Search Results (91)

Fibromyalgia, a syndrome characterized by hyperalgesia and ‘negative emotionality’, and major depressive disorder (MDD) demonstrate substantial overlaps in clinical, neurobiological, and therapeutic domains. Currently, treatment options for fibromyalgia remain limited; however, the epidemiology of this syndrome continues to grow worldwide. The use of animal models is indispensable for developing new treatment strategies for fibromyalgia. Meanwhile, the choice of animal paradigms is limited. Here, we used the ultrasound exposure of emotional stress on CBA, BALB/c, and C57BL/6 mouse strains to model this condition and to identify new molecular targets of fibromyalgia treatment. We exposed young male mice of three common strains to a three-week ultrasound stress (US) comprising emotionally negative and neutral frequencies of 20–25 kHz and 25–45 kHz, resulting in the development of altered pain sensitivity and signs of ‘negative emotionality’. Specifically, mice were studied for timid-like/aggressive behaviors and the tail flick response. Serum levels of corticosterone, cortisol, β-Endorphin, and brain-derived neurotrophic factor (BDNF), as well as brain gene expression of interleukin-33 (Il-33), Bdnf, and its receptor Trkb were investigated. Among the stressed mouse strains, C57BL/6 mice displayed augmented pain sensitivity, allodynia, and suppressed dominant behavior, whereas CBA and BALB/c mice demonstrated opposing changes. Glucocorticoid levels were increased in all stressed groups. Stressed C57BL/6 mice showed downregulated gene and protein expression of functionally inter-related BDNF and IL-33 molecules in the hippocampus, amygdala, and striatum, significantly correlating with behavioral outcomes, as well as lowered blood levels of β-Endorphin and elevated cortisol concentrations. Altogether, our study identified the BDNF/IL-33 regulatory pathway as a molecular correlate of fibromyalgia, and the use of US-exposed young C57BL/6 mice as a potential model that recapitulates this syndrome. 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

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

Nutritional strategies based on sourdough fermented breads with wholemeal ancient grains and legumes are emerging as promising modulators of (neuro)immune processes. This study investigated whether prolonged consumption of a sourdough bread enriched with a mixture of ancient cereals and legumes, commercially available in Italy (Primus^® bread, P^®B), modulates neuroimmune systemic responses to repeated lipopolysaccharide (LPS) challenge in mice. For this study, male C57BL/6J mice were fed for 14 days with either a standard diet (SD) or P^®B. Animals then received intraperitoneal LPS (3 mg/kg/day for 3 days) or vehicle. Body weight and food intake were monitored throughout. Pain-like behaviours were assessed by von Frey, plantar and tail flick tests, and plasma cytokine (32-plex panel), splenocyte and peritoneal macrophage cytokine expression, and expression of pro-inflammatory cytokines in sciatic nerves, dorsal root ganglia (DRG) and the spinal cord were analyzed by Reverse Transcription–quantitative Polymerase Chain Reaction (RT-qPCR). P^®B prevented LPS-induced body weight loss and reduced splenomegaly. Unlike SD mice, which exhibited widespread plasmatic cytokine upregulation, P^®B-fed mice displayed only limited increases Interleukin (IL)-1β, IL-12p40 and Tumor Necrosis Factor (TNF)α. Ex vivo cultures of splenocytes and macrophages confirmed attenuated cytokine overexpression. LPS-induced hypersensitivity to mechanical, thermal and nociceptive stimuli was significantly reduced in P^®B mice. Molecular analyses revealed that the P^®B diet blunted the pro-inflammatory cytokine expression present after LPS challenge in the sciatic nerves and DRG, with partial attenuation in the spinal cord. Our findings highlight the great potential of functional foods as affordable dietary strategies to mitigate systemic immune and neuroimmune dysregulation. Full article

Background: Diabetic peripheral neuropathy (DPN) is one of the most common and debilitating complications of diabetes mellitus, for which current therapies do not prevent nerve degeneration. Chitosan, a biocompatible polysaccharide with antioxidant, anti-inflammatory, and lipid-lowering properties, may exert direct neuroprotective effects. This study evaluated the impact of oral administration of chitosan on peripheral nerve function and structure in a murine model of streptozotocin (STZ)-induced diabetes. Methods: Male C57BL/6 mice were divided into three groups: Sham, untreated diabetics (T1DM) and diabetics treated with chitosan (150 mg/kg/day, 12 weeks). Metabolic, behavioral (Open Field), nociceptive (Von Frey, Tail-Flick), electrophysiological (compound motor action potential—CMAP) and histological (intraepidermal nerve fiber density—IENF) parameters were analyzed. Results: Chitosan did not significantly modify blood glucose (p = 0.3366), but showed favorable metabolic effects, reducing LDL cholesterol in T1DM+Chitosan vs. T1DM mice (43.75 ± 5.62 mg/dL vs. 82.75 ± 7.65 mg/dL, p < 0.0001) as well as triglycerides (103.5 ± 12.8 mg/dL vs. 175.5 ± 22.8 mg/dL, p < 0.0001). In nociceptive tests, chitosan ameliorated thermal hyperalgesia (Tail-Flick: T1DM 1.25 ± 0.19 s vs. T1DM+Chitosan 1.54 ± 0.16 s; p = 0.0188) and mechanical allodynia (Von Frey: T1DM 0.16 ± 0.07 g vs. T1DM+Chitosan 0.38 ± 0.15 g, p = 0.0103). Electrodiagnostically, chitosan improved CMAP amplitude (T1DM 5.756 ± 0.706 mV vs. T1DM + Chitosan 6.756 ± 0.760 mV, p = 0.0409) and reduced CMAP duration (3.161 ± 0.217 ms vs. 2.900 ± 0.080 ms, p = 0.0273). Histologically, IENF density significantly increased in the treated group (0.01991 ± 0.00246 vs. 0.01512 ± 0.00253 in T1DM; p = 0.0200). Conclusions: Oral administration of chitosan confers functional and structural neuroprotection in STZ-induced diabetic neuropathy despite persistent hyperglycemia. Full article

Background/Objectives: Lidocaine hydrochloride (LD-HCl) is the most commonly used local anesthetic in dentistry, often administered with epinephrine to extend its duration and reduce systemic absorption. However, its relatively short duration of action, the need for repeated injections, and the unpleasant taste may limit patient compliance and procedural efficiency. This study aimed to develop and evaluate a novel injectable nanoemulsion-based in situ gel depot system of LD to provide prolonged anesthetic activity. Methods: LD-loaded nanoemulsions were formulated by high-shear homogenization followed by probe sonication, employing Miglyol 812 N (oil phase), a combination of Tween 80 and soy lecithin (surfactant–co-surfactant), glycerin, and deionized water (aqueous phase). The selected nanoemulsion (S1) was dispersed in a thermoreversible poloxamer solution to form a nanoemulgel. The preparation was evaluated for globule diameter and uniformity, zeta potential, surface morphology, pH, drug content, stability, rheological behavior, injectability, and in vitro drug release. Analgesic efficacy was assessed via tail-flick and thermal paw withdrawal latency tests in Wistar rats. Cardiovascular safety was monitored using non-invasive electrocardiography and blood pressure measurements. Results: The developed nanoemulsions demonstrated a spherical shape, nanometer size (206 nm), high zeta-potential (−66.67 mV) and uniform size distribution, with a polydispersity index of approximately 0.40, while the nanoemulgel demonstrated appropriate thixotropic properties for parenteral administration. In vitro release profiles showed steady LD release (5 h), following the Higuchi model. In vivo studies showed significantly prolonged analgesic effects lasting up to 150 min (2.5 h) compared to standard LD-HCl injection (p < 0.001), with no adverse cardiovascular effects observed. Conclusions: The developed injectable LD in situ nanoemulgel offers a promising, patient-friendly alternative for prolonged anesthetic delivery in dental and operative procedures, potentially reducing the need for repeated injections and enhancing procedural comfort. Full article

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. Full article

The neuropeptide’s multifaceted involvement in various components of neural homeostasis impacts pain and behavioral regulation. One of the highly potent neuropeptides is dermorphin, extracted from the skin of the Amazon frog (Phyllomedusa sauvagei). The unique feature of dermorphin is the D-Ala residue in its sequence, which has inspired researchers to search for dermorphin analogs for use as pharmaceuticals. The primary objective of this study is to synthesize several new linear and cyclic dermorphin analogs and evaluate them as potential non-invasive analgesics. By exploring our method for converting linear peptides into 2,5-diketopiperazine(2,5-DKP) derivatives, which stabilize peptide structures, we synthesize several new dermorphin linear peptides and chimeric cyclopeptidomimetics. These compounds were tested in vitro and in vivo to determine their biological activities and potential applicability as pharmaceuticals. For the evaluation of in vitro opioid activity, the “Guinea Pig Ileum” (GPI) test was used. D2 showed the highest activity, and cyclopeptides D3 and D4 showed high activity. We can assume that dermorphin analogues D2, D3, and D4 are potent agonists of µ-type opioid receptors and have high opioid activity. However, this needs to be verified using molecular modeling methods in further research. The analgesic effects of dermorphins have been evaluated in the “Hot-Plate” and “Tail-Flick” tests. In rats, D2 dermorphin analogues demonstrated dose-dependent analgesic effect in the “Water Tail-Flick” test after intranasal administration. A smaller dose of 0.5 µg/kg resulted in 40% analgesia and a short-term state of stupor. The maximum long-lasting analgesia was observed at a dose of 1.0 µg/kg, which induced complete stupor. The analgesic effect of peptide D2 after intraperitoneal administration at a 5.0 mg/kg dose was over 50%. The “Open-Field” test demonstrated a dose-dependent (15, 50, 150 μg/kg) peptide D2 suppression effect on behavioural reactions in rats following intranasal administration. A new modification of linear peptides, combined with a 2,5-DKP scaffold (D3 and D4), proved promising for oral use based on the results of analgesic effect evaluation in mice following intragastric administration. Full article

Background: Chronic pain poses a major global health burden, often inadequately managed by conventional analgesics due to limited efficacy and side effects. In this context, plant-based therapies offer a promising alternative. This study aimed to evaluate the antioxidant and analgesic potential of four medicinal plants traditionally used for pain relief: Morus alba, Angelica archangelica, Valeriana officinalis, and Passiflora incarnata. Methods: Phytochemical analyses quantified total phenolic acid, flavonoid, and polyphenolic acid contents in the extracts. Antioxidant activity was assessed using the ABTS radical scavenging assay. Analgesic effects were evaluated in vivo using the hot-plate and tail-flick tests in mice treated for 14 days with plant extracts or paracetamol. Results: Morus alba showed the highest polyphenolic content and strongest antioxidant activity (IC₅₀ = 0.0695 mg/mL). In analgesic tests, Angelica archangelica demonstrated the most significant effect in the hot-plate test (72.2% increase in latency), while Valeriana officinalis had the highest efficacy in the tail-flick test (41.81%), exceeding paracetamol’s performance in that model. Conclusions: While antioxidant activity correlated with polyphenol content, analgesic effects appeared to involve additional mechanisms. These findings support the potential of Angelica archangelica and Valeriana officinalis as effective natural alternatives for pain relief. Full article

Primary dysmenorrhea (PD) is characterized by lower abdominal spasms and painful cramps during menstruation in females with a normal pelvic anatomy. Cymbopogon citratus (DC.) Stapf, commonly known as lemongrass, is consumed in the form of herbal tea around the world. It has been traditionally used for menstrual disorders in several communities. This study aims to evaluate the traditional use of C. citratus for its efficacy in alleviating the symptoms of PD. C. citratus extract (CcE) was chemically characterized using HPLC and GCMS, which indicated the presence of several phenolic compounds and long-chain fatty acids. The anti-inflammatory activity of CcE was assessed by COX-I, COX-II, and 5-LOX enzyme inhibition with IC₅₀ values of 143.7, 91.7, and 61.5 µg/mL, respectively, and showed good total antioxidant capacity and free radical scavenging activity. PD was induced in female Wistar rats by administering estradiol valerate followed by oxytocin to induce PD symptoms. CcE efficacy was assessed at 30, 100, and 300 mg/kg concentrations and compared with ibuprofen. CcE 300 mg/kg reduced abdominal contortions and inflammation in the rat uterus. The inflammatory (COX-II, TNFα and IL-10) and oxidative stress (TAC, TOS, MDA and SOD) markers in uterine tissue homogenate were also improved. An in vivo analgesic assessment through hot-plate, tail-flick, and acetic acid-induced writhing assays showed good analgesic activity by CcE, while ex vivo experiments described tocolytic effects in rat uterine muscles. CcE alleviates PD by its antioxidant, anti-inflammatory, analgesic, and tocolytic effects. Full article

Background/Objectives: Indomethacin (IND) is a widely used non-steroidal anti-inflammatory drug (NSAID) effective in managing pain and inflammation. However, its therapeutic use is often limited by gastrointestinal irritation and low bioavailability. This study aimed to evaluate the biocompatibility, release kinetics, and analgesic potential of IND-loaded chitosan (CHIT)-stabilized lipid vesicles (IND-ves) in comparison to free IND, focusing on their in vivo effects and impact on somatic nociceptive reactivity in mice. Methods: IND-ves were prepared using a molecular droplet self-assembly technique, followed by CHIT coating to enhance stability and control drug release. Mice were administered either free IND or IND-ves, and various physiological parameters, including liver and kidney function, oxidative stress markers, immune cell activity, and histopathological changes in key organs, were assessed. Plasma drug release kinetics and analgesic effects were evaluated using the tail-flick test. Results: Both IND and IND-ves demonstrated good biocompatibility, with no significant changes in hematological, biochemical, or immunological profiles. IND-ves exhibited a sustained release profile, with drug release initiating at 30 min and peaking at 3 h, while free IND displayed a rapid release and potential gastric mucosal damage. IND-ves did not induce oxidative stress or inflammation and maintained organ integrity, particularly protecting against gastric injury. Additionally, the prolonged release profile of IND-ves contributed to extended analgesic effects in the tail-flick test. Conclusions: CHIT-stabilized lipid vesicles offer a promising drug delivery system for IND, enhancing drug release, prolonging analgesic efficacy, and minimizing gastrointestinal irritation. These findings suggest that IND-ves could serve as a safer and more effective alternative for NSAID therapy. Full article

Hydrazones, characterized by their C=N–NH functional group, are promising candidates in medicinal chemistry due to their ability to interact with biological targets. This study evaluated the anti-inflammatory and analgesic properties of N-pyrrolylcarbohydrazide (1) and four pyrrole hydrazone derivatives (1A–D) in male Wistar rats (6 weeks old). Anti-inflammatory activity was assessed using a carrageenan-induced paw edema model, while formalin, tail flick, and paw withdrawal tests evaluated analgesia. Compound 1 exhibited dose-dependent anti-inflammatory activity. At 20 mg/kg, significant edema reductions were observed at the 2nd (p = 0.035) and 3rd hours (p = 0.022), while at 40 mg/kg, reductions remained significant at the 2nd (p = 0.008) and 3rd hours (p = 0.046). Compound 1A showed pronounced effects at 20 mg/kg at the 2nd (p = 0.005), 3rd (p < 0.001), and 4th hours (p = 0.004). Other compounds demonstrated minimal or no activity. Analgesic evaluation revealed that at 40 mg/kg, compound 1 significantly reduced paw-licking time in the second phase (p = 0.038). Compounds 1B, 1C, and 1D exhibited transient effects in the first phase only (p < 0.05). Compound 1A lacked significant analgesic activity. The findings suggest that structural modifications may enhance efficacy for broader therapeutic applications. Full article

Background/Objectives: Orally or intravenously administered acetaminophen experiences considerable liver first-pass elimination and may cause liver/kidney damage. This work examined the pharmacological effects of acetaminophen-loaded poly(lactic-co-glycolic acid) nanoparticles (AAP PLGA NPs) intranasally administered to mice rapidly entering high altitudes. Methods: AAP PLGA NPs were prepared using ultrasonication-assisted emulsification and solvent evaporation and characterized in terms of drug encapsulation efficiency and loading, in vitro and in vivo release behaviors, and toxicity to hippocampal neurons. In vivo fluorescence imaging was used to monitor the concentrations of AAP PLGA NPs (labeled with indocyanine green) in the brain and blood of the mice after intranasal administration. The effects of these NPs on the pain threshold in mice rapidly entering high altitudes were evaluated through hot plate and tail flick experiments. Results: The AAP PLGA NPs were found to be noncytotoxic, highly biocompatible and stable, with a drug encapsulation efficiency and loading capacity of 42.53% and 3.87%, respectively. The in vitro release of acetaminophen lasted for up to 72 h, and the release rate was ~82%. After intranasal administration in vivo, the drug release occurred slowly, and the drug was mainly concentrated in the brain. Compared with nonencapsulated acetaminophen, the intranasal administration of AAP PLGA NPs resulted in higher brain levels of the drug and delayed its elimination, thus increasing the pain threshold in mice rapidly entering high altitudes. Conclusions: The proposed strategy addresses the common problems of intranasal drug administration (low retention time and bioavailability) and paves the way for effective pain management in high-altitude environments. Full article

Background: Pain is a major clinical and socioeconomic problem worldwide. The available therapies are not always effective and are often associated with the multiple adverse effects that reduce their clinical application. Natural compounds are an important group of pharmaceuticals that may be used in pain management. We aimed to investigate the analgesic activity of the sanguinarine–chelerythrine from Coptis chinensis. Methods: The analgesic and anti-inflammatory activity of the sanguinarine–chelerythrine fraction of C. chinensis extract (SC 5 and 10 mg/kg), sanguinarine (SAN 1 and 2 mg/kg) and chelerythrine (CHEL 4 and 8 mg/kg) was assessed in tail flick and formalin tests. A microscopic and macroscopic examination of stomach mucosae was performed. TNFα and MMP-9 levels were measured with ELISA kits. Results: Morphine (MORF), CHEL and SC prolongated the tail withdrawal latency, with comparable analgesic activity between MORF and CHEL 8 mg/kg. MORF, CHEL 8 mg/kg, and SAN 2 mg/kg ameliorated the pain reaction in the neurogenic phase of the formalin test. In the inflammatory phase of the formalin test, all tested substances exerted analgesic activity. SAN, CHEL and SC additionally reduced TNFα and MMP-9 secretion. Conclusions: Our results confirmed analgesic effects of CHEL and SC with CHEL analgesic activity comparable to MORF. All investigated substances exerted significant anti-inflammatory activity without concomitant gastrotoxicity. Full article