Peripheral Analgesic Activity Research Articles

In vivo and in silico evaluation of antinociceptive activities of seed extract from the Holarrhena antidysenterica plant

The objective of the study was to investigate the analgesic activity of seeds extracted from the Holarrhena antidysenterica plant (Family: Apocynaceae). The seeds of H. antidysenterica were extracted with pure ethanol and administered to the experimental Swiss albino mice at three different doses (50, 100, and 150 mg/kg body weight) in pain models. Peripheral analgesic activity was evaluated using the acetic acid-induced writhing test, and heat-induced (hot plate and tail immersion test) pain models were applied for central anti-nociceptive activity evaluation. Formalin induced licking test was applied to evaluate both peripheral and central anti-nociceptive activity on mice. Computational studies were performed by Schrödinger Maestro v10.1 for molecular docking and the SwissADME online server for ADME prediction of compounds. In acetic acid-induced writhing test, dose-dependent reduction of writhing response was observed with 43.94% (p < 0.001) writhing inhibition at 150 mg/kg dose compared to standard 60.98% (p < 0.001). 150 mg/kg caused a maximum decrease in licking and biting time in both early and late phases of the formalin-induced licking test (71.2 ± 5.67, p < 0.05, and 36.6 ± 5.62, p < 0.01 respectively). In both tests of central analgesic activity, the extract also showed dose-dependent anti-nociceptive activity. In the hot plate method, the highest %MPE was 67.39 (p < 0.001) at 30 min at 150 mg/kg dose, which was even better than the standard drug. In the case of the tail immersion method, the highest %MPE was 69.84 at a dose of 150 mg/kg at 30 min (p < 0.001). In molecular docking study, Conimine, Conarrhimin, Conessine, and Funtudienine showed the best binding affinities against the COX-1 enzyme. The study indicates that the ethanolic seed extract of H. antidysenterica has the strong potentiality of having central analgesic activity and moderate peripheral analgesic activity due to the presence of bioactive compounds in its seeds.

Pharmacological investigations of Litsea lancifolia (Roxb.) Hook. F.

The petroleum ether, chloroform and ethyl acetate soluble fractions of methanolic extract of Litsea lancifolia Roxb. leaves were subjected to different pharmacological screenings to explore its potential as anti-oxidant, antimicrobial, peripheral analgesic, hypoglycemic and CNS depressing agent. The ethyl acetate soluble fraction showed highest total phenolic content and free radical scavenging activity compared to the standard, acetyl salicylic acid. Potential antimicrobial activity was shown against P. aeruginosa (23.50 mm), E. coli (22.33 mm), B. cereus (18 mm) and S. paratyphi (18 mm). The crude extract demonstrated significant peripheral analgesic (p &lt; 0.01) activity with 69.45 and 77.96% inhibition of acetic acid-induced writhing at 100 and 200 mg/kg b.w., respectively. The crude methanolic extract also showed significant hypoglycemic activity (p &lt; 0.01) at a dose of 500 mg/kg/day on the 7th day of treatment. All the organic soluble fractions exhibited noteworthy (p &lt; 0.001) CNS depressant activity. Taken together, the plant can be considered as a good material for further chemical investigation to isolate the bioactive constituents.

A study to evaluate efficacy of Tinospora cordifolia (Guduchi) as analgesic agent using albino wistar rats as an experimental animal model

Background: Pain is a very well-known symptom of many diseases and analgesics are used to relieve pain. The main problem with these drugs remains that of side effects. Herbal medicines are better in view of their cultural acceptability, better compatibility with human body systems and lesser incidence of side effects. Extract of Tinospora cordifolia (Guduchi) plant have been traditionally used to treat pain in traditional medicine.Methods: Commercially available preparation of T. cordifolia plant has been used as test drug (aqueous extract). Healthy albino rats of either sex, weighing between 140-200 g were selected for the study, divided into 4 groups of 6 each (control, standard, 100 mg/kg, 300 mg/kg). Central analgesic activity was assessed by tail flick model (morphine as standard drug I.P). Acetic acid 1% 10 ml/kg aqueous solution I.P. was used for abdominal writhing model. Diclofenac 150 mg/kg oral as standard drug for assessment of peripheral analgesic activity. Results were analysed using SPSS version 16 and Microsoft office excel 2007.Results: T. cordifolia extract significantly increased the tail flick latency time (sec) (mean tail flick latency control, T100, T300 6.833±0.25 sec, 8.65±017 sec, 10.01±0.14 respectively) (p value control vs T100, T300 at 90 min, 120 min, 0.0573, 0.0198, 0.0198 in between group) and decreased number of abdominal writhing in comparison with the control group (p value &lt;0.0001).Conclusions: Extract of T. cordifolia was found to possess analgesic activity and also exhibited dose and time dependant increase involving central and peripheral mechanisms. The analgesic activity of T. cordifolia found to be comparable to standard drug used.

Methanolic extracts and different fractions of whole plants of Leucas zeylanica show promising analgesic and antioxidative activities

Background and objective Leucas zeylanica is a medicinal plant used traditionally in tropical Asian countries including Bangladesh. This study was conducted to assess the pharmacological activities of whole plants of L. zeylanica. Materials and methods Methanolic crude extracts (MCEs) and petroleum ether-soluble fractions (PESFs), chloroform-soluble fractions (CSFs), and ethyl acetate-soluble fractions (EASFs) of whole plants were studied for the probable peripheral analgesic, central analgesic, and antioxidant and antimicrobial activities by acetic-acid-induced writhing and radiant heat tail-flick tests in mice, 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, and disk diffusion method, respectively. Results and conclusion The MCEs showed the highest peripheral analgesic activity among the test samples with an inhibition of pain sensation of 40% (at 200 mg/kg body weight dose, MCE200) and 32% (at 100 mg/kg body weight dose, MCE100) in comparison to diclofenac sodium (66.67%, P<0.001). In central analgesic activity test, elongation of flicking time was calculated at 30, 60, and 90 min of administration of test samples where morphine was the positive control. All extracts and fractionates showed significant increase in tail-flicking time. However, methanolic extract showed the highest activity (at 60 min) among all test samples (15.44±0.256, P<0.001). In antioxidant tests, butylated hydroxytoluene (BHT) was used as the positive control where methanolic extracts exhibited the highest antioxidant potentials among the test samples. IC50 (μg/ml) values were 19.61 (BHT), 28.46 (MCE), 65.61 (EASF), 84.75 (PESF), and 97.09 (chloroform-soluble fractions). Additionally, whole plant extracts showed weak antimicrobial activity. This ethnopharmacological investigation suggests that methanolic extracts and different fractions from L. zeylanica have strong analgesic and antioxidant potential and can be a significant source of natural medicine.

Synthesis and evaluation of pharmacological activities of some 3-O-benzyl-4-C-(hydroxymethyl)-1,2-O-isopropylidene-α-D-ribofuranose derivatives as potential anti-inflammatory agents and analgesics.

Background and purpose:α-D-ribofuranose analogues are reported to have multifarious biological properties such as analgesic, anti-inflammatory, and antiviral activities. The present study aims to synthesize some α-D- ribofuranose derivatives and investigate their biological properties.Experimental approach:Four derivatives (2a, 2b, 3, and 4) were synthesized from the starting material 3-O- benzyl-4-C-(hydroxymethyl)-1,2-O-isopropylidene-α-D-ribofuranose via subsequent benzylation, tosylation, and acetylation reactions in good yields. The compounds were confirmed by spectroscopic methods such as Fourier-transform infrared (FTIR) and proton nuclear magnetic resonance (1HNMR), and then evaluated for various pharmacological activities using standard in vitro and in vivo procedures.Findings / Results:Compound 2a (50 mg/kg) exhibited both central and peripheral analgesic activity in the tail immersion test (2.52 ± 0.14 min tail flicking reaction time after 30 min from administration, P < 0.001) and the acetic acid-induced writhing test (65.33 ± 2.06% reduction in abdominal writhing, P < 0.001) respectively. In the anti-inflammatory assay, percent paw edema inhibition of carrageenan-induced rats for compounds 2a and 4 (100 mg/kg) after 4 h of administration were 82.6% (P < 0.001) and 87.6% (P < 0.001), respectively. The compounds were also tested for antioxidant activity in 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, antimicrobial property in disk diffusion assay, and cytotoxicity in HeLa cell line; however, no significant results were observed in any of those tests.Conclusion and Implications:Our study indicated that some of the synthesized compounds exhibited promising analgesic and anti-inflammatory effects and may serve as potential lead compounds.

Analgesic, Anti-inflammatory and In-vitro Hyaluronidase Inhibitory Properties of the Leaf Extract and Solvent Fractions of Otostegia Fruticosa (Forssk.) Schweinf. ex Penzig.

Otostegia fruticosa is traditionally used to treat tonsillitis, stomach ache, asthma, arthritis, and febrile illness in different parts of Ethiopia and other countries. In this experiment 70% ethanolic crude extract and fractions of the leaf of Otostegia fruticosa (Forssk.) Schweinf. ex Penzig were evaluated for their in-vivo anti-inflammatory and analgesic activities and in-vitro hyaluronidase inhibition properties at different concentrations. Tail immersion, acetic acid induced writhing and carrageenan-induced paw edema model were used to assess the in-vivo analgesic and anti-inflammatory activities, respectively. Swiss albino mice of either sex were randomly divided into five groups of six mice per group and for evaluation of the fractions randomly divided into six groups of six mice per group. The test groups were treated with hydroalcoholic extract of Otostegia fruticosa (O. fruticosa) at doses of 100, 200, and 400 mg/kg. The positive control groups received either pethidine 5 mg/kg or aspirin at 100 mg/kg or 150 mg/kg. The negative control groups were orally given sunflower oil. All the fractions were administered at the dose of 400 mg/kg. In all models, the higher dose (400 mg/kg) of the crude extract and chloroform fraction showed a significant central and peripheral analgesic and anti-inflammatory activities with comparable effects to standards used. The hyaluronidase inhibition assay result showed that the test samples displayed concentration-dependent inhibitory activities. These findings indicate that 70% ethanol extract and organic solvent fractions of O. fruticosa leaves have potential analgesic, anti-inflammatory, and enzyme inhibitory activities.

Antinociceptive effects of saussurea lappa roots ethanol extract in experimental animals

The current study was designed to investigate both central and peripheral analgesic activities of crude extract of roots of Saussurea lappa (S. lappa) plant at 100% ethanol concentration. These activities were processed and evaluated through Eddy's hot plate and acetic acid induced-writhing methods, respectively, on laboratory Swiss albino mice. Reference positive control used was paracetamol, and negative control was distilled water, and statistical analysis done by SPSS version 25 to test one-way ANOVA for group mean differences, followed by Tukey and Dunnett two-sided post-hoc tests. Before the mentioned assessment, an acute oral toxicity test by a fixed-dose procedure method (FDP) was taken to check the safety of the plant. This plant was safe under experimentation, and it exerted significant (P < 0.01) analgesic effects at a dose of 500mg/kg. The crude extract revealed a noticeable increase of latency time to thermal pain stimuli when compared to paracetamol positive control at 100mg/kg concentration by 36.42%, and it reduced the number of writhing contractions by 21.73% when compared even to the positive control. It is presumed that S. lappa contains particular phytoconstituents that are responsible for presenting these effects. In both applied tests, S. lappa proved that it could be used as a safe, powerful analgesic treatment.

Analgesic activity of flavonoids isolated from Persicaria glabra (wild)

The present experimental study conducted to determine the four flavonoids (1–4) isolated from extracts of Persicaria glabra (Polygonaceae) and was tested for its potential central and peripheral analgesic activity. All animals were lowered on a hot plate (55 ± 0.5 °C), the observations were made before and after administration of respective drugs at 30, 60, and at the end of 90 min. In writhing method, acetic acid is administered intraperitoneal to the experimental animals to create pain sensation. The writhing movements were observed and counted for 30 min after acetic acid administration. The results showed that the compound quercetin (1) and its glycosides (3) at a dose of 100 and 200 mg/kg body weight significant analgesic activity (P < 0.05) in both central and peripheral models of analgesia used. The same doses, compounds 2 and 4 did not show any analgesic effects. Among them, quercetin (1) was the most potent in both models tested. Also due to structural difference of four compounds, a number of hydroxyl groups, substitution of –OCH3 and glycosylation, they will exhibit different analgesic responses. The P. glabra leaf extracts containing mixture of quercetin, isorhamnetin and their glycosides were effective in both the central and peripheral models of pain.

In-vivo and in-vitro evaluation of pharmacological activities of Ardisia solanacea leaf extract

BackgroundThe Bangladeshi rural and hilly areas people have long tradition to use various medicinal plants for treating different diseases. That’s why, the crude methanolic leaf extract of Ardisia solanacea with its different fractions (petroleum ether, carbon tetrachloride, n-hexane and chloroform fractions) were subjected to investigate bioactivities in swiss albino mice; namely analgesic, CNS, and Oral hypoglycemic activities, while in-vitro evaluation of cytotoxicity.MethodsCentral nervous system activity was investigated by various method such as Elevated plus maze, Hole board, Hole cross and Open field test apparatus. Analgesic activity was evaluated by both acetic acid induced and tail immersion method. Hypoglycemic activity was evaluated by oral glucose tolerance test and cytotoxicity was evaluated by Brine shrimp lethality bioassay.ResultsIn CNS activity, among others fractions, ASCF fraction produced a significant anxiolytic activity in both elevated plus maze and Hole board test. During open-field test almost all the fractions of A. solanacea leaves extract display decreased locomotor activities that indicates significant sedative activity. The ASME and ASCF showed significant peripheral analgesic activity at a dose of 200 mg/kg and 400 mg/kg body weight (p < 0.05). In tail immersion method, among others extracts chloroform fractions exhibited significant (p < 0.05) elongation of reaction time 30 min after oral dose of 200 and 400 mg/kg body weight respectively. The methanolic and n-hexane extracts reduced blood glucose level significantly after 90 min with value of 53.94% and 48.15% respectively (p < 0.05). In case of cytotoxicity activity, among other fractions carbon tetrachloride fraction showed lowest LC50 values.ConclusionsFrom the above results, it is clear that different fractions of A. solanacea showed significant pharmacological potentiality in different in-vitro and in-vivo study model. So, it will be very much possible source for an isolating lead compound for curing the numerous disorders.

Peripheral Analgesic Effect and Possible Mechanisms of Ferulic Acid

Ferulic acid is a bioactive phenolic compound that is found intensely in plants used in traditional medicine such as Ferula assa-foetida L.. The analgesic effect of various medicinal plants has been associated with its constituent, ferulic acid. However, there are limited number of studies about mechanism of its analgesic action. The aim of this study was to evaluate the contribution of NO/cGMP/PKG/KATP pathway in peripheral analgesic effect of ferulic acid by acetic acid-induced (0.6 % acetic acid, i.p.) writhing test in mice. For this purpose, following the determination of the analgesic effect of ferulic acid at the doses of 20, 40, 80 and 160 mg/kg (p.o.), NO precursor 100 mg/kg L-arginine (i.p.), nitric oxide synthase inhibitor 30 mg/kg L-NAME (i.p.), guanylate cyclase inhibitor 20 mg/kg methylene blue (i.p.) and KATP channel blocker 10 mg/kg glibenclamide (i.p.) were administered separately prior to ferulic acid treatment at the dose effective for clarifying the mechanism of action. Reduction in the number of writhes was evaluated as peripheral analgesic activity. Ferulic acid significantly decreased the number of writhes at the doses of 40, 80 and 160 mg/kg. 80 mg/kg ferulic acid and 100 mg/kg acetyl salicylic acid demonstrated similar efficacy. L-arginine and methylene blue relatively reversed the reduction in the number of writhes caused by ferulic acid at 80 mg/kg, whereas L-NAME did not. Glibenclamide pre-treatment significantly inhibited analgesic effect induced by ferulic acid. The results of the study indicate that ferulic acid has peripheral analgesic activity and it is mediated predominantly by activation of KATP channels and partially by cGMP. In conclusion, findings of this study demonstrate that ferulic acid may provide an advantage in KATP channel-targeted management of pain.

Evaluation of Analgesic Activities of 80% Methanol Leaf Extract of Solanum incanum L. (Solanaceae) in Mice

Solanum incanum Linnaeus is traditionally used for treatment of pain and other ailments. But there is no scientific evidence on its analgesic activity to-date. Thus the aim of this study was to evaluate the analgesic activities of 80% methanol leaf extract of S.incanum in mice. After extraction of the crude using 80% methanol, S.incanum extract was evaluated for analgesic activity in hot plate test and acetic-acid induced writhing test. Mice were randomly assigned to different groups and treated with 100, 200 and 400 mg/kg doses of the extract and reference control groups (morphine 5mg/kg and Aspirin 150 mg/kg) and negative control were treated with 2% tween 80. In the hot-plate method, all doses of the extract and the standard drug of morphine prolonged the reaction time significantly (p&lt;0.05, or p&lt;0.01 or p&lt;0.001) as compared to negative control throughout the observation period. Prolongation of reaction time produced by 100mg/kg of the extract was lower (p&lt;0.01) compared to morphine, 200mg/kg, and 400mg/kg at 90 and 120 min. However, middle and higher dose exerts comparable result at 30, 60 and 90and 120 min in relation to the standard drug. In addition 80% methanol extract of S.incanum showed a significant protection (p&lt;0.05) against acetic acid induced writhing compared to negative control. The extract produced a significant analgesic activity with 55.6, 38.2 and 44.8% inhibition of number of writhing at 100, 200 and 400 mg/kg dose levels, respectively. In conclusion, this study clearly suggests that 80% methanol leaf extract of S. incanum is endowed with central and peripheral analgesic activity. Hence, the findings collectively uphold the traditional use of the plant for pain treatment.&#x0D; Keywords: Analgesic, S.incanum , Hot plate, Acetic acid

Studies of Biological Activities of the Roots of Bombax ceiba L.

Bioactivities of the methanolic crude extract of root of Bombax ceiba L. and its organic and aqueous soluble partitionates were studied to investigate its medicinal importance. In Free radical scavenging assay by DPPH method, the aqueous soluble partitionate (AQSF) demonstrated the highest free radical scavenging activity with IC50 value of 3.33 ± 0.25 μg/ml. The brine shrimp lethality bioassay of different partitionates of the root demonstrated the significant lethality by the hexane soluble partitionate (HSF) having LC50 value of 1.19 ± 0.10 µg/ml. Among different fractionates of the root, the highest percentage (44.55 ± 0.12%) of clot lysis was exhibited by AQSF. The crude extract revealed promising antidiarrheal, hypoglycemic, central and peripheral analgesic activities at both doses of 200- and 400- mg/kg body weight in Swiss-Albino rat model.&#x0D; Bangladesh Pharmaceutical Journal 22(2): 219-223, 2019

Evaluation of Bioactivities of Gouania tiliaefolia Lam., an Indigenous Traditional Medicinal Plant of Bangladesh

The crude methanol extract of Gouania tiliaefolia Lam. was partitioned by the modified Kupchan method and the fractions were evaluated for total phenolic content, antioxidant, cytotoxic, thrombolytic, hypotonic and heat-induced membrane stabilizing activities. The petroleum ether soluble fraction (PESF) and methanol extract (ME) showed the highest phenolic content of 78.30 ±1.60 mg and 70.37 ± 0.84 mg, respectively, which were expressed in gallic acid equivalent (GAE). Similar trends were observed in case of anti-oxidant and cytotoxic activities, where the PESF possessed the highest free radical scavenging activity and brine shrimp lethality (IC50 = 2.88 ± 0.02 μg/ml, LC50 = 2.59 ± 0.14 μg/ml), followed by ME (IC50 = 4.79 ± 0.17 μg/ml, LC50 = 3.38 ± 0.08 μg/ml) and CSF (IC50 = 37.51 ± 0.96 μg/ml, LC50 = 73.55 ± 0.26 μg/ml). In case of assays for thrombolytic and membrane stabilizing activities, all extractives showed insignificant results compared to the respective standards. The crude methanol extract of G. tiliaefolia was used to examine the in-vivo analgesic (central and peripheral), antidiarrheal and antidiabetic activities in Swiss albino mice. In case of castor oil induced diarrhea, the ME gave better reduction of diarrhea by 71.43% (at 400 mg/kg-body weight) compared to loperamide (64.29%). Antidiabetic activity was evaluated by oral glucose tolerance test and the ME showed 71.42% and 75.39% reduction of blood glucose at doses 200 and 400 mg/kg-body weight, respectively when compared with the standard glibenclamide that reduced blood glucose by 66.17%. The central- and peripheral-analgesic activity was evaluated by the tail-flick test and acetic acid induced writhing test, respectively. In both the cases, ME demonstrated dose-dependent analgesic activity compared to the standards.&#x0D; Bangladesh Pharmaceutical Journal 22(2): 200-207, 2019

Bioactivities of Adina cordifolia (Roxb.) Hook. f. - growing in Bangladesh

A total of three compounds were isolated from the methanol extract of bark of Adina cordifolia (Roxb.) Hook. f. growing in Bangladesh and characterized as isoscopoletin (1), umbelliferone (2) and β-sitosterol (3) by analysis of high field NMR spectral data as well as co-TLC with authentic compounds. The minimum inhibitory concentration (MIC) of different extracts of bark of A. cordifolia was evaluated against three Gram positive and Gram negative pathogenic bacteria. The carbon tetrachloride soluble fraction showed the lowest MIC value (7.81 μg/ml) against Sarcina lutea as compared to 1.25 μg/ml for ciprofloxacin. The crude extract demonstrated significant antidiarrheal, hypoglycemic and peripheral analgesic activities at 200 and 400 mg/kg body weight in mice. On the other hand, the crude extract of bark of A. cordifolia revealed mild central analgesic activity.

Evaluation of central and peripheral analgesic activity of amitriptyline in mice

Background: Pain is one of the most frequent reasons for visiting a doctor. Large-scale studies in Western countries have shown that a fifth of the adult population suffer from chronic pain. Treatment of pain, still a major problem in clinical practice. Despite several available analgesics, unrelieved pain remains a major health care issue. Amitriptyline is a tricyclic antidepressant drug, which is regarded as adjuvant analgesic. There is a common consensus among the researchers on analgesic effect of amitriptyline which is mediated by central pathway but for the peripheral mechanism no conclusive evidence exists till now.Methods: To establish the analgesic mechanism of amitriptyline we tried to evaluate the analgesic activity on different mice models for central (Radiant heat tail flick test and Haffner’s tail clip method) and peripheral analgesia (Writhing test). We also compare the effects of amitriptyline with standard drugs for central and peripheral analgesia.Results: Both in Radiant heat tail flick test and Haffner’s tail clip method we found that the amitriptyline showed significant (p&lt;0.05 to p&lt;0.001) activity as compared to control and diclofenac group. But in comparison to pentazocin group amitriptyline didn’t show significant difference in the reaction time. In acetic acid induced writhing test amitriptyline group mice showed 41.09% reduction in number of writhes as compared to control group. While the standard control (Diclofenac) showed reduction of 65.17% as compared to control. So, amitriptyline showed comparable efficacy towards reduction in number of writhes with that of diclofenac.Conclusions: The results revealed that amitriptyline has significant analgesic activity which is mediated by modulation of both the central and peripheral pathways.

Evaluation of the hepatoprotective, anti-inflammatory, antinociceptive and antiepileptic activities of Chrysanthemum trifurcatum

Chrysanthemum trifurcatum is common to Mediterranean countries and widely-used in traditional medicine. Due to the scarcity of data about the pharmacological properties of C. trifurcatum, this present study was designed to determine the effects of C. trifurcatumethanolic extract (CEE) for its anti-nociceptive, anti-epileptic, anti-inflammatory, and hepatoprotective activities in mice and rat models. We demonstrate that CEE contains alkaloids, carbohydrates, and flavonoids, and in a dose-dependent (300 and 500 mg/kg) manner exhibited significant reductions in paracetamol (PCM; 500 mg/kg)-induced increased serum AST, ALT and ALP levels, similar to as seen by silymarin (25 mg/kg). Additionally, CEE (300 mg/kg) elicited inhibition in acetic acid-induced abdominal writhes, delayed latency time to paw’s licking in hot plate tests, exerted an anti-convulsant effect by prolonging the onset of clonic and tonic convulsions, and reduced pentylenetetrazole (PTZ; 80 mg/kg)-induced mortality. Moreover, CEE (500 mg/kg) exhibited a prominent reduction in carrageenan-induced paw edema. These studies indicate that CEE possesses profound central and peripheral analgesic, anti-convulsant, anti-inflammatory, and hepatoprotective activities.

Non-addictive orally-active kappa opioid agonists for the treatment of peripheral pain in rats

Addiction to conventional opioid pain analgesics is a major societal problem that is increasing at an alarming rate. New drugs to combat the effects of opioid abuse are desperately needed. Kappa-opioid agonists are efficacious in peripheral pain models but suffer from centrally-mediated effects. In this article, we discuss our efforts in developing peripheral kappa-based opioid receptor agonists that have the potential analgesic activity of opioids but do not manifest the negative side-effects of opioid use and abuse. Further, derivatives of the tetra-peptide D-Phe-D-Phe-D-Nle-D-Arg-NH2, such as CR665, exhibit high peripheral to central selectivity in analgesic models when administered intravenously (i.v.); however, they are inactive when administered orally. Application of our laboratory's proprietary non-natural amino acid technology to CR665 produced derivatives that exhibit peripheral analgesic activity when dosed orally but do not promote CNS-based effects. Lead compound JT09 activates the kappa-opioid receptor with EC50s in the low nM range, while agonist selectivity for kappa over other peripheral opioid receptors was >33,400 fold. Results indicate that JT09 is approximately as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated activity. Additionally, JT09 did not promote other CNS-mediated effects associated with morphine (addiction, sedation, dysphoria, tolerance, addiction). Thus, we propose that JT09 has potential for development as a novel analgesic. PerspectiveThis article presents data supporting the analgesic properties of an orally available, peripherally-restricted, kappa-opioid agonist for peripheral pain. A potential out-patient pharmaceutical that acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired CNS-mediated effects, could help reduce the current health care burden associated with prescription opioids.

Flurbiprofen-loaded ethanolic liposome particles for biomedical applications

Present study deals with the preparation, characterization and in-vivo evaluation of flurbiprofen loaded ethanolic liposome which provides predetermined and controlled release of drug through a transdermal drug delivery system. Ethanolic liposomes were prepared by using flurbiprofen, phospholipon 90-G, and ethanol in varied concentration ratio. The prepared ethanolic liposomes were optimized and characterized for particle size, zeta potential, polydispersive index and % entrapment efficiency. FTIR study was performed to analyze the interaction between drug and excipient. To study the thermal behavior of the formulation DSC and TGA were carried out. The surface morphology of ethanolic liposome was performed with the help of SEM, TEM, and AFM. In-vitro drug permeation study of the optimized formulation was carried out using the albino rat skin model and peripheral nociceptive activity was evaluated by writhing assay. In addition, formulations were also inspected for stability study for three months at a different temperature. The optimized formulation EF5 exhibited a particle size of 167.2 ± 3.7 nm with a zeta potential of −51.6 ± 0.2 mV and PDI of 0.209. The optimized formulation showed an ideal surface morphology with a maximum % entrapment efficiency i.e. 93.51 ± 2.1. In-vitro permeation study shows a release of 70.23% in 24 h and transdermal flux was found as 238.2 μg/cm2/h. Writhing assay demonstrate that the optimized formulation decreases the number of writhes and thus shows the peripheral analgesic activity. In stability study, optimized formulation showed maximum stability at 4 °C. These results suggest that transdermal system mediated application of flurbiprofen loaded ethanolic liposome can be considered as an effective way to afford consistent and predictable release of flurbiprofen which could provide beneficial effects in the management of various inflammatory diseases.

In vivo Analgesic, Antipyretic and Anti-inflammatory Activities of Ethanol Extract of Pericampylus glaucus in Experimental Animals

Pericampylus glaucus is a common Malaysian plant used traditionally in the treatments of joint pain, abdominal pain and headache. Hence, the present research was aimed to evaluate ethanolic extract of Pericampylus glaucus for analgesic, antipyretic and anti-inflammatory activities in experimental animals. The central and peripheral analgesic activity was determined by acetic acid induced writhing and hot plate method by examining the number of writhing and paw licking or jumping time. Meanwhile, the antipyretic activity was determined by Brewer’s yeast- test that induced pyrexia and carrageenan- that induced hind paw inflammation was used for anti-inflammatory activities. The ethanolic extract of Pericampylus glaucus at doses (300 and 600 mg/kg b.wt) and Ibuprofen (100 mg/kg (b.wt) was used as a reference drug in the whole experiment. Intraperitoneal administration of Pericampylus glaucus produced significant (p<0.01) inhibition in writhing response in acetic acid induced writhing test and dose-dependent (p<0.001) prolonged paw licking in hot plate test as compared to control (normal saline treated group). Similarly, significant (p<0.001) attenuation in lowering rectal temperature was noted in animal groups that were treated with ethanolic extract of Pericampylus glaucus at different doses. The attenuation was, almost the same as produced by ibuprofen treated group. Furthermore, Pericampylus glaucus extract also produced significant reduction in hind paw edema (p<0.001), 4 h after administration of carrageenan and inhibition was 60.19% and 42.17% as compared to control (normal saline treated group). The findings of this study indicated that Pericampylus glaucus possess significant analgesic, antipyretic and anti-inflammatory activities and could possibly be used in the management of fever, pain and inflammation.

Safety evaluation and analgesic studies of defatted methanol extract of Capparis spinosa L. (Capparidaceae) fruits and roots bark in albino wistar rats

Capparis spinosa L. is an indigenous plant from Algeria but has widespread distribution in Mediterranean area. It is used in traditional medicine for the treatment of various diseases by the local populations. The purpose of this study is to test toxicity and analgesic effect of defatted methanol extract of fruits and roots bark of this plant in albino Wistar rats. To evaluate the acute toxicity, 500-5000 mg/kg body weight of each extract was administered orally to rats; symptoms of toxicity and mortality were observed for 72 h. The results revealed the absence of toxicity for both extracts. In subchronic toxicity, rats were treated, with doses of 100 and 200 mg/kg/day of each extract, they were surveyed for four weeks, no symptoms of toxicity were observed. These results were confirmed by the blood biochemical analyses and the histopathology study of liver and kidney. Peripheral analgesic activity was tested orally at the dose of 100 and 200 mg/kg for each extract against pain induced by acetic acid. The dose of 200 mg/kg of both extracts presented significant analgesic effect, compared to the positive control; the acetylsalicylic acid.