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Background and Objective: Pain is the most common symptom compelling an individual to seek medical attention. The use of Vitamin D3 for nociceptive and inflammatory pain is highly debated. Therefore, this study was undertaken to compare three daily doses (15/30/60 μg/kg) and a single high dose of Vitamin D3 (260 μg/kg) to standard drugs, namely tramadol and diclofenac in two most resorted pain-models in mice. Materials and Methods: Thirty-six Swiss-albino mice were divided into six groups of six mice each. The experiment was conducted using hot plate and writhing test. Same groups of mice were reused after suitable wash-out period. Groups were dosed with 0.25% carboxymethyl-cellulose (negative-control), a positive-control (tramadol for hot-plate and diclofenac for writhing-test). Injection Vitamin D3 was given in three daily doses of 15/30/60 μg/kg. Single dose of 260 μg/kg of Vitamin D3 was also tested. Latency period (LP), percent of maximal-possible-antinociceptive-effect (%MPE), mean number and percentage inhibition of writhes were the parameters evaluated to compare analgesic effect. Data were analyzed using paired t-test, analysis of variance (ANOVA)/Kruskal–Wallis/Friedman’s-ANOVA, and repeated-measures ANOVA with post hoc Dunnett’s tests. Results: In hot-plate method, 60 and 260 μg/kg of Vitamin D3 raised mean LP when compared to baseline and negative control and all groups recorded higher percentage MPE values when compared to negative control. In writhing test, 15-, 30-, and 60 μg/kg/day showed analgesic effect in comparison to negative control. However, 15 and 30 μ/kg/day of Vitamin D3 contradicted its responses when assessed through different parameter. Interpretation and Conclusion: In hot-plate test, 60 and 260 μg/kg of Vitamin D3 showed significant analgesic effect; however, effects were not superior to tramadol. In writhing test, 15-, 30-, and 60 μg/kg/day showed significant analgesic effect which were not superior to diclofenac. Surprisingly, 15 and 30 μ/kg, on instances exhibited irritant effects.

Malcolmia aegyptiaca (locally known as El Harra) and Matthiola livida (locally known as Chegara) are medicinal plants traditionally used to relieve pain and reduce inflammation. Little is known about the flavonoid content or the analgesie and anti-inflammatory properties of these plants.

The main objective of this research work was to study some substituted quinoline derivatives as transient receptor potential vanilloid 1 (TRPV1) inhibitors via an in silico method and to verify the obtained results by experimentally using an in vivo method that is an acetic-acid-induced writhing test in rats. Total 15 ligands were selected along with one standard drug Ibuprofen for the in silico method. The methods included were molecular docking by AutoDock Vina and in silico ADME parameters by Swiss ADME. Utilizing the crystal structure of the TRPV1 protein (PDB ID: 5IS0), molecular docking was carried out to further understand the significance of important protein–ligand interactions and the binding method. Based on pharmacokinetic ADME characteristics and Lipinski's rule of five, the compounds' drug-likeliness was estimated. An acetic-acid-induced writhing test (AAIWT) in rats was performed for verification of obtained in silico results. The interaction pattern, binding moieties, and binding energy were three parameters that were identified. When compared to the reference medication Ibuprofen (–7.1 kcal/mol), several ligands, such as 11, 12, and 13, show favourable interaction patterns of –8.9, –9.0, and –8.8 kcal/mol, respectively, and exhibit TRPV1 inhibitory efficacy. Furthermore, none of the ligands 1 to 15 showed an exception to Lipinski's criterion. Additionally, all the compounds were shown in vivo to inhibit the TRPV1 in rats experimentally by the AAIWT. The molecular interaction and energy level of quinoline derivatives showed good inhibitory activity when compared with standard Ibuprofen, which was also verified by experimentally using the AAIWT. Thus, some ligands can be used as effective TRPV1 inflammatory inhibitors. [ABSTRACT FROM AUTHOR]

Background and Objective: Pain is the most common symptom compelling an individual to seek medical attention. The use of Vitamin D3 for nociceptive and inflammatory pain is highly debated. Therefore, this study was undertaken to compare three daily doses (15/30/60 μg/kg) and a single high dose of Vitamin D3 (260 μg/kg) to standard drugs, namely tramadol and diclofenac in two most resorted pain-models in mice. Materials and Methods: Thirty-six Swiss-albino mice were divided into six groups of six mice each. The experiment was conducted using hot plate and writhing test. Same groups of mice were reused after suitable wash-out period. Groups were dosed with 0.25% carboxymethyl-cellulose (negative-control), a positive-control (tramadol for hot-plate and diclofenac for writhing-test). Injection Vitamin D3 was given in three daily doses of 15/30/60 μg/kg. Single dose of 260 μg/kg of Vitamin D3 was also tested. Latency period (LP), percent of maximal-possible-antinociceptive-effect (%MPE), mean number and percentage inhibition of writhes were the parameters evaluated to compare analgesic effect. Data were analyzed using paired t -test, analysis of variance (ANOVA)/Kruskal–Wallis/Friedman's-ANOVA, and repeated-measures ANOVA with post hoc Dunnett's tests. Results: In hot-plate method, 60 and 260 μg/kg of Vitamin D3 raised mean LP when compared to baseline and negative control and all groups recorded higher percentage MPE values when compared to negative control. In writhing test, 15-, 30-, and 60 μg/kg/day showed analgesic effect in comparison to negative control. However, 15 and 30 μ/kg/day of Vitamin D3 contradicted its responses when assessed through different parameter. Interpretation and Conclusion: In hot-plate test, 60 and 260 μg/kg of Vitamin D3 showed significant analgesic effect; however, effects were not superior to tramadol. In writhing test, 15-, 30-, and 60 μg/kg/day showed significant analgesic effect which were not superior to diclofenac. Surprisingly, 15 and 30 μ/kg, on instances exhibited irritant effects. [ABSTRACT FROM AUTHOR]

The hot plate test and writhing test were both employed to investigate the analgesic effects of Citrullus colocynthis fruit resin and Cyperus rotundus tuber resin at varying concentrations and time intervals. The hot-plate test results revealed that Citrullus colocynthis fruit resin demonstrated significant dose-dependent and time-dependent analgesic effects. In contrast, Cyperus rotundus Tuber resin did not exhibit substantial analgesic effects in the hot-plate test. In the writhing test, Citrullus colocynthis fruit resin exhibited clear dose-dependent analgesic effects at higher concentrations. Cyperus rotundus Tuber resin demonstrated significant analgesic effects in reducing writhing responses, although its efficacy was not as potent as the positive control indomethacin. These results offer insights into the potential use of these natural resins for pain management while also highlighting the importance of understanding the underlying mechanisms of their analgesic effects for further clinical applications.

The plant Brugmansia suaveolens (Bercht. & Presl) belongs to the family Solanaceae and is endemic to the Malnad region (Shimoga) of the Western Ghats. Traditionally leaf extract has been applied externally to treat cut wounds, pain-killer swellings, scalds, inflammations, skin rashes, and hemorrhoids. The objective is to synthesize silver nanoparticles (AgNPs) conjugated Leaf methanol extract of B. suaveolens analyzed and characterized based on multiple (X-ray diffraction (XRD); Scanning electron microscopy (SEM); Fourier transform infrared (FTIR) spectroscopy and ultraviolet-visible (UV-Vis) spectroscopy) analytical methods. After characterization, the analgesic activity of extract bio-synthesized with silver nanoparticles was evaluated and compared with different concentrations of leaf methanol extract alone. Analgesic activity was examined by writhing and tail-flick testing. Reduction in the writhing and tail withdrawal time after administration of 250 mg/kg b.w./d of leaf methanol extract bio-synthesized with silver nanoparticle is more significant than 250, 500, and 750 mg/kg b.w./d extracts alone and is slightly less significant when compared to the standard drug. This has proved that the bio-synthesized silver nanoparticles may have played a fundamental role as drug delivery vehicles to target tissues more conveniently and efficiently compared to nascent extract. [ABSTRACT FROM AUTHOR]

For thousands of years, medicinal plants have played a pivotal role in maintaining human health and improving the quality of human life. This study was designed to analyze the analgesic, anti-inflammatory, and antibacterial potentials of a hydro-methanolic extract of Cucurbita moschata flowers, along with qualitative and quantitative phytochemical screening. The anti-inflammatory effect was tested using the in vitro membrane stabilizing method for human red blood cells (HRBC), the analgesic effect was tested using the in vivo acetic acid-induced writing method, and the antibacterial effect was tested using the disc diffusion method. In silico ADME/T and molecular docking studies were performed to assess the potential of the stated phytochemicals against Cyclooxygenase-II enzyme. Phytochemical screening confirmed the presence of flavonoids, alkaloids, glycosides, tannins, and carbohydrates. The flower extract demonstrated the maximum protection of human red blood cells at 1000 µg/mL, with a 65.73% reduction in hemolysis in a hypotonic solution. The extract also showed significant (p < 0.05) and dose-dependent analgesic effects at oral doses of 200 and 400 mg/kg on the tested animals. Furthermore, the flower extract exhibited potent antibacterial activity due to the disc diffusion method, which was compared with standard ciprofloxacin. In silico testing revealed that 42 phytochemicals exhibited notable pharmacokinetic properties and passed drug likeness screening tests. Among the six best-selected compounds, 3,4-dihydro-2H-pyran-2-yl)methanamine showed the highest binding affinity (−10.1) with significant non-bonding interactions with the target enzyme. In conclusion, the hydro-methanolic extract of Cucurbita moschata was found to be rich in various phytochemicals that may be associated with therapeutic potential, and this study supports the traditional use of Cucurbita moschata flowers in the management of inflammation and painful conditions. [ABSTRACT FROM AUTHOR]

our study aimed study aimed to detect and investigate the safety profile of flurbiprofen and evaluate the analgesic effects of the tail immersion and writhing tests, as well as its interaction with lipoic acid as an analgesic for visceral pain in mice. The up-and-down manner described by Dixon was utilized to determine the median lethal dose (LD50) and the median analgesic dose (ED50), the safety criteria were calculated, mathematical equations were applied, and the interaction between flurbiprofen and alpha-lipoic acid was evaluated using the writhing test. The LD50 of oral flurbiprofen was 1147.4 mg/kg, and the ED50 of oral flurbiprofen was 8.6 mg/kg using the tail immersion test. The therapeutic index was 133, and the standard safety margin was 35%. The highest analgesia time was one h after dosing, which faded after 24 h. Administration of flurbiprofen 10, 20, and 40 mg/kg had an analgesic effect in a dose-dependent manner. Flurbiprofen relieved visceral pain when dosed at 20, 40, and 80 mg/kg, with analgesic efficacies of 53, 56, and 65%, respectively. The simultaneous administration of flurbiprofen and alpha-lipoic acid had a synergistic analgesic effect on visceral pain. From our results, we conclude that flurbiprofen has a wide range of safety and is an effective analgesic for peripheral and visceral pain. The synergistic effect between flurbiprofen and alpha-lipoic acid may have clinical benefits, including reducing the dose of flurbiprofen when used together.

Background: Odontogenic pain has a high prevalence where this pain is the result of noxious physical stimuli or calming inflammatory mediators that stimulate receptors located at the terminal ends of nociceptive C and Aδ afferent nerve fibers. Nano propolis is an alternative material that is used as a medicine in dentistry. Nano propolis is a mixture of natural resins containing flavonoids and phenolic acids which play a role in suppressing pain response through COX and NF-kB inhibition mechanisms. Nanoparticle technology is capable of preparing active drug ingredients in nanosized particles and can affect drug effectiveness, because particle size affects the process of solubility, absorption and distribution of drugs. Research on the potential of nano propolis as an anti-pain is still minimal, so further research is needed on the function of nano propolis as an alternative anti-pain agent. Purpose: To determine the effective dose of nano propolis on pain response in Mus musculus. Methods: This research was conducted using the writhing test method to see the analgesic effect of nano propolis. The research sample consisted of 28 Mus musculus which were divided into four treatment groups, namely the piroxicam control group, and the nano propolis treatment group of 17.5 mg/kg, 35 mg/ kg, and 70 mg/kg. Results: The results showed that the four treatment groups did not have a significant difference, in other words, they had the same anti-pain effect. Conclusion: Nano propolis 35 mg/kgBB is an effective dose in suppressing pain response in Mus musculus. [ABSTRACT FROM AUTHOR]

Background and aims: Antidepressant agents such as imipramine are clinically used to control and treat different types of pain, especially neuropathic pain. Studies have shown the antidepressant-like activity of folic acid (FA). This study aimed to investigate the potential antinociceptive effects of FA using formalin and acetic acid tests in male mice. Methods: Sixty male albino mice (20-30 g) were randomly divided into 10 groups (n=6 in each group) of negative control, positive control (morphine or indomethacin), and FA (10, 15, and 30 mg/kg) groups. In the formalin test, duration of paw licking and biting the right hind paw during acute (0-5 minutes) and chronic (15-60 minutes) pain after intraplantar injection of formalin 2.5% (25 µL) was recorded. In the writhing test, the abdominal constrictions were recorded after the intraperitoneal injection of acetic acid 1%. Results: Only a high dose (30 mg/kg) of FA significantly reduced acute pain (P=0.001) compared with the control group. But all doses of FA significantly decreased chronic pain (P=0.001). In addition, morphine significantly reduced both phases of pain (P=0.020 and P=0.001, respectively). Moreover, indomethacin and all doses of FA decreased the number of abdominal constrictions induced by acetic acid (P=0.001). Conclusion: Compared with acute (neurogenic) pain, FA more potently decreases chronic (inflammatory) pain. Furthermore, FA decreases the parietal pain that could potentially represent antinociceptive effect. However, further studies are needed to elucidate the exact mechanism of FA’s analgesic activity.

Background: Odontogenic pain has a high prevalence. One of the alternative materials used as medicine in dentistry is propolis. Propolis is a mixture of natural resins containing flavonoid and phenolic acids that play a role in suppressing the pain response through COX and NF-kB inhibition mechanisms. The content of active propolis compounds is influenced by the type of bee, region, geographical conditions, climate change, seasons, and botanical sources causing different effectiveness of propolis. This is supported by several studies that show a variety of effective doses that produce an optimal analgesic effect, thus a research plan was developed to discover the effective dose of propolis extract on suppressing pain response in mice using the writhing test method. Purpose: To determine the effective dose of propolis extract towards pain response in mice. Methods: This study was conducted using the writhing test method to see the analgesic effect of propolis extract. The research sample consisted of 30 mice which were divided into five treatment groups, namely the piroxicam control group, and the propolis extract group at doses of 35 mg/kgBW, 70 mg/kgBW, 105 mg/kgBW, 140 mg/kgBW. Results: The results showed that the propolis extract dose of 70 mg/kgBW had no significant difference with the piroxicam control group, while between the doses of 35 mg/kgBW, 105 mg/kgBW, 140 mg/kgBW there was a significant difference towards the piroxicam control group. Conclusion: Propolis extract 70 mg/kgBW is the effective dose in suppressing pain response in mice. [ABSTRACT FROM AUTHOR]

Desalegn Getnet Demsie,1,2 Ebrahim M Yimer,1 Abera Hadgu Berhe,1 Birhanetensay Masresha Altaye,3 Derbew Fikadu Berhe11Department of Pharmacology and Toxicology, College of Health Sciences, Mekelle University, Mekelle, Ethiopia; 2Department of Pharmacy, College of Medicine and Health Sciences, Adigrat University, Adigrat, Ethiopia; 3Department of Pharmacy, College of Medicine, Debre Berhan University, Debre Berhan, EthiopiaBackground: Societies in developing countries use traditional medicine as alternatives for management of pain and inflammation. The plant Cucumis ficifolius has been used in Ethiopia to treat many ailments including inflammation and pain. The objective of this study was to evaluate the antinociceptive and anti-inflammatory activities of the crude root extract and solvent fractions of C. ficifolius.Methods: The analgesic activity of crude extract and solvent fractions of C. ficifolius was evaluated with acetic acid-induced writhing, hot plate, and formalin-induced paw licking tests. The anti-inflammatory effect of crude methanolic root extract and solvent fractions of C. ficifolius was evaluated using carrageenan-induced paw edema. The crude extract was given at 200, 400 and 800 mg/kg. Butanol and aqueous fractions were given at 100 and 200 mg/kg doses. The negative control groups were treated with distilled water (10 mL/kg). Standard drugs used wereacetylsalicylic acid(ASA) in acetic acid, formalin tests and carrageenan-induced paw edema and morphine (20 mg/kg) in hot plate test.Results: The crude extract, at its maximum dose, produced comparable analgesic activity (72.5%) to ASA in acetic acid writhing test. In the hot plate test, both the crude extract and solvent fractions exhibited a significant prolongation of nociception reaction time. Formalin test result indicated a significant reduction of mean lick time with maximal protection of 64% (early phase) and 83% (late phase). Aqueous and butanol fractions showed good analgesic activity in the three models. Inflammation was decreased by 69% with butanol (200 mg/kg); 71% (800 mg/kg) of crude extract and by 41% and 56% with the use of aqueous fraction at 100 and 200 mg/kg, respectively (p

Background: Callicarpa nudiflora has been usually employed as a traditional Chinese medicine for acesodyne, dispersing edema, and hemostasis; however, its analgesic effects have been poorly considered. Objectives: This article focused on the differences in the contents of seven active chemical constituents in C. nudiflora grown in different regions. Moreover, we examined the analgesic effect of C. nudiflora from five arbitrarily designated regions and studied the relationship between the compound contents and analgesic effect. Materials and Methods: A simple and delicate qualitative tandem liquid chromatography quadrupole time of flight mass spectrometry method was first established for the immediate determination of seven active components (luteolin, apigenin, quercetin, oleanolic acid, ursolic acid, protocatechuic acid, and caffeic acid) in C. nudiflora. Ethanol extracts were prepared from the mature leaves of C. nudiflora from five regions and the writhing test was performed by intragastric administration in mice. SPSS 13.0 and Graph Pad Prism 8.01 software were used to analyze the correlation of all data. Results: Calibration curves presented satisfactory linearity, with correlation coefficients >0.99 for all compounds within the concentration range. The compound contents were uppermost in plants from Hainan Province. The contents of the seven active chemical components inclined in the order of caffeic acid > luteolin > apigenin > oleanolic acid > ursolic acid > protocatechuic acid > quercetin. Pharmacological studies showed that C. nudiflora from all five regions had obvious analgesic effects. Conclusion: These results might be helpful for the screening and cultivation of C. nudiflora and its realistic clinical application. [ABSTRACT FROM AUTHOR]

Background and aims: Antidepressant agents such as imipramine are clinically used to control and treat different types of pain, especially neuropathic pain. Studies have shown the antidepressant-like activity of folic acid (FA). This study aimed to investigate the potential antinociceptive effects of FA using formalin and acetic acid tests in male mice. Methods: Sixty male albino mice (20-30 g) were randomly divided into 10 groups (n=6 in each group) of negative control, positive control (morphine or indomethacin), and FA (10, 15, and 30 mg/kg) groups. In the formalin test, duration of paw licking and biting the right hind paw during acute (0-5 minutes) and chronic (15-60 minutes) pain after intraplantar injection of formalin 2.5% (25 µL) was recorded. In the writhing test, the abdominal constrictions were recorded after the intraperitoneal injection of acetic acid 1%. Results: Only a high dose (30 mg/kg) of FA significantly reduced acute pain (P=0.001) compared with the control group. But all doses of FA significantly decreased chronic pain (P=0.001). In addition, morphine significantly reduced both phases of pain (P=0.020 and P=0.001, respectively). Moreover, indomethacin and all doses of FA decreased the number of abdominal constrictions induced by acetic acid (P=0.001). Conclusion: Compared with acute (neurogenic) pain, FA more potently decreases chronic (inflammatory) pain. Furthermore, FA decreases the parietal pain that could potentially represent antinociceptive effect. However, further studies are needed to elucidate the exact mechanism of FA’s analgesic activity. [ABSTRACT FROM AUTHOR]

Metamizole is used to relieve the visceral pain but its adverse effects limit its use. An alternative to improve its efficacy with lower doses is to combine it with a natural product as hesperidin. Aim of the study. The aim of this study was to evaluate the antinociceptive interaction between metamizole and hesperidin in a visceral pain model using an isobolographic analysis. Antinociception was evaluated in the writhing model using acetic acid (1%) to induce writhes in mice. Metamizole (1–316 mg/kg), hesperidin (3–300 mg/kg), or combinations with a fixed-dose ratio of 1:1 were administered intraperitoneally 30 min before the acetic acid and the number of writhes was counted for 30 min. Isobolographic analysis was employed to define the nature of the compound interaction. Metamizole and hesperidin in individual administration induced dose-dependent antinociceptive effects, reached an efficacy of 84.2 ± 5.9% and 66.3 ± 7.4%, respectively. The ED 50 values calculated from their dose-response curves were 84.5 ± 22.7 and 108.9 ± 17.9 mg/kg, respectively. The analysis of DRC for the metamizole + hesperidin combination, in a ratio 1:1 showed a ED 50 COMB value lower than the ED 50 ADD estimated from the additivity line from the isobologram (46.7 ± 6.3 vs. 96.7 ± 11.9 mg/kg, respectively). In addition, the pharmacological interaction calculated was of 0.48. These results suggest a synergistic interaction for the antinociceptive activity of metamizole + hesperidin combination. These data suggest that metamizole + hesperidin combination could be useful in treating visceral pain as it can interact synergistically using low dose of both drugs with the possibility of reducing the risk of adverse effects. [Display omitted] [ABSTRACT FROM AUTHOR]

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.

Objective: Berberis vulgaris has antioxidant, hepato--renal protective, antibacterial, lipid lowering, anti-inflammatory and antinociceptive activities. The genus Berberis, has another member called Berberisintegerrima which has not been studied for antinociceptive activity and therefore, this study was aimed to examine the antinociceptive effect oftotal extract and alkaloid fractions of Berberis integerrima root in mice. Materials and Methods: Methanolic total extract and alkaloid fractions of the plant namely, fractions A, B, C and D were prepared according to standard methods. Male Swiss mice (20-25 g) were used (n=6 in each group). Acetic acid-induced writhing, formalin and hot-plate tests were used to assess the antinociceptive activity. In hot plate and formalin tests, morphine (10 mg/kg, i.p.) and in acetic acid test, indomethacin (10 mg/kg, i.p.) were used as reference drugs. Results: The total extract and fractions A, B and D significantly reduced abdominal twitches in acetic acid test and licking behavior of both acute and chronic phases of formalin test. In hot-plate test, morphine as the standard drug demonstrated significant antinociception while the plant extract and fractions were ineffective. The dose of 5 mg/kg of fraction C showed slight analgesia only in acetic acid test and a dose of 10 mg/kg caused severe toxicity and even death in some animals. Conclusion: Berberis integerrima total extract and its alkaloid fractions showed antinociceptive effect and it seems that the mechanism of this action is peripherally mediated since they were effective in formalin test and acetic acid- induced writhing but not in hot-plate test.

Background: Pain is a complex mechanism which involves different systems, including the opioidergic and GABAergic systems. Due to the side effects of chemical analgesic agents, attention toward natural agents have been increased. Artemisinin is an herbal compound with widespread modern and traditional therapeutic indications, which its interaction with the GABAergic system and antinoniceptive effects on neuropathic pain have shown. Therefore, this study was designed to evaluate the antinociceptive effects of artemisinin during inflammatory pain and interaction with the GABAergic and opioidergic systems by using a writhing response test. Methods: On the whole, 198 adult male albino mice were used in 4 experiments, including 9 groups (n = 6) each with three replicates, by intraperitoneal (i.p.) administration of artemisinin (2.5, 5, and 10 mg/kg), naloxone (2 mg/kg), bicuculline (2 mg/kg), saclofen (2 mg/kg), indomethacin (5 mg/kg), and ethanol (10 mL/kg). Writhing test responses were induced by i.p. injection of 10 mL/kg of 0.6% acetic acid, and the percentage of writhing inhibition was recorded. Results: Results showed significant dose dependent anti-nociceptive effects from artemisinin which, at a 10 mg/kg dose, was statistically similar to indomethacin. Neither saclofen nor naloxone had antinociceptive effects and did not antagonize antinociceptive effects of artemisinin, whereas bicuculline significantly inhibited the antinocicptive effect of artemisinin. Conclusions: It seems that antinocicptive effects of artemisinin are mediated by GABAA receptors. [ABSTRACT FROM AUTHOR]

• Antinociceptive effects of Dimethyl itaconate. • Effects of Dimethyl itaconate on c-Fos expression in the spinal cord. • Dimethyl itaconate reduced pain perception in rats during the formalin test. • Dimethyl itaconate reduced pain perception in rats during the writing test. Itaconate has been found to have potent anti-inflammatory effects and is being explored as a potential treatment for inflammatory diseases. However, its ability to relieve nociception and the mechanisms behind it are not yet understood. Our research aims to investigate the nociception-relieving properties of dimethyl itaconate (DMI) in the formalin test and writhing test. In male Wistar rats, Itaconic acid was injected intraperitoneally (i.p.). The formalin test and writhing test were conducted to determine the nociceptive behaviors. The spinal cords were removed from the rats and analyzed for c-fos protein expression. The study found that administering DMI 10 and 20 mg/kg reduced nociception in formalin and writhing tests. Injection of formalin into the periphery of the body led to an increase in the expression of c-fos in the spinal cord, which was alleviated by DMI 20 mg/kg. Similarly, acetic acid injection into the peritoneal cavity caused an increase in c-fos expression in the spinal cord, which was then reduced by 20 mg/kg. According to our findings, DMI reduced nociception in rats during the formalin and writhing tests. One possible explanation for this outcome is that the decrease in c-fos protein expression may be attributed to the presence of DMI. [ABSTRACT FROM AUTHOR]

Various animal models, especially rodents, are used to study pain, due to the difficulty of studying it in humans. Many drugs that produce analgesia have been studied and there is evidence among which NSAIDs deserve to be highlighted. Dexketoprofen (DEX) provides a broad antinociceptive profile in different types of pain; therefore, this study was designed to evaluate the profile of antinociceptive potency in mice. Analgesic activity was evaluated using the acetic acid abdominal constriction test (writhing test), a chemical model of visceral pain. Dose-response curves for i.p. DEX administration (1, 3, 10, 30 and 100 mg/kg), using at least six mice in each of at least five doses, was obtained before and 30 min after pre-treatment with different pharmacological agents. Pretreatment of the mice with opioid receptor antagonists was not effective; however, the serotonin receptor antagonist and nitric oxide synthase inhibitor produce a significant increase in DEX-induced antinociception. The data from the present study shows that DEX produces antinociception in the chemical twisting test of mice, which is explained with difficulty by the simple inhibition of COX. This effect appears to be mediated by other mechanisms in which the contribution of the NO and 5-HT pathways has an important effect on DEX-induced antinociception. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Achillea biebersteinii is a perennial aromatic herb that grows in the Mediterranean area. The leaves of this plant are used in foods as bittering and appetizing agents. In folk medicine, it is used for the treatment of stomachache and abdominal pain. In this study, the analgesic effect of A. biebersteinii methanolic flower extract was tested in three pain models, namely: writhing, tail-flick and paw-licking (formalin) tests. A. biebersteinii extract inhibited abdominal cramps produced by acetic acid. The effect of A. biebersteinii was better than that of 70 mg/kg indomethacin. In tail flick, A. biebersteinii extract increased latency at 30 min and was as effective as 100 mg/kg diclofenac sodium. In formalin test, A. biebersteinii extracts decreased paw-licking and flinching response in early and late phases. Atropine blocked the action of A. biebersteinii extract (300 mg/kg) in the late phase of formalin test as well as in writhing and tail-flick tests. GC–MS analysis revealed that ascaridole and iso-ascaridole were the main constituents of A. biebersteinii flower extract. In conclusion, this study shows for the first time that the antinociceptive effect of A. biebersteinii is mediated by the cholinergic receptor. [ABSTRACT FROM AUTHOR]

Ajuga chamaepitys is a small herbaceous annual or biannual plant that belongs to Lamiaceae family. It grows in Europe and Eastern parts of the Mediterranean. One of the ethno-pharmacological uses of this plant is its use as a painkiller. In the present experimental work, the antinociceptive effect of the methanolic extract of A. chamaepitys collected from Jordan was investigated using chemical and thermal models of pain in mice. A. chamaepitys extract decreased significantly the number of writhes that were induced in mice by the injection of 1% acetic acid compared to negative control group. The inhibitory effect produced by 300 mg/kg of the extract given i.p was comparable to that of 300 mg/kg aspirin. The i.p administration of 450 mg/kg A. chamaepitys caused a remarkable decrease in paw licking time during the early and late phases of formalin test. Furthermore, the latency time increased in hot plate test but not in tail flick test in animals that were treated i.p with 300 mg/kg A. chamaepitys extract compared to control animals. The involvement of opioid receptor was proven in formalin and hot-plate tests by abolishing the effect of A. chamaepitys extract by pretreatment with naloxone, an opioid antagonist. LC-MS analysis resulted in the identification of 19 compounds. Isovitexin, orientin, flavonol, and cyanidin were the major compounds. Our results suggest that the methanolic extract of A. chamaepitys has pronounced antinociceptive effects, which provide the scientific basis of the traditional therapeutic use of A. chamaepitys in folk medicine. [ABSTRACT FROM AUTHOR]

Background: Pain is a complex mechanism which involves different systems, including the opioidergic and GABAergic systems. Due to the side effects of chemical analgesic agents, attention toward natural agents have been increased. Artemisinin is an herbal compound with widespread modern and traditional therapeutic indications, which its interaction with the GABAergic system and antinoniceptive effects on neuropathic pain have shown. Therefore, this study was designed to evaluate the antinociceptive effects of artemisinin during inflammatory pain and interaction with the GABAergic and opioidergic systems by using a writhing response test. Methods: On the whole, 198 adult male albino mice were used in 4 experiments, including 9 groups (n = 6) each with three replicates, by intraperitoneal (i.p.) administration of artemisinin (2.5, 5, and 10 mg/kg), naloxone (2 mg/kg), bicuculline (2 mg/kg), saclofen (2 mg/kg), indomethacin (5 mg/kg), and ethanol (10 mL/kg). Writhing test responses were induced by i.p. injection of 10 mL/kg of 0.6% acetic acid, and the percentage of writhing inhibition was recorded. Results: Results showed significant dose dependent anti-nociceptive effects from artemisinin which, at a 10 mg/kg dose, was statistically similar to indomethacin. Neither saclofen nor naloxone had antinociceptive effects and did not antagonize antinociceptive effects of artemisinin, whereas bicuculline significantly inhibited the antinocicptive effect of artemisinin. Conclusions: It seems that antinocicptive effects of artemisinin are mediated by GABAA receptors. [ABSTRACT FROM AUTHOR]

Highlights • Hemokinin-1 (HK-1) mediates chronic neuropathic mechanical and cold hyperalgesia. • HK-1 is involved in neuropathic microglia and astrocyte activation in spinal cord. • HK-1 prevents peripheral NGF increase under neuropathic conditions. • HK-1 induces acute visceral and neurogenic inflammatory pain via NK1 receptor. Abstract The Tac4 gene-derived hemokinin-1 (HK-1) is present in pain-related regions and activates the tachykinin NK1 receptor, but with binding site and signaling pathways different from Substance P (SP). NK1 receptor is involved in nociception, but our earlier data showed that it has no role in chronic neuropathic hyperalgesia, similarly to SP. Furthermore, NK1 antagonists failed in clinical trials as analgesics due to still unknown reasons. Therefore, we investigated the role of HK-1 in pain conditions of distinct mechanisms using genetically modified mice. Chronic neuropathic mechanical and cold hyperalgesia after partial sciatic nerve ligation (PSL) were determined by dynamic plantar aesthesiometry and withdrawal latency from icy water, motor coordination on the accelerating Rotarod. Peripheral nerve growth factor (NGF) production was measured by ELISA, neuronal and glia cell activation by immunohistochemistry in pain-related regions. Acute somatic and visceral chemonocifensive behaviors were assessed after intraplantar formalin or intraperitoneal acetic-acid injection, respectively. Resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia by aesthesiometry and increasing temperature hot plate. Chronic neuropathic mechanical and cold hypersensitivity were significantly decreased in HK-1 deficient mice. NGF level in the paw homogenates of intact mice were significantly lower in case of HK-1 deletion. However, it significantly increased under neuropathic condition in contrast to wildtype mice, where the higher basal concentration did not show any changes. Microglia, but not astrocyte activation was observed 14 days after PSL in the ipsilateral spinal dorsal horn of wildtype, but not HK-1-deficient mice. However, under neuropathic conditions, the number of GFAP-positive astrocytes was significantly smaller in case of HK-1 deletion. Acute visceral, but not somatic nocifensive behavior, as well as neurogenic inflammatory mechanical and thermal hypersensitivity were significantly reduced by HK-1 deficiency similarly to NK1, but not to SP deletion. We provide evidence for pro-nociceptive role of HK-1, via NK1 receptor activation in acute inflammation models, but differently from SP-mediated actions. Identification of its targets and signaling can open new directions in pain research. [ABSTRACT FROM AUTHOR]

Context: Aqueous root extract of Dalbergia saxatilis, Hook, f., (Leguminosae) (DS) is reported useful for toothache, pains, and fever, but not scientifically proven. Objective: This study determined its effectiveness in pain, inflammation, and fever, applying scientific models. Materials and methods: Swiss mice or Sprague–Dawley rats (n = 5) were pretreated with distilled water, DS (100 or 200 mg/kg), or standard drug for 30 min. The analgesic activity was measured by acetic acid writhing, tail flick, tail immersion, tail clip, hot plate, and formalin pain tests; anti-inflammatory effects were determined via carrageenan and dextran rat paw oedema tests; antipyretic activity was measured by Escherichia coli lipopolysaccharide (ECL) and turpentine in rabbits, and d-amphetamine sulphate (d-AS) pyrexia test in rats. Results: Writhing frequency inhibition was produced by 200 mg/kg DS (33.10%), aspirin (38.19%) and morphine (93.68%). Unlike morphine, DS did not produce significant prolongation of the reaction times in the hot-plate, tail immersion, tail flick, and tail clip tests. In the first and second phases of formalin test, respectively, % inhibition was: 200 mg/kg DS (25.70% and 0%), aspirin (4.76% and 67.33%), morphine (81.42% and 66.11%); for carrageenan and dextran tests, significant difference was recorded between 200 mg/kg DS and control up to 6 h. Significant reduction in ECL, turpentine and d-AS pyrexia was recorded at 100 and 200 mg/kg DS. Conclusion: DS produces mild non-steroidal analgesic and anti-inflammatory, as well as significant antipyretic actions involving cyclooxygenase, α2 adrenoceptor and interleukin-1 β1 due to any of glycosides, saponins or phenolic tannins.

In this study we investigated whether the intrathecal administration (i.t.) of the novel pyrazolyl-thiazole derivative 2-[5-trichloromethyl-5-hidroxy-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-4-(4-bromophenyl)-5-methylthiazole (B50) caused antinociception in adult male mice, using the hot plate and acetic acid writhing assays. B50 (200 nmol/ 5 ml, i.t.) caused antinociception 90-120 minutes after its administration. Naloxone (8.25 mmol/ kg, s.c.) reverted the antinociceptive action of B50 (200 nmol/ 5 ml, i.t.), in the acetic acid writhing assay, suggesting that opioid mechanisms are involved in the antinociception caused by B50. B50 had no effect on spontaneous locomotion or rotarod performance, indicating that the currently reported antinociceptive effect of B50 is not related to unspecific motor effects.

In this study we investigated whether the intrathecal administration (i.t.) of the novel pyrazolyl-thiazole derivative 2-[5-trichloromethyl-5-hidroxy-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-4-(4-bromophenyl)-5-methylthiazole (B50) caused antinociception in adult male mice, using the hot plate and acetic acid writhing assays. B50 (200 nmol/ 5 ml, i.t.) caused antinociception 90-120 minutes after its administration. Naloxone (8.25 mmol/ kg, s.c.) reverted the antinociceptive action of B50 (200 nmol/ 5 ml, i.t.), in the acetic acid writhing assay, suggesting that opioid mechanisms are involved in the antinociception caused by B50. B50 had no effect on spontaneous locomotion or rotarod performance, indicating that the currently reported antinociceptive effect of B50 is not related to unspecific motor effects.

Paracetamol is an analgesic-antipyretic compound derived from p-aminophenol. Though paracetamol has good efficacy and safety on consumption, parasetamol has hepatotoxic effect as its adverse drug reaction. 4-[N-(4-hydroxyphenyl)carboxymidoyl]-2-methoxyphenol is one of p-aminophenol derivative that was already been determined in silico using molecular docking PLANTS method, and it was known that 4-[N-(4-hydroxyphenyl) carboxymidoyl]-2-methoxyphenol has analgesic effects more potent and has hepatotoxic adverse effect lower than paracetamol. 4-[N-(4-hydroxyphenyl)carboxymidoyl]-2-methoxy-phenol can be synthesized through reaction of p-aminophenol with vanillin under acid condition. The synthesized products were recrytalized, dried, and the purity was determined with melting point determination and Thin Layer Chromatography. The structure of pure crystals were elucidated using IR, 1H-NMR, C-NMR, and Mass Spectroscopy. The analgesic evaluation was carried in vivo using writhing test method. The synthesized compound were divided into three dosage variations, 0,5; 1; and 2 mol equivalent to 100 mg/kgBB of paracetamol (reference drug). 4-[N-(4-hydroxyphenyl)carboxymidoyl]-2-methoxyphenol with 1 mol dosage has analgesic activity better than paracetamol but the difference was not significant.

Background and Objectives: The selective kappa opioid receptor agonist U50,488 was reported to have analgesic, cough suppressant, diuretic and other beneficial properties. The aim of our study was to analyze the effects of some original chitosan-coated liposomes entrapping U50,488 in somatic and visceral nociceptive sensitivity in mice. Materials and Methods: The influence on the somatic pain was assessed using a tail flick test by counting the tail reactivity to thermal noxious stimulation. The nociceptive visceral estimation was performed using the writhing test in order to evaluate the behavioral manifestations occurring as a reaction to the chemical noxious peritoneal irritation with 0.6% acetic acid (10 mL/kbw). The animals were treated orally, at the same time, with a single dose of: distilled water 0.1 mL/10 gbw; 50 mg/kbw U50,488; 50 mg/kbw U50,488 entrapped in chitosan-coated liposomes, according to the group they were randomly assigned. Results: The use of chitosan-coated liposomesas carriers for U50,488 induced antinociceptive effects that began to manifest after 2 h, andwere prolonged but with a lower intensity than those caused by the free selective kappa opioid in both tests. Conclusion: In this experimental model, the oral administration of nanovesicles containing the selective kappa opioid agonist U50,488 determined a prolonged analgesic outcome in the tail flick test, as well as in the writhing test.

Salvia sclarea essential oil is used as an aromatic therapy for dysmenorrhea. Sclareol—one of the natural products isolated from S. sclarea—displays anti-inflammatory and antioxidant activities; however, researchers have not yet evaluated the mechanism related to the pain-relieving effect of sclareol. In the present study, we aimed to investigate the potential effect of sclareol in ex vivo and in vivo dysmenorrhea models, as well as its possible mechanism. In the ex vivo study of uterine tissue from Sprague Dawley (SD) rats, the uterine contraction amplitude was observed and recorded. In the in vivo study, we measured the uterine contraction pressure of SD rats and performed writhing tests on mice. The uterine tissues from the writhing test subjects were collected and analyzed by Western blot. The results demonstrated that sclareol inhibited prostaglandin (PG) F2α-, oxytocin-, acetylcholine-, carbachol-, KCl-, and Bay K 8644-induced uterine contraction and possessed an analgesic effect in the writhing test. Sclareol affects the Ca2+ level and regulates oxytocin receptor (OTR), myosin light chain kinase (MLCK), extracellular signal-regulated kinase, p-p38, cyclooxygenase-2 (COX-2), and phospho-myosin light chain 20 (p-MLC20) protein expression. Integrating these results, we suggest that sclareol is a potential alternative supplement for dysmenorrhea.

Introduction: Gender and obesity related influences on the experience of pain have received considerable empirical attention in recent years. Differences in pain sensitivity among individuals may have implications for pain management which might account in part for the variability in analgesic requirements between individuals. Aim: To investigate the correlation of gender and serum leptin level with analgesic modulation of tramadol in high fat diet induced obese Wistar rats. Materials and Methods: A total of 48 Wistar rats (24 each male and female; body weight 100-150 gm) were housed as two rats/ cage. In addition to the normal pellet diet, these animals were orally fed with a mixture of Vanaspati daalda+Coconut oil (3:1)- 10 mL/kg/day for 90 days. After 90 days, these rats attained body weight approximately ≥300 gm (obese). Thereafter, each 24 male and 24 female obese rats were randomly divided into two groups (n=6/group) (Group I- Control: 0.9% NaCl; 1 mL/kg/ day i.p. and Group II- Test: Tramadol 10 mg/kg/day i.p.) for each nociception model-plantar test (12 male rats and 12 female rats) and acetic acid induced writhing test (12 male rats and 12 female rats). The treatment duration was of five days. Results: Paw Withdrawal Latency (PWL) was significantly decreased (p

Anisomeles indica (L.) kuntze is widely used in folk medicine against various disorders including allergy, sores, inflammation, and fever. This research investigated the antinociceptive, anxiolytic and sedative effects of A. indica methanol extract. The antinociceptive activity was assessed with the acetic acid-induced writhing test and formalin-induced flicking test while sedative effects with open field and hole cross tests and anxiolytic effects with elevated plus maze (EPM) and thiopental-induced sleeping time tests were assayed. Computer aided (pass prediction, docking) analyses were undertaken to find out the best-fit phytoconstituent of total 14 isolated compounds of this plant for aforesaid effects. Acetic acid treated mice taking different concentrations of extract (50, 100, and 200 mg/kg, intraperitoneal) displayed reduced the writhing number. In the formalin-induced test, extract minimized the paw licking time of mice during the first phase and the second phase significantly. The open field and hole-cross tests were noticed with a dose-dependent reduction of locomotor activity. The EPM test demonstrated an increase of time spent percentage in open arms. Methanol extract potentiated the effect of thiopental-induced hypnosis in lesser extent comparing with Diazepam. The results may account for the use of A. indica as an alternative treatment of antinociception and neuropharmacological abnormalities with further intensive studies. The compound, 3,4-dihydroxybenzoic acid was found to be most effective in computer aided models.

Background: Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases., Objective: The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits., Methods: Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities., Results: The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC 50 values of 0.13 to 0.05 μM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC 50 value of 0.05 μM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED 50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90., Conclusion: The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ibuprofen is classified as a BCS class II drug which has low solubility and high permeability. We conducted the formation of the cocrystalline phase of ibuprofen with coformer nicotinamide to increase its solubility. The purpose of this study was to characterize the solid state of cocrystalline phase of ibuprofen-nicotinamide, determine the solubility, and evaluate its in vivo analgesic activity. The cocrystal of ibuprofen-nicotinamide was prepared by a slow evaporation method. The solid-state characterization was conducted by powder X-ray diffraction (PXRD) analysis, differential thermal analysis (DTA), and scanning electron microscopy (SEM). To investigate the in vivo analgesic activity, 28 male Swiss-Webster mice were injected with acetic acid 0.5% following oral administration of intact ibuprofen, physical mixture, and its cocrystalline phase with nicotinamide (equivalent to 26 mg/kg ibuprofen). The number of writhes was counted, and pain inhibition was calculated. All data were analyzed with one-way ANOVA followed by Duncan's Multiple Range Test (95% confidence interval). The results revealed that a new cocrystalline phase was successfully formed. The solubility testing showed that the cocrystal formation enhanced the solubility significantly as compared with the physical mixture and intact ibuprofen. A significant increase in the analgesic activity of cocrystal ibuprofen-nicotinamide was also confirmed. [ABSTRACT FROM AUTHOR]

Introduction: Gender and obesity related influences on the experience of pain have received considerable empirical attention in recent years. Differences in pain sensitivity among individuals may have implications for pain management which might account in part for the variability in analgesic requirements between individuals. Aim: To investigate the correlation of gender and serum leptin level with analgesic modulation of tramadol in high fat diet induced obese Wistar rats. Materials and Methods: A total of 48 Wistar rats (24 each male and female; body weight 100-150 gm) were housed as two rats/ cage. In addition to the normal pellet diet, these animals were orally fed with a mixture of Vanaspati daalda+Coconut oil (3:1)-10 mL/kg/day for 90 days. After 90 days, these rats attained body weight approximately ≥300 gm (obese). Thereafter, each 24 male and 24 female obese rats were randomly divided into two groups (n=6/group) (Group I- Control: 0.9% NaCl; 1 mL/kg/ day i.p. and Group II- Test: Tramadol 10 mg/kg/day i.p.) for each nociception model-plantar test (12 male rats and 12 female rats) and acetic acid induced writhing test (12 male rats and 12 female rats). The treatment duration was of five days. results: Paw Withdrawal Latency (PWL) was significantly decreased (p<0.001) and both number of writhing movements and serum leptin concentrations were significantly increased (p<0.001) in obese female control group compared to obese male control group. Tramadol treated both obese male and female rats had significantly increased PWL (p<0.001) and decreased both number of writhing movements and serum leptin concentration (p<0.001) in comparison with both obese male and female control groups respectively. In tramadol treated obese female rats, PWL was significantly decreased (p=0.048) and both number of writhing movements and serum leptin concentration were significantly increased (p<0.001) in comparison with the tramadol treated obese male rats. PWL was negatively correlated with serum leptin concentration (Pearson correlation coefficient= -0.754, 2-tailed significance; p<0.001) and number of writhing movements were positively correlated with serum leptin concentration (Pearson correlation coefficient=0.507, 2-tailed significance; p=0.011). conclusion: The present study revealed that obese female rats have more serum leptin concentration than obese male rats which could be one of the possible reasons for having more pain sensation to noxious stimuli in obese female rats compared to obese male rats. Tramadol treatment at the dose of 10 mg/ kg for five days has decreased serum leptin level in rats which might be one of the additional analgesic mechanisms of action of tramadol. [ABSTRACT FROM AUTHOR]

Objective: Berberis vulgaris has antioxidant, hepato--renal protective, antibacterial, lipid lowering, anti-inflammatory and antinociceptive activities. The genus Berberis, has another member called Berberis integerrima which has not been studied for antinociceptive activity and therefore, this study was aimed to examine the antinociceptive effect of total extract and alkaloid fractions of Berberis integerrima root in mice. Materials and Methods: Methanolic total extract and alkaloid fractions of the plant namely, fractions A, B, C and D were prepared according to standard methods. Male Swiss mice (20-25 g) were used (n=6 in each group). Acetic acid-induced writhing, formalin and hot-plate tests were used to assess the antinociceptive activity. In hot plate and formalin tests, morphine (10 mg/kg, i.p.) and in acetic acid test, indomethacin (10 mg/kg, i.p.) were used as reference drugs. Results: The total extract and fractions A, B and D significantly reduced abdominal twitches in acetic acid test and licking behavior of both acute and chronic phases of formalin test. In hot-plate test, morphine as the standard drug demonstrated significant antinociception while the plant extract and fractions were ineffective. The dose of 5 mg/kg of fraction C showed slight analgesia only in acetic acid test and a dose of 10 mg/kg caused severe toxicity and even death in some animals. Conclusion: Berberis integerrima total extract and its alkaloid fractions showed antinociceptive effect and it seems that the mechanism of this action is peripherally mediated since they were effective in formalin test and acetic acid- induced writhing but not in hot-plate test. [ABSTRACT FROM AUTHOR]

Anisomeles indica (L.) kuntze is widely used in folk medicine against various disorders including allergy, sores, inflammation, and fever. This research investigated the antinociceptive, anxiolytic and sedative effects of A. indica methanol extract. The antinociceptive activity was assessed with the acetic acid-induced writhing test and formalin-induced flicking test while sedative effects with open field and hole cross tests and anxiolytic effects with elevated plus maze (EPM) and thiopental-induced sleeping time tests were assayed. Computer aided (pass prediction, docking) analyses were undertaken to find out the best-fit phytoconstituent of total 14 isolated compounds of this plant for aforesaid effects. Acetic acid treated mice taking different concentrations of extract (50, 100, and 200 mg/kg, intraperitoneal) displayed reduced the writhing number. In the formalin-induced test, extract minimized the paw licking time of mice during the first phase and the second phase significantly. The open field and hole-cross tests were noticed with a dose-dependent reduction of locomotor activity. The EPM test demonstrated an increase of time spent percentage in open arms. Methanol extract potentiated the effect of thiopental-induced hypnosis in lesser extent comparing with Diazepam. The results may account for the use of A. indica as an alternative treatment of antinociception and neuropharmacological abnormalities with further intensive studies. The compound, 3,4-dihydroxybenzoic acid was found to be most effective in computer aided models. [ABSTRACT FROM AUTHOR]

Bunium persicum (Boiss.) is an economically important medicinal plant growing wildly in arid regions in Iran. The fruit of B. persicum is widely used in traditional Iranian medicine to control colic pain and dysmenorrhoea. The aim of the current study was to determine antinociceptive mechanisms of B. persicum essential oil using an acetic acid-induced writhing test as a model of visceral pain and to determine the possible involvement of opioidergic, serotoninergic and histaminergic systems on antinociceptive mechanisms of B. persicum in male mice. In experiment 1, B. persicum was intraperitoneally (i.p.) injected (0.001, 0.01, 0.05, 0.1, 0.5 and 1%; 10 ml/kg) in Tween-80 (0.5%) and a writhing test served as a model of visceral pain. In experiments 2-5, opioidergic receptor antagonist (naloxone, 2 mg/kg), serotonergic receptor antagonist (cyproheptadine, 4 mg/kg), histamine H1-receptor antagonist (chlorpheniramine, 20 mg/kg) and histamine H2-receptor antagonist (cimetidine, 12.5mg/kg) injection was followed by B. persicum (0.01%; 10 ml/kg) and the writhing test response was measured for 30 min. According to the results, essential oil of B. persicum, administered i.p. (0.001, 0.01, 0.05, 0.1, 0.5, and 1%; 10 ml/kg) in Tween-80 (0.5%), elicited antinociceptive effects in a dose-dependent manner. Moreover, the antinociceptive effect of B. persicum was significantly attenuated by pre-treatment with naloxone, chlorpheniramine and cimetidine (P < 0.001). These results suggest that B. persicum-induced analgesia may be mediated via opioidergic and histamine H1 and H2 receptors.

Background: In Iranian traditional medicine, gum obtained from Astragalus gummifer and some other species of Astragalus was used as analgesic agent. Objective: In this study, we investigated the antinociceptive effect of several concentrations (125, 250, and 500 μg/kg body weight) of Astragalus gummifer gum (AGG) on thermal and acetic acid induced pain in mice. Materials and Methods: AGG was dissolved in distillated water and injected i.p to male mice 15 minute before the onset of experiment. Writhing and hot-plate tests were applied to study the analgesic effect of AGG and compared with that of diclofenac sodium (30 mg/kg, i.p.) or morphine (8 mg/kg, i.p). To investigate the mechanisms involved in antinociception, yohimbine, naloxone, glibenclamide, and theophylline were used in writhing test. These drugs were injected intraperitoneally 15 min before the administration of AGG. The number of writhes were counted in 30 minutes and analyzed. Results: AGG exhibited a significant antinociceptive effect and the most effective dose of AGG was 500 μg/kg. The most maximum possible effect (%MPE) was observed (117.4%) 15 min after drug administration. The %inhibition of acetic acid-induced writhing in AGG 125, 250 and 500 was 47%, 50% and 54% vs %15 of control and 66.3% of diclofenac sodium group. The antinociceptive effect induced by this gum in the writhing test was reversed by the systemic administration of yohimbine (α2 -adrenergic antagonist), but naloxone, glibenclamide, and theophylline did not reverse this effect. Conclusions: The findings of this study indicated that AGG induced its antinociceptive through the adrenergic system.

Empathy, which is a highly cognitive and emotional process, is the ability to share the emotional states of others. Empathy has also been observed in rodents. The empathic sharing of the distressful experience of a conspecific can even motivate altruistic behaviors, which are critical for survival. However, previous studies investigating empathy or prosocial behaviors in rodents mainly employed fearful or other stressful stimuli to elicit emotional changes; whether pain empathy can also motivate prosocial behaviors has yet to be investigated. By using the writhing test, the present study found that cagemate observer (CO) rats, compared with non-cagemate observer (NCO) rats, increased partner-directed grooming (allogrooming) toward conspecifics that had received an intraperitoneal injection of acetic acid during a dyadic social interaction. Following a dyadic social interaction with a demonstrator that received an intraperitoneal injection of acetic acid, the CO rats, compared with NCO rats, exhibited bilateral mechanical pain hypersensitivity and an enhanced acetic acid-induced writhing response. Our results here provided further evidence of pain empathy in rats, suggesting that empathy for pain may motivate prosocial behaviors in rats. [ABSTRACT FROM AUTHOR]

Background: This study investigates the analgesic properties of the aqueous extracts of Nigella sativa and Eucheuma cottonii in mice. The analgesic properties of both extracts were evaluated in an experimental model of acetic acid-induced writhing test. Materials and Methods: The mice were divided into four different groups and received the test extracts and the standard drug (aspirin) for 14 days via force-feeding. On day 15, the mice were injected with 5% acetic acid, and the number of abdominal constriction and elongation of hind limb (writhes) were counted for 20 min. Results: The numbers of writhes were counted starting after 5 min of the acetic acid injection. The N. sativa extracts significantly reduced the number of writhes as compared to the control group. Both of the extracts revealed a comparable result as referred to the aspirin effects in the mice. Conclusions: These findings indicate that N. sativa and E. cottonii may possess protective active constituent that is effective in reducing the sensation of pain in mice. [ABSTRACT FROM AUTHOR]

Context:Aqueous root extract ofDalbergia saxatilis, Hook, f., (Leguminosae) (DS) is reported useful for toothache, pains, and fever, but not scientifically proven. Objective:This study determined its effectiveness in pain, inflammation, and fever, applying scientific models. Materials and methods:Swiss mice or Sprague–Dawley rats (n = 5) were pretreated with distilled water, DS (100 or 200 mg/kg), or standard drug for 30 min. The analgesic activity was measured by acetic acid writhing, tail flick, tail immersion, tail clip, hot plate, and formalin pain tests; anti-inflammatory effects were determined via carrageenan and dextran rat paw oedema tests; antipyretic activity was measured byEscherichia colilipopolysaccharide (ECL) and turpentine in rabbits, andd-amphetamine sulphate (d-AS) pyrexia test in rats. Results:Writhing frequency inhibition was produced by 200 mg/kg DS (33.10%), aspirin (38.19%) and morphine (93.68%). Unlike morphine, DS did not produce significant prolongation of the reaction times in the hot-plate, tail immersion, tail flick, and tail clip tests. In the first and second phases of formalin test, respectively, % inhibition was: 200 mg/kg DS (25.70% and 0%), aspirin (4.76% and 67.33%), morphine (81.42% and 66.11%); for carrageenan and dextran tests, significant difference was recorded between 200 mg/kg DS and control up to 6 h. Significant reduction in ECL, turpentine andd-AS pyrexia was recorded at 100 and 200 mg/kg DS. Conclusion:DS produces mild non-steroidal analgesic and anti-inflammatory, as well as significant antipyretic actions involving cyclooxygenase, α2adrenoceptor and interleukin-1 β1 due to any of glycosides, saponins or phenolic tannins. [ABSTRACT FROM PUBLISHER]

Morphiceptin (Tyr-Pro-Phe-Pro-NH 2 ) is a selective ligand of the mu opioid receptor, an important target in pain regulation. In this study, morphiceptin was modified at positions 2 or 3 by introduction of β 2 - or β 3 -amino acids and additionally in position 1 by replacing Tyr by Dmt (2′,6′-dimethyltyrosine), which resulted in obtaining enzymatically stable analogs with mixed opioid receptor affinity profiles. An analog of the sequence Dmt- d -Ala-( R )-β 2 -1-Nal-Pro-NH 2 [Nal = 3-(1-naphthyl)-alanine] showed very high activity at the mu and delta receptors in the calcium mobilization functional test but did not cross the artificial membrane imitating the blood-brain barrier. In the in vivo test this analog induced strong antinociceptive effect in the writhing test in mice after intraperitioneal but also oral administration and inhibited diarrhea similarly to loperamide. Therefore, it may become an interesting lead compound in the development of peripherally restricted drugs for the treatment of gastrointestinal disorders. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the antinociceptive activity of the methanol extract of Tabebuia hypoleuca stems (THME).Materials and Methods: The animals were divided into 5 groups of 8 mice for each test (negative controls, positive controls, and 3 groups treated with THME at doses of 150, 300, and 500 mg/kg, p.o.). The antinociceptive effect of THME was evaluated using the writhing, formalin, tail flick, and hot plate models in mice.Results: In the writhing test, THME (150, 300, and 500 mg/kg) produced significantly (p < 0.001) fewer writhes induced by acetic acid than in the control group. In the formalin test, the licking time for THME at doses of 300 and 500 mg/kg was significantly shorter (p < 0.001) compared to the control group in the first phase of the formalin test, whereas in the second phase only the dose of 500 mg/kg showed an antinociceptive effect. In addition, THME at doses of 300 and 500 mg/kg significantly increased the latency time in the tail flick test (p < 0.05 and p < 0.001, respectively) and in the hot plate test (p < 0.01 and p < 0.001, respectively) compared to the control group.Conclusions: These results show that THME had antinociceptive activity using several models of nociception, and they suggest that the effect is mediated by the participation of both peripheral and central antinociceptive mechanisms. [ABSTRACT FROM AUTHOR]

Protocatechuic acid (PCA) is a widely distributed natural bioactive phenolic acid. The various pharmacological activities such as antioxidant, antidiabetic and anti-inflammatory activities have been identified. However, the studies focused on the analgesic effect of protocatechuic acid are limited and the action mechanisms of PCA still remain unclear. The NO-cGMP-ATP-sensitive K+ channels pathway is one of the mechanism of action for various analgesic drugs. The present study was conducted to investigate the involvement of NO-cGMP-ATP sensitive K+ channels pathway in analgesic effect of p.o. administration of 300 mg/kg protocatechuic acid in acetic acid-induced writhing test in mice. It was shown that pre-treatment with glibenclamide (10 mg/kg, i.p.), an ATPsensitive K+ channel blocker, and methylene blue (20 mg/kg, i.p.), a guanylate cyclase inhibitor, did not notably change antinociception produced by 300 mg/kg protocatechuic acid, however administration of nitro-L-arginine methyl ester (10 mg/kg, i.p.), a nitric oxide synthase inhibitor, significantly reversed protocatechuic acid antinociception. The results show that the peripheral mechanism of action of protocatechuic acid-induced antinociception involved another nitric oxide related pain pathway, not NO-cGMP-ATP sensitive K+ channels pathway. [ABSTRACT FROM AUTHOR]