Antinociceptive Activity Research Articles

Assessment of antinociceptive property of Cynara scolymus L. and possible mechanism of action in the formalin and writhing models of nociception in mice.

Cynara scolymus has bioactive constituents and has been used for therapeutic actions. The present study was undertaken to investigate the mechanisms underlying pain-relieving effects of the hydroethanolic extract of C. scolymus (HECS). The antinociceptive activity of HECS was assessed through formalin and acetic acid-induced writhing tests at doses of 50, 100 and 200 mg/kg intraperitoneally. Additionally, naloxone (non-selective opioid receptors antagonist, 2 mg/kg), atropine (non-selective muscarinic receptors antagonist, 1 mg/kg), chlorpheniramine (histamine HH1-receptor antagonist, 20 mg/kg), cimetidine (histamine H2-receptor antagonist, 12.5 mg/kg), flumazenil (GABAA/BDZ receptor antagonist, 5 mg/kg) and cyproheptadine (serotonin receptor antagonist, 4 mg/kg) were used to determine the systis implicated in HECS-induced analgesia. Impact of HECS on locomotor activity was executed by open-field test. Determination of total phenolic content (TPC) and total flavonoid content (TFC) was done. Evaluation of antioxidant activity was conducted iploying 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. HECS (50, 100 and 200 mg/kg) significantly indicated dose dependent antinociceptive activity against pain-related behavior induced by formalin and acetic acid (P < 0.001). Pretreatment with naloxone, atropine and flumazenil significantly reversed HECS-induced analgesia. Antinociceptive effect of HECS riained unaffected by chlorpheniramine, cimetidine and cyproheptadine. Locomotor activity was not affected by HECS. TPC and TFC of HECS were 59.49 ± 5.57 mgGAE/g dry extract and 93.39 ± 17.16 mgRE/g dry extract, respectively. DPPH free radical scavenging activity (IC50) of HECS was 161.32 ± 0.03 μg/mL. HECS possesses antinociceptive activity which is mediated via opioidergic, cholinergic and GABAergic pathways.

Ferroptosis inhibitor ferrostatin-1 attenuates morphine tolerance development in male rats by inhibiting dorsal root ganglion neuronal ferroptosis.

Ferrostatin-1 and liproxstatin-1, both ferroptosis inhibitors, protect cells. Liproxstatin-1 decreases morphine tolerance. Yet, ferrostatin-1's effect on morphine tolerance remains unexplored. This study aimed to evaluate the influence of ferrostatin-1 on the advancement of morphine tolerance and understand the underlying mechanisms in male rats. This experiment involved 36 adult male Wistar albino rats with an average weight ranging from 220 to 260 g. These rats were categorized into six groups: Control, single dose ferrostatin-1, single dose morphine, single dose ferrostatin-1 + morphine, morphine tolerance (twice daily for five days), and ferrostatin-1 + morphine tolerance (twice daily for five days). The antinociceptive action was evaluated using both the hot plate and tail-flick tests. After completing the analgesic tests, tissue samples were gathered from the dorsal root ganglia (DRG) for subsequent analysis. The levels of glutathione, glutathione peroxidase 4 (GPX4), and nuclear factor erythroid 2-related factor 2 (Nrf2), along with the measurements of total oxidant status (TOS) and total antioxidant status (TAS), were assessed in the tissues of the DRG. After tolerance development, the administration of ferrostatin-1 resulted in a significant decrease in morphine tolerance (P < 0.001). Additionally, ferrostatin-1 treatment led to elevated levels of glutathione, GPX4, Nrf2, and TOS (P < 0.001), while simultaneously causing a decrease in TAS levels (P < 0.001). The study found that ferrostatin-1 can reduce morphine tolerance by suppressing ferroptosis and reducing oxidative stress in DRG neurons, suggesting it as a potential therapy for preventing morphine tolerance.

Polyphenol-rich Sorghum bicolor supplement exhibits anti-nociceptive activity and protective effects against pathological changes associated with complete Freund's adjuvant induced arthritis in rodents

IntroductionArthritis is a common inflammatory joint disease; causing severe pain, anxiety, and depression. Sorghum bicolor L. Moench (Pocaeae) is used for treating cough, asthma, and arthritic pain in Traditional Chinese Medicine (TCM). This study evaluates the anti-nociceptive and anti-arthritic effects of the polyphenol-rich Sorghum bicolor supplement (SBS) in rodents. MethodsThe anti-nociceptive activity of SBS was assessed using hot plate, acetic acid mouse writhing, and formalin-induced paw licking tests in mice. In the arthritis study, rats received SBS (50, 100, and 200 mg/kg p.o) for 28 days. Thirty minutes after treatment on days, 1 and 20, rats received intra-articular injection of Complete Freund's adjuvant (CFA) for arthritis induction. Arthritic scores and paw edema were determined before assessing motor function, anxiety, depression, hyperalgesia and allodynia on day 28. Lipid profiles were determined, and ankle and brain tissues were analyzed for oxidative stress and inflammatory biomarkers, alongside histopathological studies. ResultsSBS reduced nociceptive responses induced by noxious heat, acetic acid and formalin in mice. In CFA-injected rats, SBS decreased paw volume and arthritic scores, and increased pain thresholds to thermal, cold, and mechanical stimuli. The SBS reduced motor activity, anxiety and depression, and improved serum lipid profiles in arthritic rats. It further modulated oxidative stress, pro-inflammatory cytokines, nuclear factor kappa (NF-kB), apoptotic markers, nuclear factor erythroid 2-related factor 2 (NRF2), glutamic acid decarboxylase (GAD) and brain-derived neurotrophic factor (BDNF) in CFA-treated rats. SBS produced histopathological improvements in joint tissues of arthritic rats. DiscussionThis study revealed that SBS exhibited anti-nociceptive activity in mice and reduces inflammation, hyperalgesia, anxiety and depression in CFA-arthritic rats. The ability of SBS to modulate key biomarkers such as pro-inflammatory cytokines, NF-κB, caspases, Nrf2, BDNF, and GAD highlights its multifaceted approach in addressing both the physical and psychological aspects of arthritis, providing a comprehensive therapeutic strategy, justifying its use in TCM for this debilitating condition.

Development and Assessment of Helicteres isora Extract Loaded Phospholipid Complex for Anti-Nociceptive Activity

Its primary objective is to assess the efficacy of a phospholipid complex formulation containing an extract of Helicteres isora in reducing inflammation, to determine its progress and evaluation. An Indian Screw Tree, also known as Helicteres isora, is an extremely healing plant. In addition to improving solubility and stability, the phospholipid complex formulation also increases bioavailability and efficacy. This formulation was created by combining Helicteres isora extract with phospholipids using a technique known as phospholipid complexation. Several parameters were evaluated to evaluate the formulation, including particle size, zeta potential, encapsulation efficiency, and drug release profile. Using both in vitro and in vivo models, the anti-inflammatory properties of a phospholipid complex formulation of Helicteres isora were assessed. The experiments were conducted using a rat model of carrageenan-induced paw edema. In this work, phospholipid complex formulations were shown to have improved physicochemical properties, including smaller particle sizes and higher encapsulation rates. According to the results of the in vivo evaluation, phospholipid complex formulations significantly reduced paw edema compared with plain extracts, indicating improved anti-inflammatory activity. The bioavailability, anti-inflammatory activity, and bioavailability of Helicteres isora extract are enhanced by the phospholipid complex formulation.

Exploring the antinociceptive potential of homoeriodictyol in nociception models

Context: Homoeriodictyol is a flavonoid with known antioxidant, anti-inflammatory, and anti-tumor properties found in various plants. However, its potential analgesic effects have not been explored. Aims: To investigate the pain-relieving properties of homoeriodictyol using different mouse models of nociception. Methods: Various doses of homoeriodictyol (50, 100, 150, and 200 µg/kg) were administered to mice and evaluated using the acetic acid-induced writhing test, the hot plate test, and the formalin-induced paw licking assay. These effects were compared with those of mice treated with acetylsalicylic acid or morphine, both with and without naloxone, an opioid receptor antagonist. Additionally, capsaicin- and glutamate-induced paw-licking tests were conducted to assess the involvement of the vanilloid and glutamatergic systems, respectively. Results: Homoeriodictyol demonstrated a significant and dose-dependent reduction in nociceptive behavior in the acetic acid-induced writhing test, achieving a 52.4% inhibition at a dose of 200 µg/kg. It also substantially increased the latency period in response to the hot plate test (65.8% at 200 µg/kg) and significantly suppressed both the neurogenic and inflammatory phases in the formalin-induced paw-licking test. Notably, the effects of homoeriodictyol in the hot plate test and formalin-induced paw-licking test were significantly reversed by naloxone. Furthermore, homoeriodictyol effectively reduced neurogenic nociception induced by intraplantar injections of glutamate and capsaicin (57.8% and 76.9%, respectively, at a dose of 200 µg/kg). Conclusions: This study concludes that homoeriodictyol exhibits antinociceptive activity in mice, acting through both central and peripheral pathways.

Synthesis and pharmacological activity of various organic and inorganic salts of phenyl derivatives of imidazobenzimidazole

Introduction: The creation of new opioid analgesics that are devoid of the main undesirable effects – euphoria, respiratory depression, tolerance – is an important task for the treatment of pain syndrome. Eighteen salts of 9-pyrrolidinoethyl-(1a), 9-piperidinoethyl-(1b), and 9-morpholinoethyl-2-(4-fluorophenyl)benzo[d]imidazo[1,2-a]imidazole (1c) were synthesized and tested for kappa agonist and analgesic activity. Materials and Methods: Specific analgesic activity studies were conducted using models of nociceptive pain in the “Hot/Cold-plate” and ”Plantar Test” tests, and in neuropathic pain against the background of sciatic nerve ligation. The relationship between the physicochemical and pharmacological properties of the compounds was studied in silico using quantum chemistry methods and artificial neural network technology. Results: The most active compound identified was 4-(2-(2-(4-fluorophenyl)-benzo[d]imidazo[1,2-a]imidazol-9-yl)ethyl)morpholine dihydrochloride (1c.2HCl). EC50, acute toxicity, and conditional therapeutic index values were calculated, which were 38.8 times superior to the kappa agonist U50488. It was established that compound 1c.2HCl exhibits a dose-dependent analgesic effect in the “Hot/Cold-plate” test, which is six times superior to that of butorphanol, maintaining a statistically significant effect for six hours in the “Plantar test” and without causing the formation of tolerance with a ten-day administration. In models of neuropathic pain syndrome, 1c.2HCl with a fourteen-day administration significantly reduced tactile and cold allodynia by three and 1.6 times, respectively, and was not inferior in activity to gabapentin. The kappa-opioidergic mechanism of the antinociceptive action of 1c.2HCl compound was confirmed. Quantum chemistry methods and artificial neural network technologies have shown that the high level of kappa-opioid agonist activity of hydrochlorides, in contrast to other salts, results in lower total energy production; therefore, there is a significant increase in energy during the formation of a salt supramolecular complex. Conclusion: The most active compound was identified – 1c.2HCl, for which kappa-opioid activity in vitro and analgesic properties were revealed in various in vivo models. It has been shown that the compound does not cause the formation of tolerance and is not toxic.

Additive antinociceptive action of intrathecal anandamide reuptake inhibitor and morphine in the management of post-incisional pain in rats

Spinal opioids have mixed efficacy and their adverse effects force treatment cessation of postoperative pain. Consequently, there is an ongoing search for new therapeutic strategies. Here, we evaluated the analgesic efficacy of intrathecal UCM707, an anandamide reuptake inhibitor, and morphine combination. Firstly, we assessed the effects of morphine (1, 5 and 10 μg), UCM707 (75 μg) and its combination in the hot plate. Then, morphine + UCM707 at sub-effective doses was evaluated in a rat post-incisional pain model. In addition, μ-, CB1r-, CB2r- and TRPV1-antagonists were pre-administered before the combination. Activation of μ-opioid and CB1r, and Cnr1, Cnr2, Oprm1 and TRPV1 expressions were evaluated in the lumbar sacra and periaqueductal grey by [35 S]-GTPγS binding autoradiography and qPCR studies. In the hot plate, morphine (1 μg) and UCM707 (75 μg) induced a more robust analgesic effect than each drug alone. Morphine plus UCM707 did not modify μ-opioid nor CB1 receptor function in the PAG or LS. Cnr1 and TRPV1 expression increased in the lumbar sacra (LS). Morphine plus UCM707 significantly reduced post-incisional pain at 1 and 4 days after surgery. Cnr1, Cnr2 and TRPV1 expressions increased in the LS. Blockade of μ-opioid receptor reduced combination effects on days 1 and 4. CB1r- and CB2r-antagonism reduced morphine + UCM707 effects on days 1 and 4, respectively. CB1r and TRPV1-antagonism improved their antinociceptive effects on day 4. These results revealed a synergistic/additive analgesic effect of UCM707 and morphine combination controlling postincisional pain. CB1r, CB2r and TRPV1 contribute differently as central sensitization occurs.

Improved Anti-nociceptive, Anti-pyretic and Anti-inflammatory Effects of Orally Administered Liposome-encapsulated Piroxicam

Piroxicam, a nonsteroidal anti-inflammatory drug, has been shown with low oral bioavailability and delayed onset of its therapeutic effects. In this work, a promising nano/liposomal drug delivery system was exploited to improve the in vivo therapeutic efficacies of piroxicam. The current liposome-encapsulated piroxicam formulation effectively boosted and prolonged peripherally mediated anti-nociceptive activities in tests for abdominal writhing induced by acetic acid (inhibition of pain 70.19% was in mice treated with 30 mg/kg liposome-encapsulated piroxicam), paw licking induced by formalin (81.36% inhibition when compared to free unencapsulated piroxicam), and hyperalgesia induced by carrageenan (55.8% inhibition when compared to free unencapsulated piroxicam). Even lower dose of liposomes-encapsulated piroxicam was also significantly inhibit Brewer’s yeast-induced hyperthermia. Carrageenan-induced paw-edema test and cotton pellet-induced granuloma test revealed that liposomes-encapsulated piroxicam had significantly more potent acute and chronic anti-inflammatory effects than piroxicam, even if lower drug dosages were used to treat animals. A better modulation in the generation of inflammatory mediators (nitric oxide, tumour necrosis factor-α, interleukin-1β, and interleukin-10) at 18.02% (TNFa), 23.97% (IL-1β) and 10.27% (IL-10) inhibition when compared to 30mg/kg free piroxicam group respectively. was ascribed to the higher in vivo therapeutic actions. Present nano-encapsulated piroxicam also significantly enhanced the inhibition of cyclooxgenase-2 (total percentage inhibition was increased by 18.25% and 19.22% at drug dosage of 3 and 30 mg/kg, respectively), but not cyclooxgenase-1 enzyme. In conclusion, present study showed that liposomal drug formulation was able to improve the in vivo therapeutic effects of orally administered piroxicam.

BNT12, a novel hybrid peptide of opioid and neurotensin pharmacophores, produces potent central antinociception with limited side effects

The development of multitarget opioid drugs has emerged as an attractive approach for innovative pain management with reduced side effects. In the present study, a novel hybrid peptide BNT12 containing the opioid and neurotensin (NT)-like fragments was synthesized and pharmacologically characterized. In acute radiant heat paw withdrawal test, intracerebroventricular (i.c.v.) administration of BNT12 produced potent antinociception in mice. The central antinociceptive activity of BNT12 was mainly mediated by μ-, δ-opioid receptor, neurotensin receptor type 1 (NTSR1) and 2 (NTSR2), supporting a multifunctional agonism of BNT12 in the functional assays. BNT12 also exhibited significant antinociceptive effects in spared nerve injury (SNI)-neuropathic pain, complete Freund's adjuvant (CFA)-induced inflammatory pain, acetic acid-induced visceral and formalin-induced pain after i.c.v. administration. Furthermore, BNT12 exhibited substantial reduction of acute antinociceptive tolerance, shifted the dose-response curve to the right by only 1.3-fold. It is noteworthy that BNT12 showed insignificant chronic antinociceptive tolerance at the supraspinal level. In addition, BNT12 exhibited reduced or no opioid-like side effects on conditioned place preference (CPP) response, naloxone-precipitated withdrawal response, acute hyperlocomotion, motor coordination, gastrointestinal transit, and cardiovascular responses. The present investigation demonstrated that the novel hybrid peptide BNT12 might serve as a promising analgesic candidate with limited opioid-like side effects.

Sub-acute toxicity, antinociceptive and anti-inflammatory effects of Mucuna pruriens L. leaves in experimental rodents

Ethnopharmacological relevanceMucuna pruriens L is a wild and cultivated leguminous plant which have been used as an aphrodisiac, diuretic, nerve tonic, and antiarthritic agent. AimTo evaluate the toxicity, antinociceptive, and anti-inflammatory activities of M. pruriens (EEMP) ethanol extract in experimental models. MethodsM. pruriens dried leaves were extracted using aqueous ethanol (30:70). Tests for acute and subacute toxicity were conducted on rats and mice. Mice were used in hotplate, acetic acid, and formalin models to test the antinociceptive activity of EEMP. The anti-inflammatory properties of EEMP (25, 100, and 400 mg/kg) were assessed egg albumin, carrageenan, and formalin-induced oedema models. The study examined the anti-inflammatory mechanism of EEMP (25–400 mg/kg) in rats with an air pouch caused by carrageenan. Air pouch exudates were tested for total leucocytes and differential cell counts, TNF-α, IL-6, myeloperoxidase activity, malondialdehyde, nitrites, and reduced glutathione (GSH). ResultsThe acute oral toxic dose of EEMP is greater than 2000 mg/kg. There were no significant behavioral, hematological or biochemical alterations seen after 14-days repeated administration of EEMP (200, 400 and 800 mg/kg) in mice. The EEMP demonstrated significant antinociceptive activity in hotplate, acetic acid and formalin-induced nociception in mice. The EEMP significantly and dose dependently reduced paw oedema at 2, 4 and 96 h in the egg-albumin, carrageenan- and formalin-induced paw oedema, respectively. Exudates volume, inflammatory cell counts, TNF-α, IL-6, myeloperoxidase, malondialdehyde and nitrites were significantly reduced, while GSH increased in carrageenan-air pouch of EEMP-treated rats. ConclusionMucuna pruriens leaves ethanol extract demonstrated good safety profile as well as antinociceptive and anti-inflammatory activity through mechanisms related to inhibition of oxidative stress and pro-inflammatory cytokines as well as lysosomal membrane stability.

Tannic acid inhibits pain mediators, inflammation and oxidative stress in mice exposed to glyphosate-based herbicide.

Chronic exposure to glyphosate-based herbicide (Gly) has been associated with neurological disorders. Tannic acid (TA) is an antioxidant with attenuating action against neuroinflammation-associated conditions. This study evaluated the effect of Gly on pain perception alongside antinociceptive and anti-inflammatory actions of TA in Gly-exposed mice. Male Swiss mice were randomly divided into six groups (n=8): control (distilled water 0.2 ml/kg), Gly (Gly 500 mg/kg), Pre-TA + Gly (TA 50 mg/kg pre-treatment, afterwards Gly-administered), TA + Gly (TA 50 mg/kg and Gly co-administered), Pre-AA + Gly (ascorbic acid (AA) 10 mg/kg pre-treatment, afterwards Gly-administered), and AA + Gly (AA 10 mg/kg and Gly co-administered). Mechanical, thermal, and chemical pain were evaluated six weeks post vehicle/drugs administrations orally, followed by brain biochemical measurements. TA treatment alleviated Gly-induced hyperalgesia in similar version to the values of control and AA groups by increasing significantly (p < 0.05) nociceptive thresholds. Moreover, TA-treatment significantly decreased malondialdehyde (MDA) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels, significantly increased anti-inflammatory cytokines (IL-10, IL-4, and TGF-1β) levels, and antioxidant enzymes, catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities compared to Gly-treated mice (p < 0.05). Conclusively, TA treatment exerted antinociceptive and anti-inflammatory actions, possibly through its antioxidant and anti-inflammatory actions in Gly-exposed mice. Notably, TA pre-treatment showed a better response than TA and Gly co-administration. We propose the potential neuroprotective and ameliorative functions of TA in Gly-induced hyperalgesia. This merits further clinical research into protective roles of TA against pesticide-related conditions.

Evaluation of anti-nociceptive and anti-inflammatory activities of solvent fraction of the roots of Echinops kebericho Mesfin (Asteraceae) in mice model.

The present study was aimed at investigating the antinociceptive and anti-inflammatory activities of the solvent fractions of the roots ofEchinops keberichoMesfin in rodent models of pain and inflammation. Successive maceration was used as a method of extraction using solvents of increasing polarity: methanol and water. Ethyl acetate, chloroform and distilled water were used as solvents of the fraction process. Swiss albino mice models were used in acetic acid induced writhing, hot plate, carrageenan induced paw edema and cotton pellet granuloma to assess the analgesic and anti-inflammatory activities. The test groups received different doses (100 mg/kg, 200 mg/kg and 400 mg/kg) of the three fractions (chloroform, ethyl acetate and aqueous). The positive control groups received ASA (150 mg/kg) for the writing test, morphine (10 mg/kg) for the hot plate method, diclofenac Na for carrageenan-induced paw edema, and dexamethasone (10 mg/kg) for granuloma, while the negative control group received distilled water. EA fraction at all test doses employed (100 mg/kg, 200 mg/kg, and 400 mg/kg) showed statistically significant (p<0.05, p<0.01, p<0.001 respectively) analgesic and anti-inflammatory activities in a dose-dependent manner. The AQ fraction on the other hand produced statistically significant (p<0.05, p<0.012) analgesic and anti-inflammatory activities at the doses of 200 mg/kg and 400 mg/kg, while the CH fraction exhibited statistically significant (p<0.05) analgesic and anti-inflammatory activity at the dose of 400 mg/kg. In general, the data obtained from the present study elucidated that the solvent fractions of the study plant possessed significant analgesic and anti-inflammatory activities and were recommended for further investigations.

Lippia alba essential oil: A powerful and valuable antinociceptive and anti-inflammatory medicinal plant from Brazil

Ethnopharmacological relevanceIn Brazilian popular medicine, Lippia alba leaves are used in teas to treat pain and inflammatory diseases. Aim of the studyto evaluate the chemical composition, antinociceptive, and anti-inflammatory activities of Lippia alba essential oil and its major compound geraniol. Material and methodsLippia alba leaves were collected in Pará state, Brazil. The leaf essential oil was obtained using a modified Clevenger-type extractor. Then, the oil was analyzed by GC and GC-MS analyses. To evaluate the toxicity of LaEO and geraniol, the doses of 50, 300, and 2000 mg/kg were used in a mouse model. For antinociception tests, abdominal contortion, hot plate, and formalin tests were used; all groups were treated with LaEO and geraniol at doses of 25, 50, and 100 mg/kg; and to evaluate inflammation using the ear edema model. ResultsThe constituents identified in the highest content were oxygenated monoterpenes: geraniol (37.5%), geranial (6.7%) and neral (3.8%). The animals treated with LaEO and geraniol demonstrated atypical behaviors with aspects of lethargy and drowsiness, characteristics of animals in a state of sedation; the relative weights showed no significant difference compared to the controls. In the abdominal contortion test, LaEO at 25 mg/kg, 50 mg/kg doses, and 100 mg/kg reduced the number of contortions, representing a percentage reduction of 84.64%, 81.23%, and 66.21% respectively. In the hot plate test, LaEO and geraniol increased the latency time at doses of 25, 50, and 100 mg/kg in all test periods; there was no statistical difference between LaEO and geraniol. In the first phase of the formalin test, only doses of 25 mg/kg and 100 mg/kg of LaEO showed significant activity, reducing the latency time by 53.40% and 58.90%. LaEO at doses of 25 mg/kg and 100 mg/kg reduced the size of the edema, demonstrating an anti-inflammatory activity of 59.38% (25 mg/kg) and 50% (100 mg/kg). ConclusionLippia alba essential oil and geraniol showed central/peripheral analgesic and anti-inflammatory potential and can be used as an alternative or complementary treatment to conventional drugs. More studies are needed to evaluate its action mechanisms and its analgesic effects.

Insights into Metabolites Profiling and Pharmacological Investigation of Aconitum heterophyllum wall ex. Royle Stem through Experimental and Bioinformatics Techniques.

The Aconitum genus is a leading source of a wide range of structurally diverse metabolites with significant pharmacological implications. The present study investigated metabolite profiling, pharmacological investigation, anticancer potential, and molecular docking analysis of the stem part of Aconitum heterophyllum (AHS). The metabolite profiling of the AHS extract was experimentally examined using LC-MS/MS-orbitrap in both modes (ESI+/ESI-) and GC-MS in EI mode. The in vitro MTT model was used to study the anticancer potential, while the in vivo animal model was used to study the anti-inflammatory and antinociceptive activities. The MOE software was used for the molecular docking study. A total of 118 novel and previously known metabolites, among 44 metabolites (26 in ESI+ positive mode and 18 in ESI- negative mode) in the MeOH extract, while 74 metabolites (46 in ESI+ and 28 in ESI- mode) were identified in the n-hexane extract via LCMS/MS. The identified metabolites include 24 phenolic compounds, 18 alkaloids, 10 flavonoids, 24 terpenoids, 2 coumarins, 2 lignans, and 38 other fatty acids and organic compounds. The major bioactive metabolites identified were hordenine, hernagine, formononetin, chrysin, N-methylhernagine, guineesine, shogaol, kauralexin, colneleate, zerumbone, medicarpin, boldine, miraxinthin-v, and lariciresinol-4-O-glucoside. Furthermore, the GC-MS study helped in the identification of volatile and nonvolatile chemical constituents based on the mass spectrum and retention indices. The methanol extract significantly inhibited tumor progression in H9c2 and MDCK cancer cells with IC50 values of 186.39 and 199.63 μg/mL. In comparison, the positive control aconitine exhibited potent IC50 values (132.32 and 141.58 μg/mL) against H9c2 and MDCK cell lines. The anti-inflammatory (carrageenan-induced hind paw edema) and antinociceptive (acetic acid-induced writhing) effects were significantly dose-dependent, (p < 0.001) and (p < 0.05), respectively. In addition, a molecular docking study was conducted on identified ligands against the anti-inflammatory enzyme (COX-2) (PDB ID: 5JVZ) and the cancer enzyme ADAM10 (PDB ID: 6BDZ) which confirmed the anti-inflammatory and anticancer effects in an in silico model. Among all ligands, L2, L3, and L7 exhibit the most potent potential for inhibiting COX-2 inflammation with binding energies of -7.3424, -7.0427, and -8.3562 kcal/mol. Conversely, against ADAM10 cancer protein, ligands L1, L4, L6, and L7, with binding energies of -8.0650, -7.7276, -7.0454, and -7.2080 kcal/mol, demonstrated notable effectiveness. Overall, the identified metabolites revealed in this AHS research study hold promise for discovering novel possibilities in the disciplines of chemotaxonomy and pharmacology.

Chemical profiling, toxicity assessment, anti-diarrhoeal, anti-inflammatory and antinociceptive activities of Canarium schweinfurthii Engl. (Burseraceae) bark in rats

Ethnopharmacological relevanceThe bark of Canarium schweinfurthii is used in ethnomedicine for the treatment of diabetes, pain, malaria, fever and diarrhoea. Aim of the studyThe chemical phytoconstituents, antidiarrheal, anti-inflammatory and antinociceptive effects and safety profile of the aqueous extract of Canarium schweinfurthii bark (AECSB) were investigated. Materials and methodsGas chromatography-mass spectrometry (GC-MS) was used to analyse the phytochemical composition. In the acute toxicity test, AECSB were administered up to 2 g/kg by oral gavage. For the subacute toxicity test (28 days), rats in group 1 (control) received no AECSB, while rats in groups 2–4 were administered different doses of AECSB. Charcoal meal transit and castor oil-induced diarrhoea models were used to study the antidiarrheal effect, while egg albumin/carrageenan and acetic acid/tail immersion models were used for the anti-inflammatory and antinociceptive studies, respectively. With the exception of the acute toxicity experiment, AECSB was administered orally at doses of 200, 400 and 800 mg/kg. ResultsBioactive phytoconstituents identified include p-cymene, δ-terpinene, linalool and phytol. No adverse effects or mortality were observed in acute and subacute studies. Treatment with AECSB (28 days) had no significant effect on organ weight, biochemical, hematologic and histopathologic parameters compared to the control groups (p > 0.05). Comparable antidiarrheal and antinociceptive effects were observed in both AECSB- and standard drug-treated groups, while the 400 and 800 mg/kg AECSB-treated groups showed remarkable anti-inflammatory effects compared to the standard drug-treated and control groups (p < 0.05). ConclusionAECSB has antidiarrheal, antinociceptive and anti-inflammatory effects and can be safely used for therapeutic purposes.

Anandamide Modulates Thermal Avoidance in Caenorhabditis elegans Through Vanilloid and Cannabinoid Receptor Interplay.

Understanding the endocannabinoid system in C. elegans may offer insights into basic biological processes and potential therapeutic targets for managing pain and inflammation in human. It is well established that anandamide modulates pain perception by binding to cannabinoid and vanilloid receptors, regulating neurotransmitter release and neuronal activity. One objective of this study was to demonstrate the suitability of C. elegans as a model organism for assessing the antinociceptive properties of bioactive compounds and learning about the role of endocannabinoid system in C. elegans. The evaluation of the compound anandamide (AEA) revealed antinociceptive activity by impeding C. elegans nocifensive response to noxious heat. Proteomic and bioinformatic investigations uncovered several pathways activated by AEA. Enrichment analysis unveiled significant involvement of ion homeostasis pathways, which are crucial for maintaining neuronal function and synaptic transmission, suggesting AEA's impact on neurotransmitter release and synaptic plasticity. Additionally, pathways related to translation, protein synthesis, and mTORC1 signaling were enriched, highlighting potential mechanisms underlying AEA's antinociceptive effects. Thermal proteome profiling identified NPR-32 and NPR-19 as primary targets of AEA, along with OCR-2, Cathepsin B, Progranulin, Transthyretin, and ribosomal proteins. These findings suggest a complex interplay between AEA and various cellular processes implicated in nociceptive pathways and inflammation modulation. Further investigation into these interactions could provide valuable insights into the therapeutic potential of AEA and its targets for the management of pain-related conditions.

Evaluation of Anticancer, Anthelminthic, Anti-Nociceptive, Antidiabetic and Toxicological Investigation of Ludwigia adscendens

The present research investigated Ludwigia adscendens crude methanol extract invitro anticancer anthelminthic, and invivo anti-nociceptive, antidiabetic and toxicological properties. The coarsely dried plant powder was extracted using methanol. The methanolic extract (MELA) was further tested for anticancer, anthelminthic, anti-nociceptive, antidiabetic and toxicological activities. Cell Viability Assay was used for anticancer testing, and the earthworm assay was used for anthelminthic testing using different concentrations. Antinociceptive tests were done on Swiss albino mice at 200 and 400 mg/kg utilizing a hot plate, acetic acid induced writhing &amp; formalin-induced paw licking tests. Antidiabetic test was done using Blood Glucose Determination test using the dose of 150 mg/kg and 300 mg/kg. Acute toxicity was tested utilizing cinnamon oil-induced toxicological tests at 3000, 5000 and 7000 mg/kg. The MELA demonstrated 39.16% inhibition at 1000µg/mL in the Cell Viability Assay. The earthworm died after 6 minutes and 4 seconds in the 100 mg/mL anthelminthic test, whereas Albendazole killed it in 4 minutes and 20 seconds. Hot plate test results were substantial. The formalin-induced nociception test demonstrated strong inhibition rates of 79.54% in the early phase and 74.54% in the late phase at 400 mg/kg, compared to 62.99% and 68.18% for diclofenac sodium. Acetic acid-induced writhing test showed 77.66% of pain inhibition where’s Diclofenac sodium showed 79.61%. MELA inhibited blood glucose level very significantly compared to the standard Glibenclamide. In toxicological testing, 7000 mg/kg killed mice 2/5, whereas cinnamon oil killed 5/5 within 24 hours. The study shows that MELA has moderate anticancer, significant anthelmintic, anti-nociceptive, antidiabetic and mild toxicological properties. They may support the plant's use in conventional medicine to relieve pain, minimize drug intoxication, and prevent cancer, control diabetes and parasitic disorders.

Medicinal Properties of Crotalaria burhia: A Review

Background: Natural products have a crucial role in the discovery and development of drug molecules. The secondary metabolites derived from the plant have potential therapeutic value and reveal many pharmacological effects. Crotalaria burhia Buchham, a Leguminaceae herb, is mostly present in arid parts of India, Pakistan, China, and Afghanistan. Shinio, Bhip, Bhata, Ghugato, and Ban Sutra are just a few of the names it goes by. It is used to cure gout, eczema, hydrophobia, and inflammation. Plant root porridge is used for typhoid, wounds and cuts, rheumatism, flatulence, earaches, nasal bleeding, and stone problems. The powder form of the plant is used for digestive disorders. The plant has potent pharmacological activity and is also carcinogenic and anticarcinogenic in nature. Various phytoconstituents are present, like tannins, amino acids, alkaloids, steroids, triterpenoids, mucilage, flavonoids, gum, polyphenols, anthraquinones, carbohydrates, glycosides, and saponins. Croburhine is a novel pyrrolizidine alkaloid obtained from it. This review focuses on the existing knowledge of the phytochemistry and pharmacological action of C. burhia, which will provide broad information for a proper assessment of the plant as a medicinal agent. Methods: The experimental analysis and data reported on the species of Crotalaria were reviewed from 2005 to 2022. Various databases were used as article sources, like Medline and Pubmed, and a literature review was done using the keywords Crotalaria burhia, habitat, species, pharmacological action, and traditional uses. Result: On the basis of our perception, we have stated that the species Crotalaria burhia is a golden herb that possesses potent pharmacological activities. It is widely used as a conventional drug for the cure of various diseases, but its active constituents need to be evaluated more for future drug development and pharmacological action. Conclusion: There were a total of 21 research articles about the phytochemical screening of herbs, which showed the presence of different active constituents like alkaloids, tannins, flavonoids, steroids, glycosides, mucilage, gum, polyphenols, carbohydrates, terpenoids, etc., which are responsible for different pharmacological activities like antioxidant, antimicrobial, anti-inflammatory, antinociceptive, antihypertensive, antitumor, and analgesic activity.

Phytochemical and Pharmacological Attributes of Nerium oleander: A Review

Background: Nerium Oleander is an Indian folk medicine popularly known as oleander, contains numerous phytoconstituents and nutritional agents for the treatment of multiple ailments. Objective: The prime objective for the current comprehensive review is to focus on the elaboration of phytochemistry along with the Pharmacological significance of N. oleander. Methods: As per literature investigations it was noticed that plant contains various phytochemical constituents, including Oleandric acid, Kaneroside, Cardenolide, Nerizoside, Neritaloside, Odoroside- H,3-Ocaffeoylquinic acid along with structural isomer, 5-Ocaffeoylquinic acid, α-tocopherol, Oleandrin, Digitoxgenin along with nutritional ingredients viz essential fatty acids like omega- 3 fatty acids, and other polyphenols reported in N. oleander. Results: In recent investigations, it was observed that oleander possesses a wide range of medicinal attributes viz. anti-inflammatory, larvicidal, anti-cancer, Antidiabetic, Cellular/humoral immune response, Hepatoprotective, Wound healing, Anti-microbial, Antioxidant, Antinociceptive, Locomotor, Diuretic, and Anti leukemic activities. Conclusion: N. oleander could be an excellent candidate for discovering new medications because of its wide range of pharmacological action and the large diversity of active phytochemicals. However, to disclose the favorable therapeutic, safety, and pharmacological virtues of N. oleander and its phytoconstituents, more clinical and experimental investigations are needed.

SYNTHESIS AND STUDY OF ANTINOCICEPTIVE ACTIVITY OF SUBSTITUTED 2-(3-CYANO-4,5,6,7-TETRAHYDROBENZO[B]THIOPHEN-2-YLAMINO)-4-OXOBUT-2-ENOATES

In the current work, we present results the study of synthetic transformations of substituted 3-thienylimino-3H-furan-2-one derivatives containing a nitrile substituent in the third position of the thiophene ring under the action of nucleophilic reagents. This class of compounds is of great for study due to the presence of several reaction centers in its structure, which makes it possible to obtain products of various structures, while retaining important pharmacophore groups - fragments of 2-aminothiophene and a fragment of 2,4-dioxobutanoic acid. We have synthesized and studied for biological activity substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates, which were obtained by a multistep synthesis method. The proposed method provides high yields of target compounds and includes the reaction of 4-aryl-2-hydroxy-4-oxobutanoic acids with 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile, followed by intramolecular cyclization of the resulting products under the action of propionic anhydride, as well as decyclization of the resulting substituted 3-thienylimino-3H-furan-2-ones under the action of primary alcohols. The structure of the finally isolated compounds was confirmed by 1H and 13C NMR spectroscopy and the elemental analysis. The resulting compounds were screened in vivo to detect and evaluate their biological activity and acute toxicity. Antinociceptive activity was studied in white outbred mice of both sexes by the hot plate test with intraperitoneal injection. Acute toxicity was studied according to the Pershin method, based on monitoring the condition of mice for 10 days after intraperitoneal injection of the test compounds. According to the results obtained, the tested compounds have a pronounced antinociceptive activity, and the assessment of acute toxicity indicates that they belong to the V class of practically non-toxic drugs. The high values of antinociceptive activity in combination with low toxicity make the considered substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates a highly promising class for further study in order to search for and develop new biologically active compounds with analgesic effect. For citation: Sharavyeva Yu.O., Makhmudov R.R., Shipilovskikh D.A., Silaichev P.S., Gorbunova I.A. Synthesis and study of antinociceptive activity of substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 7. P. 19-27. DOI: 10.6060/ivkkt.20246707.7029.