crucian carp, reduce fish mortality, exert anti-inflammatory and antioxidant activities, and maintain the structural and functional integrity of internal organs. Thus, the MCR-WE holds promise as a therapeutic agent against A. veronii infection in fish. Full article

Background/Objectives: Cannabis sativa is the source of cannabidiol (CBD), a non-intoxicating phytocannabinoid with analgesic and anti-inflammatory qualities that has demonstrated therapeutic potential in inflammatory skin conditions like dermatitis. However, low bioavailability and poor water solubility restrict its topical application. This study attempted to improve CBD solubility and transdermal delivery using an amorphous solid dispersion (ASD)-based hydrogel system. Methods: CBD was stabilized in its amorphous form using an ASD strategy and incorporated into a hydrogel matrix. The CBD-ASD hydrogel was characterized by particle size analysis, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), rheological assessment, swelling studies, and diffusion experiments using Franz cells. Biological evaluations included cytotoxicity testing in human dermal fibroblast (HDF) cells, wound-healing assays, RT-qPCR-based anti-inflammatory analysis, antioxidant activity (DPPH assay), and antibacterial testing against Staphylococcus aureus. Results: Physicochemical analyses confirmed successful amorphous dispersion of CBD within a stable hydrogel network. The formulation exhibited sustained drug release over 144 h, achieving 86.32% cumulative release with diffusion-controlled kinetics. Rheological and swelling properties demonstrated mechanical stability and hydration suitability for long-term topical application, while Franz diffusion studies confirmed effective transdermal permeation. The CBD-ASD hydrogel showed no cytotoxicity in HDF cells and significantly enhanced wound closure. It also downregulated pro-inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Additionally, the formulation demonstrated 65.63 ± 10.00% DPPH radical scavenging activity and over 99% antibacterial inhibition. Conclusions: The CBD-ASD hydrogel represents a stable, multifunctional delivery platform that overcomes CBD solubility limitations and enhances therapeutic efficacy for inflammatory skin diseases. Full article

Alkyn-1,2-diones have gained great attention as useful building blocks in organic synthesis. Regioselective synthetic routes towards 3,5-disubstituted isoxazoles, containing the methylfuroyl or diterpenylfuroyl moiety at the C-3 or C-5 position from alkyne-1,2-diones 1, 2, 3, are reported. The reaction with hydroxylamine hydrochloride 6 in ethanol afforded the 1,2-addition products: 5-aryl-3-(methylfuran-2-carbonyl)isoxazoles (yield 61–94%) or 16-(5-arylisoxazole-3-carbonyl)labdatrienes (yield 48–97%). The reaction of alkynediones 1–3 with 6 in THF in the presence of triethylamine led to 5-hydroxy-4,5-dihydroisoxazoles and subsequent dehydration afforded regioisomeric 3-aryl-5-(methylfuran-2-carbonyl)isoxazoles or 16-(3-arylisoxazole-5-carbonyl)labda-trienes (yield 65–98%). New heterocyclic compounds exhibited significant analgesic action in acetic acid writhing and hot-plate tests, and the activity was comparable to reference drugs diclofenac sodium and celecoxib. Isoxazoles, which possessed the most analgesic activity, reduced the concanavalin A-induced inflammation by 34–51%; the effect was comparable to the drug indomethacin. The results of in vitro biological assays (MTT test) revealed that isoxazoles were non-toxic against the normal epithelial VERO cells, and 16-(3-aryl-5-hydroxyisoxazoline-5-carbonyl)labdatrienes 20–24 exhibited selective cytotoxicity against the breast adenocarcinoma MCF 7 (GI₅₀ = 4.7–8.3 μM) and cervical cancer cells C33 A (GI₅₀ = 3.4–4.7 μM). Molecular docking analysis to determine the binding potential of new molecules to the active site of human COX-1 and COX-2 enzymes was conducted. Full article

Schoenoplectus californicus, a macrophyte from Peruvian marine–coastal wetlands, is traditionally used for medicinal purposes, yet its pharmacological potential remains insufficiently explored. This study evaluated the chemical profile, antioxidant capacity, psychopharmacological effects, and analgesic activity of a hydroethanolic extract from its rhizomes. Phytochemical screening and LC–MS/MS analyses were performed to characterize secondary metabolites. Antioxidant activity was assessed using DPPH and ABTS assays, while in vivo anxiolytic, sedative, and analgesic effects were evaluated in Balb/c mice through open field, elevated plus maze, rotarod, analgesimeter, tail-flick, and hot plate tests, with diazepam and tramadol as reference drugs. In silico PASS and BOILED-Egg analyses were used to predict pharmacological mechanisms and central nervous system permeability. The extract contained flavonoids, phenolic compounds, and stilbenes and exhibited notable antioxidant activity (IC₅₀: 0.7319 mg/mL for DPPH and 0.6207 mg/mL for ABTS). Anxiolytic effects were observed at 50 mg/kg, sedative effects at 200 mg/kg, and significant analgesic activity at 50 mg/kg. Several compounds were predicted to cross the blood–brain barrier, with inhibition of GABA aminotransferase suggested as a potential mechanism. Acute toxicity was detected (LD₅₀ > 2000 mg/kg). These findings support S. californicus as a promising source of neuroactive and analgesic compounds, although further mechanistic and dose-optimization studies are required. Full article

Venlafaxine, a serotonin–norepinephrine reuptake inhibitor, shows analgesic effects in rodents, but its efficacy and pharmacological profile in acute stimulus-evoked nociception may depend on the nociceptive test used and the pharmacological context. The aim of this review was to identify the receptors implicated in venlafaxine antinociceptive effects and to examine which molecular processes most consistently explain its acute antinociceptive profile. We reviewed in vivo rodent studies testing venlafaxine in acute nociceptive assays (writhing, tail-flick, hot-plate, and other eligible acute tests) as monotherapy or associated with other pharmacologically active substances. PubMed/MEDLINE and Web of Science were searched from 1993 to 5 January 2026, and reference lists were also screened. Outcomes were synthesized and stratified by type of nociceptive test and interaction class. Fourteen studies were identified as relevant to the scope of this review. Venlafaxine produced dose-dependent antinociception across tests, reducing writhing and increasing thermal withdrawal latency. Central administration generally yielded effects at lower absolute doses than systemic routes. Interaction studies most consistently supported modulation of opioid receptors (e.g., leftward opioid dose–response shifts and attenuation of morphine tolerance in repeated-exposure designs), with convergent evidence implicating opioid and α₂-adrenergic mechanisms and context-dependent serotonergic contributions. Additional pathways were variably implicated, including nitric oxide—cyclic guanosine monophosphate (NO–cGMP) signaling and oxidative/mitochondrial processes in opioid tolerance paradigms. Preclinical evidence supports venlafaxine as a modulator of acute nociceptive control with notable opioid-interaction potential. Standardized pharmacodynamic reporting and translationally oriented studies are needed. Full article

Kratom (Mitragyna speciosa) is a botanical candidate for pain management with potentially reduced opioid-related risks, partly through modulation of neuroimmune pathways involving Toll-Like Receptor 4 (TLR4). This study aimed to characterize the phytochemical profile of kratom ethanol extract and evaluate its effects on TLR4 signalling, neuroinflammatory cytokines, analgesic activity, withdrawal behaviours, and organ safety in morphine-dependent mice. Metabolite profiling was conducted using UHPLC–Q-Exactive Orbitrap HRMS, followed by molecular docking of major constituents to the TLR4 complex. In vivo assessments included flow cytometry and gene expression analyses of TLR4-mediated cytokines (NF-κB, IL-1β, IL-6), behavioural assays for antinociception, endurance, and withdrawal symptoms, and histopathological and biochemical evaluation of liver, kidney, and spleen tissues. More than 100 metabolites were identified, including mitragynine and flavonoids such as rutin and isoquercetin, which showed interactions with key TLR4 residues. Selected fractions suppressed pro-inflammatory cytokine expression, increased tail-pinch latency comparable to morphine, reduced withdrawal manifestations, and demonstrated nephroprotective and immunomodulatory effects, although mild reversible hepatic alterations were observed in specific fractions. Overall, kratom ethanol extract exhibited fraction-dependent analgesic and anti-neuroinflammatory activities associated with TLR4 modulation, supporting its potential as a botanical analgesic candidate while emphasizing the importance of safety optimization and standardized fraction development. Full article

Background/Objectives: Paracetamol is a widely analgesic and antipyretic drug; however, its limited anti-inflammatory efficacy and safety concerns motivate the search for novel non-opioid alternatives. In this study, a series of 4-hydroxyphenylamino-naphthoquinones were designed as paracetamol-inspired analogs and synthesized via a solvent-free, silica-assisted Michael addition, providing a sustainable and efficient synthetic route. Methods: The compounds were evaluated using an integrated strategy combining in silico prediction, density functional theory calculations, molecular docking, ADMET profiling, and in vivo phenotypic pharmacological assays. Results: In vivo evaluation revealed pronounced peripheral antinociceptive activity in the acetic acid-induced writhing model and robust anti-inflammatory effects in carrageenan-induced paw edema, comparable to those of naproxen. These findings suggest a predominantly peripheral mechanism consistent with anti-inflammatory and antinociceptive profiles linked to cyclooxygenase inhibition. A normalization-based multi-criteria analysis integrating peripheral, anti-inflammatory, central, and antipyretic endpoints enabled transparent phenotypic prioritization within the series. Under this framework, compound 7 emerged as the most balanced peripheral–anti-inflammatory candidate, whereas compound 8, evaluated experimentally as a regioisomeric mixture, showed comparatively stronger central antinociceptive activity in the hot plate test. Antipyretic activity in an LPS-induced fever model was limited and not sustained. Conclusions: Overall, these findings indicated that the 4-hydroxyphenylamino-naphthoquinone scaffold emerges as a promising non-opioid platform for peripheral inflammatory pain, supporting further investigation of its pharmacological and mechanistic properties. Full article

This study examines the effect of microfluidization on the physicochemical properties, stability, release behavior, and cytocompatibility of cannabidiol (CBD) nanoemulsions intended for topical application. CBD is a non-psychoactive cannabinoid characterized by anti-inflammatory and analgesic activity; however, its therapeutic use is limited by low solubility and poor bioavailability. To address these limitations, nanoemulsions were formulated using avocado oil and Tween 80 and optimized through a Box–Behnken experimental design evaluating microfluidization pressure (5000–20,000 PSI), CBD concentration (0–2%), and oil content (8–10%). Nanoemulsions were characterized over a 60-day period in terms of droplet size, dispersity index (D), and zeta potential. An increase in processing pressure led to a reduction in both droplet size and dispersity, with optimal conditions identified between 11,000 and 15,000 PSI. Higher oil and CBD concentrations were associated with an increase in the magnitude of the zeta potential, contributing to electrostatic stabilization of the system. Encapsulation efficiency reached approximately 81.4%. Cell viability assays in HaCaT keratinocytes indicated no significant cytotoxic effects. The optimized formulation exhibited a sigmoidal CBD release profile best described by Weibull and Gompertz models (R² ≈ 0.99), suggesting combined diffusion and interfacial mechanisms that support efficient topical delivery. 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

Background/Objectives: Primary dysmenorrhea is a common gynecological disorder characterized by painful uterine contractions. Danggui Buxue Decoction (DBD) is used to treat menstrual irregularities, but its mechanism in primary dysmenorrhea remains unclear. This study investigated the efficacy of DBD against dysmenorrhea and its calcium signaling-related mechanism. Methods: DBD components were analyzed by UPLC–Orbitrap MS. Isolated uterine muscle strips precontracted with oxytocin (OT, 50 ng/mL) or KCl (60 mM) were used to assess the effects of DBD and its active compounds (Quercetin, Formononetin, Ononin, Ferulic acid, Senkyunolide I, Calycosin, Ligustilide, Calycosin-7-O-β-D-glucoside). Ca²⁺-dependent experiments, intracellular calcium release assays, and inhibitor treatments (Nifedipine, 2-APB) were performed to evaluate the involvement of L-type calcium channels and the IP₃R pathway. A primary dysmenorrhea model induced by estradiol benzoate and oxytocin was used to assess the analgesic effects, histopathology, inflammatory factors, and IP₃/Ca²⁺-related proteins and genes following DBD and Quercetin treatment. Results: A total of 161 compounds were identified in DBD. DBD and its eight active constituents relaxed OT (50 ng/mL) or KCl (60 mM)-induced uterine contractions, with Quercetin, Calycosin, and Ligustilide showing particularly prominent relaxant activity. These three compounds suppressed extracellular calcium influx and intracellular calcium release through the blockade of L-type calcium channels and IP₃R. In vivo, DBD and Quercetin alleviated pain, reduced inflammation, and decreased uterine Ca²⁺ and IP₃ levels in dysmenorrhea mice. Conclusions: DBD and its active component Quercetin promote uterine relaxation by lowering Ca²⁺ levels, which is achieved through suppression of L-type calcium channels and the IP₃/Ca²⁺ pathway. This contributes to their therapeutic action against primary dysmenorrhea. Full article