Acid-induced Writhing Research Articles

Fused Triazole-Azepine Hybrids as Potential Non-Steroidal Antiinflammatory Agents

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the oldest and most widely used groups of drugs nowadays. However, the problem of searching for and creating new NSAIDs remains open, primarily due to the risks owing to their short- and long-term use. In this context, triazole-azepine hybrid molecules are attractive and prospective objects for the rational design of novel potential NSAIDs. In the present work studies of 3-aryl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepines as potential non-steroidal anti-inflammatory agents are reported. Evaluation of drug-like properties for all tested triazole-azepine hybrids was performed in silico using SwissADME. The screening of analgesic and anti-inflammatory activities was performed in vivo using acid-induced writhing and carrageenin-induced hind paw oedema models in mice. Derivatives with activity levels more potent compared with reference drugs ketorolac and diclofenac sodium were identified. Preliminary SAR was performed based on the screening results.

Medial and dorsal lateral septum involving social disruption stress-primed escalation in acid-induced writhes.

Stress may cause prospective escalations in abdominal pain magnitude and accumbal TRPV1 expression, while central neural circuits mediating these stress effects remain unclear. Using retrograde tracing methods, we first demonstrated the existence of a medial septal-dorsal lateral septal -accumbal circuit very likely involving social disruption stress-primed escalations in acid-induced writhes and accumbal TRPV1 level. An intersectional viral strategy and virus-carrying hM3Dq and hM4Di DREADDs were, then, employed to selectively modulate GABAergic and cholinergic neuronal activity in medial and dorsal lateral septum. Exciting medial septal GABAergic neuron was found to prevent social disruption stress-primed escalations in acid-induced writhes and accumbal TRPV1 and PKCε expressions. Likewise, inactivating dorsal lateral septal cholinergic neurons was also effective in abolishing these stress-primed escalations. Inactivating GABAergic neuron in non-stressed animals' medial septum was found to reproduce the stress-primed effects in causing heightened acid-induced writhes and accumbal TRPV1 and PKCε levels. These results, taken together, prompt us to conclude that social disruption stress may produce plastic changes in a newly-identified medial septal-dorsal lateral septal-accumbal circuit. Moreover, medial septal GABAergic hypoactivity and dorsal lateral septal cholinergic hyperactivity are, at least, two likely causes reflecting such stress-produced escalations in abdominal pain magnitude and pain transduction-related protein over-expression in nucleus accumbens.

Evaluation of the systemic and spinal antinociceptive effect of a new hybrid NSAID tetrahydropyran derivative.

Pain is responsible for inducing physical and mental stress, interfering negatively in patients' quality of life. Classic analgesic drugs, such as opioids and non-steroidal anti-inflammatory drugs, are known for their wide range of adverse effects, making it important to develop new drugs. Thus, this study aimed to analyse the action of the hybrid compound cis- (±) -acetate of 4-chloro-6- (naphthalene-1-yl) -tetrahydro-2h-pyran -2-yl) methyl2- (2- [2,6-dichlorophenylamine] phenyl (LS19) under acute nociceptive conditions, and deepened the understanding of the responsible mechanisms. Male Swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail flick, capsaicin- and glutamate-induced nociception, thermal stimulation in animals injected with capsaicin and rotarod tests besides the acute and subchronic toxicological evaluation. The compound showed effect on the acetic acid-induced abdominal writhing, formalin (both phases), tail flick, thermal stimulation in animals injected with capsaicin and capsaicin-induced nociception tests. In the study of the mechanism of action was observed reversion of the antihyperalgesic effect of the compound from the previous intraperitoneal and intrathecal administration of naloxone, nor-binaltorphimine, naltrindole, methylnaltrexone, 7-nitroindazole, L-NAME, ODQ, glibenclamide on the tail flick test. In the thermal stimulation in animals injected with capsaicin, the compound showed antinociceptive effect by oral and intraplantar routes, besides to reducing the levels of TNF-α, IL-1β and PGE2 in the paws previously administered with capsaicin. There were no signs of acute and subchronic intoxication with the compound. In summary, the compound LS19 presented spinal and local antihyperalgesic effect, demonstrating participation of the opioid/NO/cGMP/K+ ATP pathway and TRPV1 receptors and it demonstrated safety in its use in mice.

Bioguided Isolation of Alkaloids and Pharmacological Effects of the Total Alkaloid Fraction from Aspidosperma pyrifolium Mart. (Apocynaceae).

Aspidosperma pyrifolium is used in traditional medicine to treat inflammatory disorders. The aim of the study was to perform phytochemical characterization and evaluate the anti-inflammatory, anti-nociceptive and acute toxicity effects of the total alkaloid fraction (TAF-Ap) from stem barks. Two monoterpenic indole alkaloids were isolated by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) and the structural elucidation was performed using 1D and 2D NMR analysis. As for toxicity, no animals died at 50 mg kg−1 and this concentration presented mild sedation and forced breathing within the first 24 h. The lethal dose capable of killing 50% of the animals (LD50) was estimated to be 160 mg kg−1. In the pharmacological tests, the models used were 1% carrageenan-induced paw edema and peritonitis, 1% formalin-induced nociception and 1% acetic acid-induced abdominal writhing in Swiss mice. The study made it possible to isolate 15-methoxyaspidospermine and 15-methoxypyrifolidine, corroborating the results of pharmacological assays, which showed anti-inflammatory and analgesic potential, especially at 30 mg kg−1 (p < 0.001). Thus, the species was shown to be a promising source of active substances, with special attention paid to its toxicological potential.

LASSBio-596: a New Pre-clinical Candidate for Rheumatoid Arthritis?

Pain and inflammatory disorders are significant health problems because of prevalence and associated disabilities. In this context, LASSBio-596 is a hybrid compound able to modulate TNF-α and phosphodiesterases 4 and 5, exhibiting an anti-inflammatory effect in the pulmonary inflammatory model. Aiming at a better description of the activities of LASSBio-596, we initially conducted nociception tests (acetic acid-induced abdominal writhing, glutamate, and formalin-induced nociception and hot plate test) and later inflammatory tests (acute, peritonitis; and chronic, arthritis) that directed us to this last one. In the abdominal writhing test, there was a dose-dependent inhibition, whose response occurred at the maximum dose (50mg/kg, p.o.), used in the subsequent tests. LASSBio-596 also inhibited nociception induced by chemical (glutamate by 31.9%; and formalin, in both phases, 1st phase: 25.7%; 2nd phase: 23.9%) and thermal agents (hotplate, by increased latency for pain at two different times). These effects were independent of the motor function, legitimated in rotarod. As there was a response in the inflammatory component of nociception, we performed the peritonitis test, in which migration was inhibited by LASSBio-596 by 39.9%. As the inflammatory process is present in autoimmune diseases, we also performed the arthritis test. LASSBio-596 reduced paw edema from the 15th day to the 21st day of treatment (no liver changes and with fewer paw injuries). In addition, LASSBio-596 decreased serum levels of TNF-α by 67.1%. These data demonstrated the antinociceptive effect of LASSBio-596 and reinforces its anti-inflammatory property (i.e., RA), amplifying the therapeutic potential of this molecule.

Essential oil of Myrciaria tenella (DC.) O. Berg: effects of distillation time on its chemical composition and evaluation of its anti-inflammatory and antinociceptive effects

ABSTRACT The objective of the present study was to characterize the essential oil of Myrciaria tenella (MTEO) leaves, to determine the effects of distillation time (1 to 5 h), and to evaluate its action on acute pain and inflammation both in vivo and in vitro. MTEO was obtained by hydrodistillation for 4 h and 36 compounds were detected, mainly consisting of hydrocarbon terpenes such as β-pinene (21.46%), α-pinene (19.43%), E-caryophyllene (10.89%) and aromadendrene (9.17%). A high yield of α-pinene/β-pinene-rich MTEO was obtained after only 2 h of extraction. For in vivo biological assays, MTEO was administered to male Swiss mice, showing an action against hypernociception (acetic acid-induced abdominal writhing, formalin and Von Frey models) and inhibiting carrageenan-induced paw edema. Production of IL-6, TNF-α, IL-1β, PGE2 was reduced and production of IL-10 was increased, with no change in motor performance. MTEO also reduced cell production of NO and cytokines, in addition to inhibiting COX activity.

Assessment of the antinociceptive and anti-inflammatory activities of the stem methanol extract of Diplotropis purpurea

Context: Since there is still a great need to search for plant species with antinociceptive and anti-inflammatory activities, Diploptropis purpurea (Rich.) Amshoff (Fabaceae) is studied for the first time.Objective: This evaluates the analgesic and anti-inflammatory activities of the stem methanol extract of Diplotropis purpurea (MEDP).Material and methods: The anti-inflammatory and analgesic effects of MEDP of D. purpurea were evaluated in vivo. The antinociceptive activity was assessed in CD1 male mice were treated by oral gavage with 500 mg/kg of MEDP 30 min before submitting to acetic acid-induced abdominal writhing, hot-plate, and formalin tests. Paws oedema induced by carrageenan, histamine or serotonin were performed in male Sprague–Dawley rats to determinate the anti-inflammatory activity.Results: Oral administration of MEDP produced significant antinociceptive effects on the inflammatory phase in the formalin test [12.0 s versus 72.5 s in carboxymethyl cellulose (CMC) control group]. MEDP produced an analgesic effect in the hot-plate model, although the effect was modest compared to tramadol (40 and 60%, respectively). The oral administration of MEDP in a dose of 500 mg/kg showed maximum inhibition (75.1%) after 0.5 h in carrageenan-induced oedema, but it did not modify histamine or serotonin-induced oedemas.Discussion and conclusion: In the peripheral nociception model, acetic acid-induced abdominal writhing, the MEDP did not show a protective effect, but its analgesic effects were evident in the inflammatory phase of the formalin test and in the hot-plate model. These results show that the anti-inflammatory effect was accompanied by a reduction in the perception of painful stimuli.

Participation of cytokines, opioid, and serotoninergic systems on antinociceptive and anti-inflammatory activities of Simira grazielae peixoto (Rubiaceae)

Background: Simira grazielae P. is widely found at Brazil. S. grazielae have been used to treat pain and inflammation in the Northeast of Brazil. Objective: This study investigated the mechanisms of the extract and partitions using pharmacological techniques in mice. Materials and Methods: Male Swiss mice (20–22 g) were used in models of pain (acetic acid-induced abdominal writhing, formalin, and tail-flick tests) and inflammation (edema paw and air pouch tests) as well as in model for the evaluation of motor activity (open field test). Furthermore, we evaluate the probable action mechanism of S. grazielae using naloxone, L-nitro-arginine methyl ester, L-arginine, glibenclamide, atropine, 4-chloro-DL-phenylalanine, and ondansetron in tail-flick test. The cytokines production was also evaluated. The methanolic extract from the S. grazielae and its partitions were administered orally at doses of 10–100 mg/kg. Results: Methanolic extract from the wood of S. grazielae (SGM) and its partitions showed antinociceptive properties in models of acute pain (SGM and ethyl acetate partition [SGMAc]) as well as in models of inflammation (dichloromethane partition [SGMD]). Prior administration of ondansetron and naloxone reduced the antinociceptive effect of SGMAc. SGMD reduced the production of tumor necrosis factor-α (TNF-α) induced by carrageenan. Conclusion: The results show that the anti-inflammatory activity showed by SGMD involves to reduction of the TNF-α, and the antinociceptive activity showed by SGMAc has relation to participation of the serotoninergic receptors and opioid system. These evidence justify the popular therapeutic use of this species in the control of pain and inflammation. Abbreviations Used: PCPA: 4-chloro-DL-phenylalanine, SGM: Methanolic extract of Simira grazielae, SGMAc: Ethyl acetate partition, SGMD: Dichloromethane partition, SGMH: Hexane partition, SGMB: Butanol partition, SGMR: Residual partition, 5-HT: Serotonin, TNF-α: Tumor necrosis factor-α, n-C6H14: Hexane, CH2Cl2: Dichloromethane, EtOAc: Ethyl acetate, BuOH: Butanol, TLC: Thin-layer chromatography, HPLC: High-performance liquid chromatography, DAD: Diode array detector, COX-2: Cyclooxygenase-2, PGE2: Prostaglandin E2, eNOS: Endothelial nitric oxide synthase, NO: Nitric oxide, TRPA 1: Transient receptor potential cation, LT: Latency time, IBL: Increase in baseline, BL: Baseline.

THE 2α-3β-6β-23-TETRAHYDRO-OLEAN-12-EN-28-OIC ACID FROM THE LEAVES OF CHRYSOBALANUS ICACO L. ATTENUATES THE INFLAMMATORY HYPERNOCICEPTION IN MICE

Objective: The species Chrysobalanus icaco L., popularly known as abajurú, abajeru, has frequently been associated with antiangiogenic, anti-inflammatory and antirheumatic effects. The 2α-3β-6β-23-tetrahydro-olean-12-en-28-oic acid (THOA) was isolated from the methanolic extract of Chrysobalanus icaco leaves. Thus, the aim of the study was to evaluate the antinociceptive and anti-inflammatory activities of THOA.Methods: Acetic acid-induced abdominal writhing, formalin, von frey and open field tests were performed in mice. The number of writhes, licking time, mechanical threshold and walked squares by animals were the evaluation parameters applied, respectively. In addition, quantification of IL-1β and TNF-α were also performed. The THOA was administered orally at doses of 1–10 mg/kg in male mice. In addition, water, vehicle, morphine (5.01 mg/kg), acetylsalicylic acid (100 mg/kg), and dexamethasone (2.25 mg/kg) were administered.Results: The THOA showed effect with 5 and 10 mg/kg in the acute pain induced by acetic acid (49% and 62% contortion inhibition), carrageenan (150% and 188% increase in mechanical threshold) and formalin (36% and 60% licking inhibition), respectively. These results indicate an inhibition of hyper nociception, while the reduction in the production of cytokines (TNF-α inhibition–64% and 88%; IL-1β inhibition–48% and 55%, respectively) confirmed the inflammatory inhibition by carrageenan. The THOA did not induce motor impairment. The THOA was not toxic after oral administration (LD50&gt;50 mg/kg).Conclusion: These data provide initial evidence that THOA decreases the inflammatory hyper nociception probably by inhibition of IL-1β and TNF-α production, proving to be effective in reducing pain and inflammation.

Antinociceptive and Anti-inflammatory Activities of the Methanolic Extract from the Stem Bark of Lophanthera lactescens.

Lophanthera lactescens is a medicinal plant commonly used in traditional medicine to relieve fever and pain in inflammatory processes. In the present study, the in vivo antinociceptive and anti-inflammatory effects of the methanolic extract from L. lactescens have been investigated. Antinociceptive activity was evaluated through writhing, formalin, and tail flick tests, while the anti-inflammatory activity was evaluated through paw oedema and air pouch tests in mice. A phytochemical analysis was performed. The extract produced significant inhibition on nociception induced by acetic acid-induced abdominal writhing, formalin, and tail flick tests, and on inflammation induced by oedema and air pouch tests. The previous administration of atropine and glibenclamide reduced the antinociceptive effect produced by the methanolic extract from L. lactescens on the tail flick test in 89% and 66%, respectively. The methanolic extract had no significant effect in the open field test. No intoxication symptoms were observed in the animals administered orally at increasing doses up to 2000 mg/kg. The methanolic extract from the stem bark of L. lactescens possesses antinociceptive properties on models of acute pain induced by chemical and thermal stimuli as well as in models of inflammation and further suggests that this anti-inflammatory activity might involve inhibition of the proinflammatory cytokines, and the antinociceptive activity might involve participation of the cholinergic system and adenosine triphosphate-dependent K+ channel.

Essential oil from Myrcia ovata: chemical composition, antinociceptive and anti-inflammatory properties in mice.

The leaves of Myrcia ovata, popularly known as "laranjinha do mato", are frequently used as an infusion in folk medicine. The essential oil obtained from these leaves is rich in citral, a mixture of neral and geranial isomers, known for its analgesic effect. Male Swiss mice (20-22 g) were tested in models of acute pain (acetic acid-induced abdominal writhing, tail flick, and formalin tests) and acute inflammation (paw oedema and air pouch tests) as well as in a model for evaluation of spontaneous motor performance (open-field test). The essential oil from M. ovata was administered orally at doses of 50-300 mg/kg. In addition, water, vehicle, morphine (5.01 mg/kg for evaluation of pain and motor performance), acetyl salicylic acid (200 mg/kg in the formalin test), and dexamethasone (2.25 mg/kg for evaluation of oedema formation, leukocyte extravasation, and quantification of cytokines) were administered. The essential oil showed a significant effect at doses of 200 and 300 mg/kg in the acute pain and acute inflammation tests. The effect of the essential oil was reduced by pretreatment with naloxone. The essential oil did not induce motor impairment. The extract was not toxic after oral administration (LD50 > 3000 mg/kg). These data provide initial evidence that the traditional use of M. ovata can be effective in reducing pain and inflammation.

The antinociceptive properties of the novel compound (±)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one in acute pain in mice

The compound (±)-trans-4-hydroxy-6-propyl-1-oxocyclohexan-2-one [(±)-δ-lactone] was isolated from the plant Vitex cymosa Bertero, and determined to be the active principle. The present study aimed to evaluate the antinociceptive effect of (±)-δ-lactone and to elucidate its mechanism of action. Mice were subjected to in-vivo models of acute pain (acetic acid-induced abdominal writhing, formalin and hot-plate tests) and the open-field test. (±)-δ-Lactone, administered orally (6-900 µmol/kg), exerted a dose-dependent antinociceptive effect in the acetic acid-induced abdominal writhing, formalin and hot-plate tests. (±)-δ-Lactone administered by the intrathecal (i.t.) and subplantar (s.p.) routes (10-600 nmol) exerted concentration-dependent antinociceptive effects in the formalin test, showing its spinal and peripheral activity, respectively. In the hot-plate test, (±)-δ-lactone was also active when administered i.t., confirming its spinal effect. The previous intraperitoneal (i.p.) application of naloxone, yohimbine, mecamylamine or glibenclamide did not alter the effect produced by the i.t. administration of (±)-δ-lactone, whereas the previous application of atropine and L-arginine significantly reduced its effects in the formalin and hot-plate tests. The previous i.p. application of L-NAME enhanced the antinociceptive effect of the i.t. administration of (±)-δ-lactone in the formalin and hot-plate tests. The previous i.p. application of L-NAME and L-arginine increased and decreased, respectively, the activity of (±)-δ-lactone administered by s.p. administration. These results indicate that (±)-δ-lactone has significant spinal and peripheral antinociceptive activity, and that its effects are at least partially mediated by a reduced nitric oxide production/release, most likely through mechanisms involving the cholinergic system.

Analgesic and anti‐inflammatory activity of the ethanolic extract from Spiranthera odoratissima A. St. Hillaire (Manacá) roots

Acetic acid-induced abdominal writhing, the tail flick test and carrageenan-induced peritonitis were used to study the analgesic and anti-inflammatory activity of the crude ethanolic extract from Spiranthera odoratissima roots. Pentobarbital-induced sleeping time was used to study the central depressant effect of the extract. The ethanolic extract caused a dose dependent inhibition of acetic acid-induced abdominal writhing and leukocyte migration, and produced a significant, dose-related increase in the duration of sleep. The results suggest that Spiranthera odoratissima roots contain compounds with anti-inflammatory and central depressant actions.

Chemical Constituents and Pharmacological Activities ofPeschiera australis

AbstractSeven indole alkaloids (coronaridine, tabersonine, olivacine, coronaridine-hydroxyindolenine, catharinensine, decarbomethoxyvoacamine AND tabernamine) were isolated from Peschiera australis in Brazil. Four phenolic acids (vanillic acid, syringic acid, gentisic acid AND salicylic acid) were also found. Crude extracts of P. australis seeds AND leaves showed in vivo antineoplastic activity against two experimental tumor models: Ehrlich's carcinoma AND Sarcoma 180. Aqueous AND alcohol leaf extracts administered to rats 1 h before subplantar carrageenan injection had a significant dose-related anti-inflammatory effect. The same extracts also showed analgesic activity against acetic acid-induced abdominal writhing.

Analgesic cross-tolerance between morphine and opioid peptides.

The analgesic effect of intracerebroventricular administration of morphine, ketocyclazocine, [D-ala2]-methionine enkephalinamide (DAM), [D-ala2-D-leu5]-enkephalin (DADLE), leuenkephalin, metenkephalin, and beta-endorphin on acetic acid-induced abdominal writhing (AAW) was investigated in naive and morphine-tolerant mice. It was found that the relative potencies of a series of opioids are different in naive and morphine-tolerant groups. In naive animals, the order of potency (ED50, nmol) was beta-endorphin greater than morphine = DAM greater than DADLE greater than ketocyclazocine = leuenkephalin = metenkephalin. The morphine-tolerant animals were cross-tolerant to ketocyclazocine and to all the peptides studied; DAM and beta-endorphin exhibited the highest degree of tolerance. In morphine-tolerant animals, the order of potency was morphine = DADLE = beta-endorphin greater than DAM = ketocyclazocine = metenkephalin greater than leuenkephalin. The results indicate that endogenous opioid systems may be affected by tolerance development to morphine.