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Background: The genus Phoradendron belongs to the Santalaceae family and possesses several species with antitumor, cytotoxic, and immunomodulatory activity, where pain and inflammation are common symptoms. It is used in venereal and liver diseases in Paraguayan folk medicine. In addition, it claims to have tonic properties for the heart and central nervous system. Previous studies have shown that crude extract of Phoradendron bathyoryctum Eichler (Pb) has anxiolytic and antidepressant activity. Objective: This work aimed to determine the anti-nociceptive and anti-inflammatory activity ofPb using acute models in mice. Methods: the anti-nociceptive activity of Pb was evaluated using mechanical pressure (Randall-Selitto test), acetic acid (writhing test), and heat (hot plate test) noxious stimulus in mice. The anti-inflammatory activity was assessed through carrageenan-induced plantar edema in mice previously treated with Pb. Results: Presences of high polarity alkaloids, steroids/ free triterpenoids, leucoanthocyanidins, and tannins were detected in phytochemical studies. Oral doses of 30 (p<0.01) and 300 (p<0.001) mg/kg of Pb denoted a significant dose-dependent increase in pain threshold, using the Randall-Selitto and Writhing test (30; p<0.05; and 300; p<0.01. In addition, consistent with the above anti-nociceptive effect, an increase in the reaction latency time after oral administration of Pb at a dose of 300 mg/kg (p<0.05) in the hot plate test was denoted. Finally, a significant reduction of edema (30 mg/kg; p<0.01) induced by 1% carrageenan was evidenced, demonstrating a potential anti-inflammatory activity of Pb compared to the positive edema control. Interestingly, the anti-edematous activity of Pb showed a similar intensity response compared to the group treated with 10 mg/kg indomethacin (p<0.01). Conclusion: This work revealed that the crude extract of Pb can increase pain threshold, be compatible with an analgesic effect, and reduce edema (anti-inflammatory) induced by Carrageenan in mice. Further pharmacological and chemical studies are being conducted to elucidate molecular mechanisms and components involved in the observed effects.

The role of carbon monoxide (CO) has evolved albeit controversial disputes on its toxicity. This biological gasotransmitter participates in the endogenous regulation of neurotransmitters and neuropeptides released in the nervous system. Exogenous CO gas inhalation at a lower concentration has been the subject of investigations, which have revealed its biological homeostatic mechanisms and protective effects against many pathological conditions. This therapeutic procedure of CO is, however, limited due to its immediate release, which favours haemoglobin at a high affinity with the subsequent generation of toxic carboxyhaemoglobin in tissues. In order to address this problem, carbon monoxide releasing molecule-2 (CORM-2) or also known as tricarbonyldichlororuthenium II dimer is developed to liberate a controlled amount of CO in the biological systems. In this review, we examine several potential mechanisms exerted by this therapeutic compound to produce the anti-nociceptive effect that has been demonstrated in previous studies. This review could shed light on the role of CORM-2 to reduce pain, especially in cases of chronic and neuropathic pain.

Brassaiopsis palmata, an androgynous tree from Araliaceae family, has been widely found in the Asian subcontinent, and reported to have potentiality against skin infection, and many therapeutic properties still unidentified. Here, our current investigation aims to discover the innovative pharmacological potentials of the methanol extract of B. palmata leaves (MEBPL) through in‐vivo and in‐vitro approaches. Several secondary metabolites were revealed throughout the qualitative phytochemical screening of the plant extracts. MEBPL exhibited strong radical scavenging properties (IC50 178.13 µg/mL) through the 2, 2‐diphenyl‐1‐picryhydrazyl (DPPH) assay, and through the quantitative (phenolic and flavonoid) assays with a moderate (LD50 153.14 µg/mL) toxic effect. In anti‐inflammatory screening, MEBPL showed significant dose dependent inhibitory activity; and the peak inhibition were found 78.01 ± 1.22% and 82.46 ± 1.52% at 1000 µg/mL concentration on hypotonic‐induce RBC hemolysis & protein denaturation test respectively. Moreover, the plant extracts manifested moderate percentage of clot lysis (28.24 ± 2.50%) on the investigation of thrombolytic assay. The anti‐nociceptive activity of MEBPL was analyzed through acetic acid and formalin induce pain tests. Both 200 and 400 mg/kg dose of MEBPL exerted significant (p ˂ 0.001) dose depending depletion of acetic acid induced writhing and formalin stimulated licking test which indicated strong analgesic properties of plant extracts. In addition, the outcomes of anti‐depressant evaluation suggested that treatment with both 200 and 400 mg/kg doses showed potential dose depending activity on both FST and TST model. Furthermore, the plant extracts manifested dose dependent reduction of anxiety like behaviors in the rodent model. Particularly, mice administrated with 400 mg/kg dose of MEBPL significantly (p ˂ 0.05) enhanced the percentage of entries and time spent in the open arm in EPM, and also showed the highest amount of head dipping tendency in HBT. In contrast, the outcomes of this research suggest that B. palmata could be another source of antioxidant, cytotoxic, anti‐inflammatory, thrombolytic, anti‐nociceptive, anti‐depressant, and anxiolytic agents. Further research on the mechanisms underlying bioactivities is required. Brassaiopsis palmata, an androgynous tree from Araliaceae family, has been widely found in the Asian subcontinent, and reported to have potentiality against skin infection, and many therapeutic properties still unidentified.

Β-sitosterol is a phytosterol, documented to possess various activities including protection against inflammation, diabetes and Alzheimer’s disease. The current investigation was designed to explore the analgesic potential of β-sitosterol and the possible molecular mechanism involved in the observed effect. β-sitosterol was administered at varying doses of 10, 20, and 40 mg/kg before subjecting the mice to acetic acid and formalin challenges. The number of writhings in acetic acid and the number of flinchings and foot tappings were quantified in the formalin test. For mechanistic studies, substance P (cyclooxygenase-2 (COX-2) stimulator) and L-Nitro arginine methyl ester (L-NAME) (nitric oxide synthetases (NOS) inhibitor) and L-arginine (nitric oxide precursor) were administered before β-sitosterol treatment. β-sitosterol (10, 20, 40 mg/kg) treatment significantly reduced acetic acid-induced writhings and ameliorated the formalin-induced inflammatory phase dose-dependently. Whereas, 40 mg/kg dose of β-sitosterol abrogated the formalin-induced neurogenic phase. Substance-P abrogated the effect of β-sitosterol in both neurogenic and inflammatory phases. Whereas, L-arginine only abrogated the inflammatory phase. In biochemical analysis, β-sitosterol treatment reduced the level of interleukin-6 (IL-6), thiobarbituric acid reactive substances (TBARS) and increased the level of reduced glutathione (GSH). Furthermore, L-arginine and substance-P abrogated the GSH increasing and TBARS lowering effect of β-sitosterol (40 mg/kg). Overall, the current study delineated that β-sitosterol may induce an anti-nociceptive effect via inhibiting the IL-6, oxidative stress, cyclo-oxygenase and nitric oxide.

Cuscuta reflexa Roxb. is traditionally used by the indigenous communities of Bangladesh to treat different diseases, such as pain, edema, tumor, jaundice, and skin infections. This study tested neuro-pharmacological, anti-nociceptive, and antidiarrheal activities by in vivo and in silico experiments for the metabolites extracted (methanol) from the leaves of Cuscuta reflexa (MECR). During the anxiolytic evaluation analyzed by elevated plus maze and hole board tests, MECR (200 and 400 mg/kg) exhibited a significant dose-dependent reduction of anxiety-like behavior in mice. Similarly, mice treated with MECR demonstrated a dose-dependent decrease in the time of immobility in both forced swimming and tail suspension tests. In addition, anti-nociceptive activity was assessed by the chemical-induced (acetic acid and formalin) pain models. In both cases, 400 mg/kg was found to be most effective and significantly (p < 0.001) inhibited acetic acid stimulated writhing and formalin-induced licking (pain response) in mice. Furthermore, antidiarrheal efficacy determined by the castor-oil induced diarrheal model manifested an evident inhibition of diarrheal stool frequency. In parallel, previously isolated bioactive compounds were documented based on the biological activities and subjected to in silico studies to correlate with the current pharmacological outcomes. The selected isolated compounds (15) displayed favorable binding affinities to potassium channels, human serotonin receptor, COX-1, COX-2, M3 muscarinic acetylcholine receptor, and 5-HT3 receptor proteins. Additionally, the ADME/T and toxicological properties were justified to unveil their drug-like properties and toxicity level. Overall, Cuscuta reflexa is bioactive and could be a potential source for the development of alternative medicine.

This article describes how to extract chemical compounds from Sambucus nigra and make multifunctional nanofabric doping/undoping nano-zinc oxide particles using an electrospinning apparatus. The created sample was examined using field emission scanning electron microscope (FESEM), which revealed that the manufactured fibers have an approximate diameter of 35 nm. An elemental mapping study also demonstrated the excellent distribution of nano-ZnO over the surface of the nanocomposite. The anti-nociceptive effect of the samples was studied, and the results suggested that the presence of Sambucus nigra caused pain prevention, and this effect demonstrated the anti-nociceptive effect in the samples studied by tail-flick experiments. Additionally, the anti-inflammatory properties of the samples were tested and showed favorable data results. Meanwhile, the self-cleaning of the prepared nanocomposites was studied. The results show that nano-zinc oxide doping has a direct impact on improving self-cleaning properties. Furthermore, ultraviolet (UV) transmission analysis of the samples showed that the prepared nanocomposites had excellent UV-blocking properties.

Objective: Morphine is a widely used analgesic for severe pain, but tolerance is a major challenge in long-term pain management. This study examined the potential of Daflon® to enhance morphine’s pain-relieving effects and to reduce tolerance in a rat model with neuropathic pain induced by partial sciatic nerve transection (PSNT). Methods: Male Wistar rats were divided into five groups: (1) Sham + Saline, (2) PSNT + Saline, (3) PSNT + morphine, (4) PSNT + Daflon, and (5) PSNT + morphine + Daflon. Morphine tolerance was induced through continuous intrathecal infusion (15 µg/µL/h, i.t.) for 7 days, starting on day 7 post-PSNT, while Daflon was administered orally (50 mg/kg/day, oral) for 7 days. Pain relief was assessed using tail-flick and paw withdrawal on days 1, 4, and 7 after osmotic pump implantation. Spinal cords were collected for immunohistochemistry to analyze glial expression, and serum biomarkers (TNF-α, IL-1β, IL-6, and IL-10) were measured to evaluate neuroinflammation. Results: The results showed that oral Daflon significantly enhanced morphine’s analgesic effects, evidenced by improved pain thresholds in all behavioral tests. Moreover, Daflon reduced morphine tolerance. Mechanistically, Daflon upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and activated heme oxygenase-1 (HO-1), reducing oxidative stress and modulating neuroinflammation through glial regulation. Combining morphine and Daflon reduces pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and enhances anti-inflammatory IL-10 serum level, showing a synergistic effect in managing neuropathic pain with greater efficacy and lower drug dependence. Histology and immunohistochemistry evaluations further confirmed that morphine and Daflon co-treatment substantially reduced mononuclear cell infiltration, astrocyte activation (as indicated by GFAP expression), and microglial activation (as indicated by Iba-1 expression) compared to single treatment. Conclusions: Our findings suggest that dual therapy synergistically targets both oxidative stress and inflammatory pathways, leading to stronger neuroprotection and pain relief. Importantly, the combination approach may allow for lower opioid dosages, minimizing the risks of opioid-related side effects. Overall, morphine and Daflon co-administration offers a promising and safer strategy for managing neuropathic pain and preserving spinal cord integrity.

Background:Bougainvillea x buttiana is an ornamental plant with antioxidant, anti-inflammatory, and cytotoxic activities, which has been traditionally used to treat respiratory diseases. This study aimed to investigate whether the acetonic extract of Bougainvillea x buttiana var. Rose (BxbRAE-100%) has analgesic and anti-inflammatory properties and its potential action mechanisms. Methods: Analgesic and anti-inflammatory activities were evaluated using three murine pain models and two acute inflammation models. In vitro, the ability of the extract to inhibit proteolytic activity and the activities of the enzymes phospholipase A2 (PLA2) and cyclooxygenase (COX) were evaluated. In silico analysis was performed to predict the physicochemical and Absorption, distribution, metabolism, and excretion (ADME) profiles of the compounds previously identified in BxbRAE-100%. Results: In vivo BxbRAE-100% decreased the nociceptive behaviors in the writhing model, the tail immersion, and the formalin test, suggesting that the extract has the potential to relieve pain at peripheral and central levels. Additionally, topical or oral BxbRAE-100% treatment reduced dose-dependent 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammation and carrageenan-induced paw edema, respectively. In vitro, BxbRAE-100% significantly inhibited proteolytic activity and PLA2, COX-1 and COX-2 activities. In silico, the compounds previously identified in BxbRAE-100% met Lipinski’s rule of five and showed adequate ADME properties. Conclusions: These results support the use of B. x buttiana in Traditional Mexican Medicine and highlight its potential for the development of new treatments for pain and inflammation.

Palmitoylethanolamide (PEA) exhibits multiple skincare functions such as anti-nociceptive and anti-inflammatory effects. However, its topical application is limited due to its difficulty in bypassing the stratum corneum barrier, relatively low bioavailability, and low stability. Herein, elastic nano-liposomes (ENLs) with excellent deformability and elasticity were utilized as a novel drug delivery system to encapsulate PEA to overcome the abovementioned issues and enhance the biological effects on the skin. ENL was prepared with phosphatidylcholine, cholesterol, and cetyl-PG hydroxyethyl palmitamide with a molar ratio mimicking skin epidermal lipids, and PEA was loaded. The PEA-loaded ENL (PEA-ENL) demonstrated efficient transdermal delivery and enhanced skin retention, with negligible cytotoxicity toward HaCaT cells and no allergic reaction in the human skin patch test. Notably, PEA-ENL treatment increased cell migration and induced significant regulation in the expression of genes associated with anti-nociceptive, anti-inflammatory, and skin barrier repair. The mechanism of the anti-nociceptive and anti-inflammatory effects of PEA was further investigated and explained by molecular docking site analysis. This novel PEA-ENL, with efficient transdermal delivery efficiency and multiple skincare functionalities, is promising for topical application.

Background Chukrasia velutina is an enthnomedicinally used plant reported to have significant medicinal values. The present study aimed to explore the pharmacological activities of bark methanol extract using in vitro, in vivo and in silico models. Methods The study was designed to investigate the pharmacological effects of methanol extract of Chukrasia velutina bark (MECVB) through in vitro, in vivo and in silico assays. Analgesic activity was tested using formalin‐induced nociception and acetic acid‐induced writhing assays while the antipyretic effect was tested using yeast‐induced hyperthermia in mice model. The antioxidant effect was tested using the DPPH and reducing power assay and the cytotoxic screening was tested using the brine shrimp lethality bioassay. In addition, in silico studies were conducted using computer aided methods. Results In the acetic acid‐induced writhing assay, the extract showed 28.36% and 56.16% inhibition of writhing for doses of 200 and 400 mg/kg, respectively. Moreover, a dose‐dependent formalin‐induced licking response was observed in both early and late phase. In yeast‐induced pyrexia, the MECVB exhibited (p < 0.05) antipyretic effect. The extract demonstrated an IC50 value of 78.86 μg/ml compared with ascorbic acid (IC50 23.53 μg/ml) in the DPPH scavenging assay. The compounds sitosterol, 5,7‐dimethoxycoumarin and scopoletin were seen be effective in molecular docking scores against COX‐I (2OYE), COX‐II (6COX) and human peroxiredoxin 5 (1HD2). In ADME/T analysis, 5,7‐dimethoxycoumarin and scopoletin satisfied Lipinski's rule of five and thus are potential drug candidates. Conclusion The bark of Chukrasia velutina showed significant analgesic and antipyretic properties and is a potential source of natural anti‐oxidative agents. Pharmacological activities of Chukrasia velutina.