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1.  Antinociceptive effect of Encholirium spectabile: A Bromeliaceae from the Brazilian caatinga biome 
Pharmacognosy Magazine  2014;10(Suppl 3):S655-S660.
Encholirium spectabile is a species found in outcrops rocky throughout the Brazilian Caatinga.
This study was carried out to evaluate the antinociceptive effects of ethanolic extract of the leaves from E. spectabile (Es-EtOH) in mice using chemical and thermal models of nociception.
Material and Methods:
HPLC was used to determine the fingerprint chromatogram. The Es-EtOH was examined for its antinociceptive activity at the doses of 100, 200 and 400 mg/kg intraperitoneal (i.p.). The evaluation of antinociceptive activity was carried out by the acetic acid-induced writhing, formalin and hot plate tests in mice. Rota-rod test was used for the evaluation of motor coordination.
In the acetic acid-induced writhing test, the Es-EtOH (100, 200 and 400 mg/kg, i.p.) reduced the number of writhings by 68.59, 79.33 and 65.28%, respectively. Additionally, Es-EtOH (100, 200 and 400 mg/kg, i.p.) decreased by 34.14, 52.61 and 60.97% the paw licking time in the first phase, as well as 89.56, 79.90 and 96.71% in the second phase of the formalin test, respectively. Es-EtOH also showed effect in the hot plate test, since increased the latency time at dose of 100 mg/kg after 60 minutes. In addition, Es-EtOH did not impair motor coordination. The presence of phenolic compounds in the extract was confirmed using HPLC. These results indicate that Es-EtOH has antinociceptive activity, probably of peripheral origin. The mechanism involved is not completely understood but, at least in part there is the participation of opioid receptors.
PMCID: PMC4189285  PMID: 25298687
Antinociceptive effect; Bromeliaceae; Encholirium spectabile; Pain
2.  Evaluation of antinociceptive, in-vivo & in-vitro anti-inflammatory activity of ethanolic extract of Curcuma zedoaria rhizome 
The present study was aimed to investigate the antinociceptive and anti-inflammatory activity of the Curcuma zedoaria (family Zingiberaceae) ethanolic rhizome extract in laboratory using both in vitro and in vivo methods so as to justify its traditional use in the above mentioned pathological conditions.
Phytochemical screening was done to find the presence of various secondary metabolites of the plant. In vivo antinociceptive activity was performed employing the hot plate method, acidic acid induced writhing test and formalin induced writhing test on Swiss albino mice at doses of 250 and 500 mg/kg body weight. Anti-inflammatory activity test was done on Long Evans rats at two different doses (250 and 500 mg/kg body weight) by using carrageenan induced paw edema test. Finally in vitro anti-inflammatory test by protein-denaturation method was followed. Data were analyzed by one-way analysis of variance (ANOVA) and Dunnett’s t-test was used as the test of significance. P value <0.05 was considered as the minimum level of significance.
Phytochemical screening revealed presence of tannins, saponins, flavonoids, gums & carbohydrates, steroids, alkaloids, reducing sugars and terpenoids in the extract. In the hot plate method, the extract increased the reaction time of heat sensation significantly to 61.99% and 78.22% at the doses of 250 and 500 mg/kg BW respectively. In acetic acid induced writhing test, the percent inhibition of writhing response by the extract was 48.28% and 54.02% at 250 and 500 mg/kg doses respectively (p < 0.001). The extract also significantly inhibited the licking response in both the early phase (64.49%, p < 0.01) and the late phase (62.37%, p < 0.01) in formalin induced writhing test. The extract significantly (p < 0.05, p < 0.01 and p < 0.001) inhibited carrageenan induced inflammatory response in rats in a dose related manner. In in-vitro anti-inflammatory test, the extract significantly inhibited protein denaturation of 77.15, 64.43, 53.04, 36.78 and 23.70% for doses of 500, 400, 300, 200 and 100 μg/mL respectively.
The results obtained from the tests indicate that the plant might have one or more secondary metabolite(s) having central and peripheral analgesic and anti-inflammatory activity.
PMCID: PMC4190444  PMID: 25242194
Curcuma zedoaria; Antinociceptive activity; In-vivo & in-vitro anti-inflammatory activity
3.  Phytochemical screening and anti-inflammatory activity of Cnidoscolus quercifolius (Euphorbiaceae) in mice 
Pharmacognosy Research  2014;6(4):345-349.
Cnidoscolus quercifolius is a species popularly known as favela and faveleira, and belonging to the Caatinga biome (semi-arid vegetation, Brazil), where is used in folk medicine as an anti-inflammatory.
The aim was to evaluate the anti-inflammatory effect of the ethanolic extract from barks (Cqb-EtOH) and leaves (Cql-EtOH) of C. quercifolius in mice using experimental models of inflammation.
Materials and Methods:
The preliminary phytochemical analysis of the ethanolic extract was performed. The activity was evaluated by paw edema induced by carrageenan and leukocytes migration to the peritoneal cavity induced by carrageenan methods.
A preliminary analysis of Cqb-EtOH revealed that it contained coumarins, flavonoids, monoterpenes/diterpenes and naphthoquinones, while the Cql-EtOH showed positive reaction to coumarins, anthracene derivatives, flavonoids, lignans and triterpenes/steroids. Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited significantly (P < 0.01) the increase in the edema volume after administration of carrageenan. In the peritonitis test, acute pretreatment with Cqb-EtOH and Cql-EtOH (100, 200 and 400 mg/kg) inhibited the leukocyte migration.
It can be concluded that extracts from the barks and leaves of C. quercifolius have anti-inflammatory activity, which supports the popular use of this plant to treat inflammation. Thus, extracts has significant anti-inflammatory properties, which are related probably to inhibition of release of mediators of the inflammatory process.
PMCID: PMC4166825  PMID: 25276074
Cnidoscolus quercifolius; Euphorbiaceae; inflammation; medicinal plants
4.  A Single, Moderate Ethanol Exposure Alters Extracellular Dopamine Levels and Dopamine D2 Receptor Function in the Nucleus Accumbens of Wistar Rats 
The nucleus accumbens (NAc) has been implicated in the neurochemical effects of ethanol (EtOH). Evidence suggests that repeated EtOH exposures and chronic EtOH drinking increase dopamine (DA) neurotransmission in the NAc due, in part, to a reduction in D2 autoreceptor function. The objectives of the current study were to evaluate the effects of a single EtOH pretreatment and repeated EtOH pretreatments on DA neurotransmission and D2 autoreceptor function in the NAc of Wistar rats.
Experiment 1 examined D2 receptor function after a single intraperitoneal (i.p.) injection or repeated i.p. injections of 0.0, 0.5, 1.0, or 2.0 g/kg EtOH to female Wistar rats. Single EtOH pretreatment groups received 1 daily i.p. injection of 0.9% NaCl (saline) for 4 days, followed by 1 day of saline or EtOH administration; repeated EtOH pretreatment groups received 5 days of saline or EtOH injections. Reverse microdialysis experiments were conducted to determine the effects of local perfusion with the D2-like receptor antagonist (−)sulpiride (SUL; 100 uM), on extracellular DA levels in the NAc. Experiment 2 evaluated if pretreatment with a single, moderate (1.0 g/kg) dose of EtOH would alter levels and clearance of extracellular DA in the NAc, as measured by no-net-flux (NNF) microdialysis. Subjects were divided into the EtOH-naïve and the single EtOH pretreated groups from Experiment 1.
Experiment 1: Changes in extracellular DA levels induced with SUL perfusion were altered by the EtOH dose (p < 0.001), but not the number of EtOH pretreatments (p > 0.05). Post-hoc analyses indicated that groups pretreated with single or repeated 1.0 g/kg EtOH showed significantly attenuated DA response to SUL, compared with all other groups (p < 0.001). Experiment 2: Multiple linear regression analyses yielded significantly (p < 0.05) higher extracellular DA concentrations in the NAc of rats receiving EtOH pretreatment, compared with their EtOH-naïve counterparts (3.96 ± 0.42 nM and 3.25 ± 0.23 nM, respectively). Extraction fractions were not significantly different between the 2 groups.
The present results indicate that a single EtOH pretreatment at a moderate dose can increase DA neurotransmission in the NAc due, in part, to reduced D2 autoreceptor function.
PMCID: PMC2858589  PMID: 19572982
Microdialysis; Ethanol; Dopamine; Nucleus Accumbens; D2 Autoreceptor
5.  Evaluation of antinociceptive effect of methanolic extract of leaves of Crataeva nurvala Buch.-Ham. 
Crataeva nurvala Buch.-Ham. (Family: Capparidaceae) is widely used as anti-inflammatory, contraceptive, laxative, lithotropic, febrifuge and as tonic in traditional medicine. This study evaluated the antinociceptive effect of the methanolic extract of the leaves of Crataeva nurvala (MECN).
The antinociceptive activity was investigated using heat-induced (hot-plate and tail-immersion test) and chemical-induced (acetic acid, formalin and glutamic acid) nociception models in mice at different doses (50, 100, and 200 mg/kg, p.o.) of MECN. Morphine sulphate (5 mg/kg, i.p.) and diclofenac sodium (10 mg/kg, i. p.) were used as reference analgesic drugs.
MECN produced significant dose-dependent antinociception when assessed using hot plate test, tail immersion test and acetic acid-induced abdominal writhing test (65.55%). Likewise, MECN at similar doses produced significant dose-dependent inhibition in both neurogenic (50.82%) and inflammatory pain (73.53%) induced by intraplantar injection of formalin (2.5% formalin, 20 μl/paw). Besides, MECN also significantly inhibited the glutamate-induced (10 μM/paw) pain in mice (74.68%). It was demonstrated that pretreatment with naloxone (2 mg/kg, i.p.) significantly reversed antinociception produced by MECN in hot plate and tail immersion test suggesting the involvement of opioid receptor. In addition, administration of glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+ channel antagonist could not reverse antinociceptive activity induced by MECN.
The results suggest that MECN possesses antinociceptive activity involving inhibition of opioid system as well as the glutamatergic system supporting its traditional uses.
PMCID: PMC4182810  PMID: 25248349
Antinociceptive; Crataeva nurvala; Capparidaceae; Opioid system; Glutamatergic system; Medicinal plants
6.  Analgesic effects of stem bark extracts of Trichilia monadelpha (Thonn.) JJ De Wilde 
Indian Journal of Pharmacology  2012;44(6):765-773.
Various parts of Trichilia monadelpha (Thonn) JJ De Wilde (Fam. Meliaceae) are used in Ghanaian traditional medicine for the treatment of painful and inflammatory conditions. The present study examined the analgesic properties of the petroleum ether (PEE), ethyl acetate (EAE), and the hydro-ethanolic (HAE) extract of the stem bark of the plant in murine models.
Materials and Methods:
PEE, EAE, and HAE were assessed in chemical (acetic acid-induced abdominal writhing and formalin tests), thermal (hot plate test), and mechanical (Randall-Selitto paw pressure test) pain models. The possible mechanisms of the antinociceptive action were also examined with various antagonists in the formalin test.
HAE, EAE, and PEE, each at doses of 10–100 mg/kg orally, and the positive controls (morphine and diclofenac) elicited significant dose-dependent antinociceptive activity in the chemical (acetic acid abdominal writhing and formalin tests), thermal (hot plate test), and mechanical (Randall-Selitto paw pressure test) pain models in rodents. The antinociceptive effect of HAE was partly or wholly reversed by systemic administration of atropine, naloxone, and glibenclamide. The antinociceptive effects of EAE and PEE were inhibited by atropine.
The extracts HAE, EAE, and PEE caused dose-related antinociception in chemical, thermal, and mechanical models of pain in animals. The mechanism of action of HAE involves an interaction with muscarinic cholinergic, adenosinergic, opioidergic pathways, and ATP-sensitive K+ channels while that of EAE and PEE involve the muscarinic cholinergic system.
PMCID: PMC3523507  PMID: 23248409
Formalin test; hot plate; pain; randall-selitto test; writhing test
7.  Antinociceptive Activity of Ethanol Extract from Duguetia chrysocarpa Maas (Annonaceae) 
The Scientific World Journal  2012;2012:859210.
The ethanol extract from the fruits of Duguetia chrysocarpa was evaluated for its antinociceptive activity in chemical and thermal models of nociception in mice. The intraperitoneal administration of the ethanol extract (100, 200, and 400 mg/kg body weight) showed a dose-dependent inhibition of acetic-acid-induced abdominal writhes. The extract also produced a significant inhibition of both phases of the formalin test in all doses tested and increased the reaction time in hot-plate test at dose of 200 mg/kg. The data obtained suggest that the antinociceptive effect of the extract may be mediated via both peripheral and central mechanisms. The phytochemical investigation yielded the isolation of the benzenoid derivative 3-methoxy-4-ethoxy benzoic acid which is being reported for the first time in this genus.
PMCID: PMC3356742  PMID: 22645460
8.  Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice 
BMC Pharmacology  2002;2:7.
Crocus sativus L. (saffron) is used in folk medicine, for example as an antiedematogenic agent. We aimed to evaluate the antinociceptive and anti-inflammatory activity of saffron extracts in mice.
We used aqueous and ethanolic maceration extracts of Crocus sativus L. stigma and petals. Antinociceptive activity was examined using the hot plate and writhing tests. The effect of extracts against acute inflammation was studied using xylene induced ear edema in mice. The activity of the extracts against chronic inflammation was assessed by formalin-induced edema in the rat paw. In the hot plate tests, intraperitoneal injection of both extracts showed no significant antinociceptive activity in mice. The extracts exhibited antinociceptive activity against acetic acid induced writhing. Naloxone partially blocked only the antinociceptive activity of the stigma aqueous extract. Only the stigma extracts showed weak to moderate effect against acute inflammation. In chronic inflammation, both aqueous and ethanolic stigma extracts, as well as ethanolic petal extract, exerted anti-inflammatory effects.
We conclude that aqueous and ethanolic extracts of saffron stigma and petal have an antinociceptive effect, as well as acute and/or chronic anti-inflammatory activity.
PMCID: PMC101384  PMID: 11914135
9.  Bioassay-guided evaluation of Dioscorea villosa – an acute and subchronic toxicity, antinociceptive and anti-inflammatory approach 
Dioscorea villosa (DV) has been used in Brazil as an alternative medicine to attenuate menopause symptoms, as well as for the treatment of joint pain and rheumatoid arthritis. In spite of the popular use of DV for the treatment of various disorders, there are limited scientific data regarding safety aspects of this herb. In this regard, we carried out to evaluated both antinociceptive and anti-inflammatory activities in experimental models and assess the toxic effects of the acute (single dose) and subchronic (30 days) oral administration of dry extract of Dioscorea villosa in rodents.
The LC analyses were performed to assess the presence of the diosgenin in samples of DV. The antinociceptive study of DV was performed using models of acetic acid-induced writhing and formalin-induced pain in mice. The anti-inflammatory study was accomplished by leukocyte migration to the peritoneal cavity. A dry extract of DV was tested at doses of 100, 200 and 400 mg/kg (per os or p.o.). The toxicological properties of the dry extract were evaluated by toxicity assays of acute (5 g/kg, single dose) and subchronic (1 g/kg/day, 30 days) treatment. Haematological, biochemical, and histopathological parameters were studied. The results are expressed as mean ± S.D., and statistical analysis of the data were performed with the Student’s t-test or one-way analysis of variance (ANOVA) followed by Tukey’s test. In all cases differences were considered significant if p < 0.05.
HPLC-DAD analysis of the extract from DV revealed the presence of diosgenin as the major compound. Doses of 200 and 400 mg⁄kg significantly reduced the amount of acetic acid-induced writhing in relation to the vehicle (p < 0.0001). In the first phase, using the formalin-induced neurogenic pain test, only the 400 mg/kg dose of DV showed significant inhibition of neurogenic pain (p < 0.001). In the second phase, 200 and 400 mg/kg of DV showed significant inhibition of inflammatory pain (p < 0.0001). Significant inhibition of leukocyte migration was observed with doses of 100 (p < 0.001), 200 (p < 0.01) and 400 mg/kg (p < 0.01). Haematological, biochemical and histopathological data obtained in both acute and subchronic toxicological assays revealed only unremarkable changes, which are unlikely to indicate DV toxicity with oral administration.
We found that DV possesses antinociceptive and anti-inflammatory properties in rodent models. In addition, no acute or subchronic toxicity was evident when the herbal extract was administered orally. These results supporting the folkloric usage of the plant to treat various inflammatory diseases.
PMCID: PMC3734200  PMID: 23889998
Dioscorea villosa; Toxicity; Antinociceptive effect; Anti-inflammatory effect
10.  Phytochemical Composition and Antinociceptive Activity of Bauhinia glauca subsp. hupehana in Rats 
PLoS ONE  2015;10(2):e0117801.
In traditional medicine, Bauhinia glauca subsp. hupehana has long been used as an analgesic agent in China. The aim of this study was to evaluate the antinociceptive activity of the ethanol extract of the aerial parts of B. glauca subsp. hupehana (BHE) in rats and its chemical fingerprint. The antinociceptive activity of BHE was assessed in mice using chemically and heat–induced pain models, such as the acetic acid–induced writhing, hot plate, tail–flick and glutamate tests. Naltrexone hydrochloride, a non–selective opioid receptor antagonist, was utilized to determine the involvement of the opioid system. In addition to this, the involvements of the cGMP and ATP–sensitive K+ channel pathways were also detected using methylene blue and glibenclamide. The oral administration of BHE (at doses of 50, 100 and 200 mg/kg) produced significant and dose–related inhibitions in both the chemically and heat–induced pain models. Interestingly, in the abdominal constriction test, when the dose of BHE was increased to 800 mg/kg (p.o., n = 10), the inhibition rate was 100%. The antinociceptive mechanism may involve the cGMP pathway and ATP sensitive K+ channel pathway. The central antinociceptive effect was not antagonized by naltrexone. One phenolic acid, one lignin and five flavonoids were isolated from BHE. The antinociceptive activity of BHE was most likely due to the presence of the flavonoids. The acute toxicity results showed that BHE was safe at a high dose (2 g/kg, p.o.). The current investigation demonstrates that B. glauca subsp. hupehana is a potential candidate for the development of novel, non–opioid, analgesic phytomedicines.
PMCID: PMC4320050  PMID: 25658740
11.  Altered Anxiety-like Behavior and Long-term Potentiation in the Bed Nucleus of the Stria Terminalis in Adult Mice Exposed to Chronic Social Isolation, Unpredictable Stress and Ethanol Beginning in Adolescence 
Alcohol (Fayetteville, N.Y.)  2010;45(6):585-593.
Alcohol and chronic stress exposure, especially during adolescence, can lead to an increased risk in adulthood of developing alcohol use disorders (AUDs). To date, however, no study has assessed the potential long-term effects of chronic intermittent and unpredictable ethanol (EtOH) exposure in mice chronically stressed beginning in adolescence on brain function and anxiety-like behaviors in adulthood. In particular, alterations in function of the bed nucleus of the stria terminalis (BNST), a brain region heavily implicated in anxiety-related behaviors and altered plasticity following EtOH exposure, may play a key role in the pathological responses to chronic stress and EtOH. In the present study, adolescent and adult C57Bl/6J mice were exposed to a regimen of chronic social isolation and unpredictable stressors and EtOH (or air (sham); CSI-CUS-EtOH and CSI-CUS-Sham, respectively) for 8–10 weeks. In adulthood, mice were tested for altered anxiety-like behavior [elevated plus maze (EPM) and modified social interaction (SI) test]. Following behavioral testing, mice were re-exposed to CSI-CUS-EtOH (and CSI-CUS-Sham for controls) for an additional three days. 4–6 hours following the final EtOH (or air) exposure, field potential recordings of the dorsal-lateral (dl)BNST were performed. Mice first exposed during adolescence to CSI-CUS-EtOH displayed lower levels of anxiety-like behavior on the EPM compared to mice first exposed to CSI-CUS-EtOH during adulthood and control mice only exposed to CSI-CUS-Sham, regardless of age of first exposure. However, mice first exposed to CSI-CUS-EtOH during adulthood displayed lower levels of anxiety-like behavior on the SI test compared to mice first exposed during adolescence and control CSI-CUS-Sham mice. CSI-CUS-EtOH exposure, regardless of age, produced blunted expression of long-term potentiation (LTP) in the dlBNST compared to CSI-CUS-Sham mice. This study demonstrates age-dependent effects of chronic unpredictable ethanol exposure in chronically stressed mice on anxiety-like behaviors during adulthood. Further, CSI-CUS-EtOH exposure results in blunted LTP expression in the adult dlBNST.
PMCID: PMC3085602  PMID: 21194878
anxiety; alcohol; addiction; stress; plasticity
Alcohol (Fayetteville, N.Y.)  2010;44(7-8):699-705.
N-acetylcysteine (NAC) is a derivative of the amino acid L-cysteine that previously has been shown to protect against ethanol (EtOH)-induced apoptosis during early development. Ongoing research is demonstrating that NAC is also proving clinically beneficial in reducing oxidative stress-mediated lung, liver and kidney damage, with protection likely resulting from a NAC-mediated increase in glutathione levels. In the present study, the hypothesis that co-administration of NAC and EtOH via liquid diet on days 7 and 8 of pregnancy in mice would reduce EtOH's teratogenicity was tested. For this work, adult non-pregnant female mice were acclimated to a liquid diet containing EtOH for 16 days, withdrawn from the EtOH, bred and then returned to the liquid diet containing 4.8% EtOH and/or either 0.5 or 1 mg NAC/ml diet on their 7th and 8th days of pregnancy. At the concentrations employed, the mice received NAC dosages of approximately 300 or 600 mg/kg/day and achieved peak blood EtOH levels (BEC) that averaged approximately 200 mg/dl. There was no difference in BEC between the EtOH alone and EtOH plus 600 mg/kg NAC group. Following maternal euthanasia, gestational day (GD) 14 fetuses were removed, fixed, weighed and examined for the presence and severity of ocular abnormalities, a readily assessed endpoint that results from GD 7 and 8 EtOH exposures. While the lower dosage of NAC (300 mg/kg) resulted in a decrease in the incidence of ocular defects in both the left and right eyes, this reduction was not statistically significant. However, doubling the NAC concentration did yield a significant change; as compared to the group treated with EtOH alone, the incidence of ocular abnormalities was diminished by 22%. These results show the potential of an orally administered compound with proven clinical efficacy to reduce EtOH's teratogenic effects and support the premise that oxidative damage plays an important mechanistic role in Fetal Alcohol Spectrum Disorders.
PMCID: PMC2993176  PMID: 21112471
Fetal Alcohol Spectrum Disorders; N-acetylcysteine; Ocular abnormalities
13.  Antinociceptive and Anti-Inflammatory Activity from Algae of the Genus Caulerpa 
Marine Drugs  2011;9(3):307-318.
Marine natural products have been the focus of discovery for new products of chemical and pharmacological interest. The aim of this study was to evaluate the antinociceptive activity of the methanolic (ME), acetate (AE), hexanic (HE) and chloroform (CE) extracts obtained from Caulerpa mexicana, and ME, CE and HE obtained from Caulerpa sertularioides. These marine algae are found all over the world, mainly in tropical regions. Models such as the writhing test, the hot plate test and formalin-induced nociception test were used to evaluate antinociceptive activity in laboratory mice. In the writhing test, all the extracts were administered orally at a concentration of 100 mg/kg, and induced high peripheral antinociceptive activity, with a reduction in the nociception induced by acetic acid above 65%. In the hot plate test, treatment with extracts from C. sertularioides (100 mg/kg, p.o.) did not significantly increase the latency of response, although the ME, AE and HE from C. mexicana showed activity in this model. This result suggests that these extracts exhibit antinociceptive activity. In the formalin test, it was observed that ME, AE and HE obtained from C. mexicana reduced the effects of formalin in both phases. On the other hand only CE from C. sertularioides induced significant inhibition of the nociceptive response in the first phase. To better assess the potential anti-inflammatory activity of the extracts, the carrageenan-induced peritonitis test was used to test Caulerpa spp. extracts on cell migration into the peritoneal cavity. In this assay, all extracts evaluated were able to significantly inhibit leukocyte migration into the peritoneal cavity in comparison with carrageenan. These data demonstrate that extracts from Caulerpa species elicit pronounced antinociceptive and anti-inflamatory activity against several nociception models. However, pharmacological and chemical studies are continuing in order to characterize the mechanism(s) responsible for the antinociceptive action and also to identify the active principles present in the Caulerpa species.
PMCID: PMC3083652  PMID: 21556161
antinociceptive; anti-inflammatory; Caulerpa mexicana; Caulerpa sertularioide; marine algae
14.  Regulation of the Activity and Expression of Aryl Hydrocarbon Receptor by Ethanol in Mouse Hepatic Stellate Cells 
During the course of alcohol-induced liver damage, hepatic stellate cells are transformed into proliferative, fibrogenic, and contractile myofibroblasts. Aryl hydrocarbon receptor (AhR) is a transcription factor that controls the expression of genes involved in the metabolism of xenobiotics, inflammation, cell proliferation, and death.
Immortal mouse hepatic stellate cells (MHSCs) were isolated from transgenic mice that expressed a thermolabile SV40 tumor antigen. Quantitative real-time reverse transcription polymerase chain reaction assays, Western blot analysis, promoter activity assays, and chromatin immunoprecipitation analyses were performed for studying the effect of ethanol (EtOH) on AhR expression and transcriptional activity.
Treatment of MHSCs with 50 to 200 mM EtOH for 6 hours induced AhR nuclear translocation, enhanced the promoter activity of cytochrome P450 (CYP) 1A1, increased the amount of AhR bound to the promoter of CYP1A1 and 1B1, and up-regulated the mRNA expression of these AhR target genes in a dose-dependent manner. In contrast, EtOH exposure down-regulated AhR mRNA and protein expression. Similarly, benzo(a)pyrene (BaP) at 10 nM reduced AhR and increased CYP1A1 and 1B1 mRNAs. Pretreatment of MHSCs with 50 mM EtOH for 7 days diminished the capacity of MHSCs to express CYP1A1 and 1B1 induced by a 200 mM EtOH challenge, or by 10 nM BaP. However, the up-regulatory effect of EtOH on solute carrier family 16, member 6 (SLC16a6) was unaffected by EtOH pretreatment. Similar to EtOH, dimethyl sulfoxide (DMSO) at concentrations of 50 to 100 mM down-regulated AhR and up-regulated CYP1A1 mRNA expression in a dose-dependent manner.
These data, for the first time, demonstrate that EtOH activates MHSC AhR and down-regulates its expression. Chronic EtOH pretreatment lowers the availability of AhR, and specifically diminishes the inducibility of CYP genes. The effect on AhR appears to not be an EtOH-specific response, as DMSO alone (and possibly other organic solvents) was also able to activate AhR.
PMCID: PMC3462894  PMID: 22486318
Ethanol; Mouse Hepatic Stellate Cells; Aryl Hydrocarbon Receptor; Cytochrome P450 Protein
15.  Antinociceptive Activity of Melicope ptelefolia Ethanolic Extract in Experimental Animals 
Melicope ptelefolia is a medicinal herb commonly used in Malaysia to treat fever, pain, wounds, and itches. The present study was conducted to evaluate the antinociceptive activity of the Melicope ptelefolia ethanolic extract (MPEE) using animal models of nociception. The antinociceptive activity of the extract was assessed using acetic acid-induced abdominal writhing, hot-plate, and formalin-induced paw licking tests. Oral administration of MPEE produced significant dose-dependent antinociceptive effects when tested in mice and rats using acetic acid-induced abdominal constriction test and on the second phase of the formalin-induced paw licking test, respectively. It was also demonstrated that MPEE had no effect on the response latency time to the heat stimulus in the thermal model of the hot-plate test. In addition, the antinociception produced by MPEE was not blocked by naloxone. Furthermore, oral administration of MPEE did not produce any effect in motor performance of the rota-rod test and in acute toxicity study no abnormal behaviors as well as mortality were observed up to a dose level of the extract of 5 g/kg. These results indicated that MPEE at all doses investigated which did not produce any sedative and toxic effects exerted pronounce antinociceptive activity that acts peripherally in experimental animals.
PMCID: PMC3022215  PMID: 21274262
16.  Increased operant responding for ethanol in male C57BL/6J mice: specific regulation by the ERK1/2, but not JNK, MAP kinase pathway 
Psychopharmacology  2009;204(1):135-147.
Extracellular signal-regulated protein kinase (ERK1/2) is a member of the mitogen-activated protein kinase (MAPK) signaling pathway and a key molecular target for ethanol (EtOH) and other drugs of abuse.
The aim of the study was to assess the role of two MAPK pathways, ERK1/2 and c-Jun N-terminal kinase (JNK), on the modulation of EtOH and sucrose self-administration.
Materials and methods
C57BL/6J mice were trained to lever press on a fixed-ratio 4 schedule with 9% EtOH/2% sucrose, or 2% sucrose, as the reinforcer. In experiments 1 and 2, mice were injected with the MEK1/2 inhibitor SL 327 (0–100 mg/kg) and the JNK inhibitor AS 6012452 (0–56 mg/kg) prior to self-administration. In experiment 3, SL 327 (0–100 mg/kg) was administered prior to performance on a progressive ratio (PR) schedule of EtOH reinforcement. In experiment 4, SL 327 and AS 601245 were injected 2 h before a locomotor test.
SL 327 (30 mg/kg) significantly increased EtOH self-administration without affecting locomotion. Higher doses of SL 327 and AS 601245 reduced EtOH-reinforced responding and locomotor activity. Reductions of both ligands on sucrose self-administration were due to decreases in motor activity. SL 327 pretreatment had no effect on PR responding.
ERK1/2 activity is more directly involved in modulating the reinforcing properties of EtOH than JNK activity due to its selective potentiation of EtOH-reinforced responding. The specificity of this effect to EtOH self-administration, rather than sucrose self-administration, suggests that the mechanism by which ERK1/2 increases EtOH-reinforced responding does not generalize to all reinforcing solutions and is not due to increased motivation to consume EtOH.
PMCID: PMC2845162  PMID: 19125235
Alcohol drinking; ERK/MAPK; SL 327; AS 601245; Self-administration; Progressive ratio; Motor activity; Reinforcement; Protein kinase; Operant conditioning
17.  Antinociceptive, anti-inflammatory, antimicrobial and central nervous system depressant activities of ethanolic extract of leaves and roots of Gomphostemma parviflorum var. parviflorum wall 
Pharmacognosy Research  2013;5(4):233-240.
Gomphostemma parviflorum (Lamiaceae) is a medicinal plant of Bangladesh which has been used traditionally in the treatment of painful and inflammatory conditions such as asthma, headache, fever, etc.
To investigate the antinociceptive, anti-inflammatory, central nervous system (CNS) depressant and antimicrobial activities of ethanolic extracts of leaves (GPLE) and roots (GPRE) of the plant.
Materials and Methods:
The antinociceptive potentials of the extracts were studied using acetic acid-induced writhing test in mice, anti-inflammatory activity was investigated using carrageenan-induced paw edema in rats, CNS depressant activities were evaluated using pentobarbitone-induced sleeping time, Hole cross and Open field tests in mice while the anti-microbial activity was studied by in vitro disc diffusion method.
The extracts GPLE and GPRE significantly (P < 0.001) and dose dependently inhibited the acetic acid-induced writhing in mice with 73.15% and 53.69% inhibition, respectively at the dose of 200 mg/kg. At the same dose GPLE and GPRE significantly inhibited carrageenan-induced rats paw edema at the end of 4 hour with 35.54% and 28.17% inhibition, respectively. The extracts significantly prolonged the pentobarbitone-induced sleeping time and decreased the locomotory activities in open field and Hole cross tests in mice. The GPLE showed strong antimicrobial activity against Gram-positive and Gram-negative bacteria with zones of inhibition ranging from 8 to 20 mm at a concentration of 400 μg/disc.
The findings of the study indicate that the leaves and roots of G. parviflorum possess antinociceptive, anti-inflammatory and CNS depressant activity and revealed the antimicrobial activities of leaves extract of the plant. The results justify the traditional use of the plant in the treatment of painful and inflammatory disorders.
PMCID: PMC3807986  PMID: 24174815
Anti-inflammatory; antimicrobial activities; antinociceptive; central nervous system depressant; Gomphostemma parviflorum; writhing
18.  Antinociceptive, Anti-Inflammatory and Acute Toxicity Effects of Juglans Regia L. Leaves in Mice 
Juglans regia leaves have been used in folk medicine to alleviate inflammatory diseases. This study investigates the antinociceptive, anti-Inflammatory and acute toxicity effects of Juglans regia L. leaves in mice.
351 Male and female albino mice were divided into negative (saline), positive (morphine or diclofenac) controls as well as test groups (n=6-8). The acute (intraperitoneally) toxicity was evaluated for 2 days. Antinociceptive activities were done using hot-plate and writhing tests. Anti-inflammatory effects were studied using xylene induced ear edema and cotton pellet tests.
The LD50 values of J. regia aqueous and ethanolic extrats were 5.5 and 3.3 g/kg, respectively. The aqueous (2.87 and 1.64 g/kg) and ethanolic (2.044 and 1.17 g/kg) extracts showed antinociceptive activity in hot-plate test. The pretreatment of naloxone (2 mg/kg, s.c.) did not inhibit the extracts activities. The extracts exhibited antinociceptive activity in writhing test, which were not blocked by naloxone. In xylene test, both extracts showed anti-inflammatory activity in some doses. The extracts showed anti-inflammatory activity against the chronic inflammation.
J. regia leaves demonstrated antinociceptive effect through non-opioid receptors and anti-inflammatory effect against acute and chronic inflammation. The extracts of J. regia could be considered as a promising analgesic and anti-inflammatory agents against diseases such as rheumatoid arthritis.
PMCID: PMC3407583  PMID: 22946016
Juglans regia; Hot-plate test; Writhing test; Xylene induced ear edema test; Cotton pellet test; Mice
19.  Intra-cornu ammonis 1 administration of the human immunodeficiency virus-1 transcription factor Tat exacerbates the ethanol withdrawal syndrome in rodents and activates N-methyl-d-aspartate glutamate receptors to produce persisting spatial learning deficits 
Neuroscience  2009;163(3):868-876.
Human immunodeficiency virus-1 (HIV-1) infection may produce neurological deficits, such as cognitive decline, that may be worsened by concurrent ethanol (EtOH) abuse. Among the many biochemical cascades likely mediating HIV-1 associated neuronal injury is enhancement of N-methyl-d-aspartate (NMDA) receptor function and progression to excitotoxicity, an effect that may be directly or indirectly related to accumulation in brain of the HIV-1 transcription factor Tat. The present studies were designed to examine the hypothesis that binge-like EtOH pre-exposure would enhance effects of Tat on NMDA receptor function. These studies employed a modified in vivo binge EtOH exposure regimen designed to produce peak blood EtOH levels (B.E.L.) of <200 mg/dl in adult male rats and were designed to examine effects of intra-hippocampal injection of Tat (0.5 µl/500 pM/2 min) on EtOH withdrawal-related behavior, spatial learning, and histological measures. Unilateral cannulae were implanted into the cornu ammonus 1 (CA1) pyramidal cell layer of animals prior to beginning a 4-day binge EtOH regimen. EtOH was administered via intragastric intubation (~3.0–5.0g/kg) with dose determined by behavioral ratings of intoxication daily for four days (at 0800, 1600, and 2400 hrs). EtOH withdrawal behaviors were monitored 12 hr after the last administration of EtOH. Morris water maze learning was assessed during the following 4 days, at which times brains were harvested for autoradiographic measurement of NMDA receptor density and neuroinflammation. Maximal B.E.L.s of 187.69 mg/dl were observed 60 min after EtOH administration on Day 2 of the regimen. In contrast, peak B.E.L.s of approximately 100 mg/dl were observed 60 min after EtOH administration on Day 4 of the regimen, suggesting development of metabolic tolerance. Significant behavioral abnormalities were observed in EtOH withdrawn animals, including tremor and seizures. Intra-CA1 region injection of Tat significantly potentiated EtOH withdrawal behavioral abnormalities, an effect that was reduced by MK-801 pre-exposure. While EtOH withdrawn animals showed learning similar to control animals, EtOH withdrawn animals that received intra-CA1 Tat injection demonstrated persisting deficits in spatial learning on Days 3 and 4 of training, effects that were markedly reduced by administration of the competitive NMDA receptor antagonist MK-801 30 min prior to Tat injection. No changes in [3H]MK-801 binding were observed. Binding density of [3H]PK11195, a ligand for peripheral benzodiazepine receptors expressed on activated microglia, was elevated proximal to cannulae tracts in all animals, but was not altered by EtOH or Tat exposure. These finding suggest that EtOH abuse and/or dependence in HIV-positive individuals may promote HIV-1-associated cognitive deficits by altering NMDA receptor function in the absence of microglial activation or neuroinflammation.
PMCID: PMC2773563  PMID: 19619615
Alcoholism; AIDS; Memory; Substance Abuse; HIV-Associated Dementia; Hippocampus
20.  Antinociceptive and Anti-Inflammatory Activities of Leaf Methanol Extract of Cotyledon orbiculata L. (Crassulaceae) 
Leaf methanol extract of C. orbiculata L. was investigated for antinociceptive and anti-inflammatory activities using acetic acid writhing and hot-plate tests and carrageenan-induced oedema test in mice and rats, respectively. C. orbiculata (100–400 mg/kg, i.p.) significantly inhibited acetic acid-induced writhing and significantly delayed the reaction time of mice to the hot-plate-induced thermal stimulation. Paracetamol (300 mg/kg, i.p.) significantly inhibited the acetic acid-induced writhing in mice. Morphine (10 mg/kg, i.p.) significantly delayed the reaction time of mice to the thermal stimulation produced with hot plate. Leaf methanol extract of C. orbiculata (50–400 mg/kg, i.p.) significantly attenuated the carrageenan-induced rat paw oedema. Indomethacin (10 mg/kg, p.o.) also significantly attenuated the carrageenan-induced rat paw oedema. The LD50 value obtained for the plant species was greater than 4000 mg/kg (p.o.). The data obtained indicate that C. orbiculata has antinociceptive and anti-inflammatory activities, justifying the folklore use of the plant species by traditional medicine practitioners in the treatment of painful and inflammatory conditions. The relatively high LD50 obtained shows that C. orbiculata may be safe in or nontoxic to mice.
PMCID: PMC3251909  PMID: 22235200
21.  Evaluation of Analgesic and Anti-Inflammatory Effects of Ethanol Extract of Ficus Iteophylla Leaves in Rodents 
This study was undertaken to investigate the leaf part of the plant for analgesic and anti-inflammatory. The ethanol extract of Ficus iteophylla leaves (100, 200, and 400mgkg−1, i.p) was evaluated for analgesic and anti-inflammatory activities. The analgesic effect was studied using acetic acid-induced abdominal constriction and hot plate test in mice, while the anti-inflammatory effect was investigated using carrageenan induced paw oedema in rats. The ethanol extract at 100mgkg−1, 200mgkg−1, and 400mgkg−1 significantly (P< 0.05) inhibited acetic acid induced writhes by 1.50 ± 0.43, 3.0 ± 0.82 and 1.0 ± 0.82 respectively. It also exhibited significantly (P< 0.05) anti-inflammatory by 0.11 ± 0.02, 0.11 ± 0.03, 0.08 ± 0.01 respectively. The preliminary phytochemical screening of the plant extract revealed the presence of flavonoids, steroids, tannins and saponins while the effect of flavonoids, steroids and tannins on analgesic and inflammatory has been reported. The intraperitoneal median lethal dose (LD50) value of the extract was found to be 3807.8 mgkg−1 body weights. The result obtained from this study shows that the extract of Ficus iteophylla contained phytochemical constituents with analgesic and anti-inflammatory activities, therefore the leaf part of the plant could be used in the management of pain and inflammatory conditions.
PMCID: PMC3218457  PMID: 22654227
Ficus iteophylla; analgesic; anti-inflammatory; intraperitoneal
22.  Antioxidant, total phenolic contents and antinociceptive potential of Teucrium stocksianum methanolic extract in different animal models 
Oxidative stress and analgesia are connected with different pathological conditions. The drug candidates from synthetic sources are associated with various side effects; therefore, researchers are giving priority to find novel, effective and safe phytomedicines. Teucrium species possesses antioxidant, analgesic, anti-inflammatory and hepatoprotective activities. The essential oils of Teucrium stocksianum have shown strong antinociceptive potential. Our current study is designed to embark total phenolic content (TPC), antioxidant and antinociceptive potential of the methanolic extract of Teucrium stocksianum (METS).
Phytochemical composition was determined by using standard methods. Free radical scavenging potential and TPC of METS were assessed by using 2, 2-diphenyl-1-picryl-hydrazyl (DPPH) and Folin-Ciocalteu Reagent (FCR) respectively. Antinociceptive potential was determined by acetic acid induced abdominal writhing, formalin induced paw licking and tail immersion tests. Different test dose 50, 100 and 150 mg/kg body weight of METS were administered intra peritonealy (i.p) to various groups of mice for the evaluation of analgesic potential.
Phytochemical screening confirmed the presence of flavonoids, tannins, saponins, anthraquinone, steroid, phlobatannin, terpenoid, glycoside and reducing sugars. METS was found safe at a dose of 1000 mg/kg body weight. A concentration dependent free radical scavenging effect was observed with methanolic aerial parts extract of Teucrium stocksianum (MAPETS) and methanolic roots extracts of Teucrium stocksianum (MRETS). MAPETS and MRETS have shown highest antioxidant activity 91.72% and 86.19% respectively at 100 μg/ml. MAPETS was found more rich (115.32 mg of GAE/g of dry material) in TPC as compared to MAPETS (105.41 mg of GAE/g). METS demonstrated a dose dependent antinociceptive potential in different pain models, like in acetic acid, formalin and tail immersion showing 83.103%, 80.872% and 67.58% at a dose of 150 mg/kg, similar to acetylsalicylic acid (74.79%, 82.87%, 100 mg/kg) and TramadolR (74%, 30 mg/kg) respectively.
Strong antioxidant potential and high TPCs are residing in the methanolic extract of T. stocksianum. METS showed analgesic potential in all models of nociception implying that both peripheral and central pathways of analgesia are involved. This might be due to the presence of various classes of phytochemicals in the plant extract.
PMCID: PMC4059475  PMID: 24893601
Teucrium stocksianum; Antioxidant; Total phenolic contents; Analgesic
23.  A preliminary report on oral glucose tolerance and antinociceptive activity tests conducted with methanol extract of Xanthosoma violaceum aerial parts 
Xanthosoma violaceum is commonly observed in fallow areas of Bangladesh but almost no scientific studies exist on this plant. Rural people consume the plant on a frequent basis. The objective of this study was to scientifically analyze the antinociceptive property of methanol extract of aerial parts of the plant along with antihyperglycemic activity.
Antihyperglycemic activity was measured by oral glucose tolerance test (OGTT). Antinociceptive activity was determined by observed decreases in abdominal constrictions in intraperitoneally administered acetic acid-induced pain model in mice.
Administration of methanol extract of aerial parts led to dose-dependent and significant reductions in blood glucose levels in glucose-loaded mice. At doses of 50, 100, 200 and 400 mg per kg body weight, the extract reduced blood sugar levels by 19.3, 23.2, 31.8, and 47.1%, respectively compared to control animals. By comparison, a standard antihyperglycemic drug, glibenclamide, when administered at a dose of 10 mg per kg body weight, reduced blood glucose level by 48.9%. In antinociceptive activity tests, the extract at the above four doses reduced the number of abdominal constrictions by 41.4, 44.8, 48.3, and 55.2%, respectively. A standard pain relieving (antinociceptive) drug, aspirin, reduced the number of writhings by 31.0 and 51.7%, respectively, when administered at doses of 200 and 400 mg per kg body weight.
To our knowledge, this is the first report on oral glucose tolerance and antinociceptive activity evaluation of aerial parts of the plant. Since the plant is widely available in Bangladesh, the aerial parts can be a readily available source for particularly the rural population for lowering blood sugar in diabetic patients and for alleviating pain.
PMCID: PMC4168192  PMID: 25216815
Antihyperglycemic; Xanthosoma violaceum; OGTT; Antinociceptive; Araceae
24.  Antinociceptive and Anti-Inflammatory Activities of Crude Methanolic Extract of Red Alga Bryothamnion triquetrum  
Marine Drugs  2012;10(9):1977-1992.
The marine environment is an extraordinary reservoir of bioactive natural products, many of which exhibit chemical and structural features not found in terrestrial natural products. In this regard, the aim of this study was to investigate the possible antinociceptive and anti-inflammatory activities of a crude methanolic extract of the red alga Bryothamnion triquetrum (BT-MeOH) in murine models. Groups of Swiss mice of both sexes (25–30 g) were used throughout the experiments. The potential antinociceptive of BT-MeOH was evaluated by means of the following tests: acetic acid-induced writhing, hot-plate test and glutamate- and formalin-induced nociception. The anti-inflammatory activity of BT-MeOH was investigated using the zymosan A-induced peritonitis test. The tests were conducted using 100 mg/kg (p.o.) BT-MeOH, 33.3 mg/kg (p.o.) dipyrone, 35.7 mg/kg (p.o.) indomethacin and 5.7 mg/kg (s.c.) morphine. The extract and all standard drugs were administered 40 min before the nociceptive/inflammatory stimulus. In the acetic acid-induced writhing test, BT-MeOH and dipyrone inhibited the nociceptive response by 55.9% (22.2 ± 2.0 writhings; p < 0.01) and 80.9% (9.6 ± 2.1 writhings; p < 0.01). In the hot-plate test, BT-MeOH did not increase the latency time of the animals in the time evaluated. In addition, BT-MeOH inhibited glutamate-induced nociception by 50.1%. While BT-MeOH did not inhibit the neurogenic phase in formalin-induced nociception, the inflammatory phase was inhibited by 53.1% (66.8 ± 14.2 s; p < 0.01). Indomethacin inhibited the inflammatory phase by 60.2% (56.8 ± 8.7 s; p < 0.01). In the zymosan-induced peritonitis test, BT-MeOH inhibited 55.6% (6.6 ± 0.2 × 106 leukocytes/mL; p < 0.01) of leukocyte migration, while indomethacin inhibited 78.1% (3.2 ± 0.1 × 106 leukocytes/mL; p < 0.01). Based on the results obtained in this study, we conclude that BT-MeOH has peripheral antinociceptive and anti-inflammatory activities. However, more studies need to be conducted to confirm these properties.
PMCID: PMC3475267  PMID: 23118715
Bryothamnion triquetrum; red algae; antinociceptive; anti-inflammatory
25.  Evaluation of Antinociceptive Activity of Aqueous Extract of Bark of Psidium Guajava in Albino Rats and Albino Mice 
Background: Psidium guajava is commonly known as guava. Psidium guajava is a medium sized tree belonging to the family Myrtaceae found throughout the tropics. All the parts of the plant, the leaves, followed by the fruits, bark and the roots are used in traditional medicine. The traditional uses of the plant are Antidiarrheal, Antimicrobial Activity, Antimalarial/Antiparasitic Activity, Antitussive and antihyperglycaemic. Leaves are used as Anti-inflammatory, Analgesic and Antinociceptive effects.
Aim: To evaluate the antinociceptive activity of aqueous extract of bark of Psidium guajava in albino rats with that of control and standard analgesic drugs aspirin and tramadol.
Materials and Methods: Mechanical (Tail clip method) and thermal (Tail flick method using Analgesiometer), 0.6% solution of acetic acid writhing models of nociception were used to evaluate the extract antinociceptive activity. Six groups of animals, each consists of 10 animals, first one as control, second and third as standard drugs, Aspirin and Tramadol, fourth, fifth and sixth groups as text received the extract (100, 200, and 400 mg/ kg) orally 60 min prior to subjection to the respective test.
Results: The results obtained demonstrated that aqueous extract of bark of Psidium guajava produced significant antinociceptive response in all the mechanical and thermal-induced nociception models.
Conclusion: AEPG antinociceptive activity involves activation of the peripheral and central mechanisms.
PMCID: PMC4225914  PMID: 25386462
Analgesiometer anti-nociceptive; Psidium guajava; Tail flick; Tail clip; Writhing

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