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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  Antinociceptive activity of acute and chronic administration of Murraya koenigii L. leaves in experimental animal models 
Indian Journal of Pharmacology  2012;44(1):15-19.
To evaluate the antinociceptive activity of acute and chronic administration of petroleum ether extract of Murraya koenigii L. leaves (PMK) and total alkaloids separated from petroleum ether extract of Murraya koenigii leaves (AMK) in mice.
Materials and Methods:
PMK was subjected for isolation of total alkaloid fraction AMK. The antinociceptive activity of PMK (100 and 300 mg/kg, p.o.) and AMK (100 and 300 mg/kg, p.o.), after acute and chronic administration (for 15 days), was evaluated using peripheral model like acetic acid-induced writhing method and central model like hot plate method and tail immersion method. Statistical analysis was carried out by one-way ANOVA followed by Dunnett's test.
In acute studies, PMK and AMK significantly and dose-dependently reduced the number of acetic acid-induced writhing, significantly increased the latency of paw licking in hot plate method, and significantly increased the basal reaction time in tail immersion method. With chronic administration of PMK and AMK, highest activity was observed on day 9 in acetic acid-induced writhing model. In hot plate and tail immersion method, chronic administration of PMK and AMK initially showed fluctuating responses but produced highest degree of antinociception on day 9 of the study.
The degree of antinociception produced by PMK and AMK at the end of 15 days study suggest that Murraya koenigii has potential to use as an analgesic.
PMCID: PMC3271532  PMID: 22345863
Antinociceptive; acetic acid-induced writhing; tail immersion method; Murraya koenigii
13.  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
14.  Analgesic activity of the ethanolic extract of Shorea robusta resin in experimental animals 
Indian Journal of Pharmacology  2012;44(4):493-499.
Shorea robusta (Sal), an important traditional Indian medicinal plant used in various ailments and rituals and the indigenous use of the resin of this plant as a medicament for treatment of various inflammatory conditions is well documented in literature. In the present study, ethanolic extract of S. robusta resin (SRE) was evaluated for its analgesic activity by making use of different central and peripheral pain models.
Materials and Methods:
The analgesic activity of SRE was assessed by employing different pain models such as, i) hot plate and tail flick tests for central analgesia, ii) acetic acid- induced writhing (peripheral analgesic model), iii) formalin-induced hind paw licking (both central and peripheral model), iv) carrageenan-induced hyperalgesia (peripheral analgesic model) and v) post-surgical pain (peripheral analgesic model).
The extract produced significant central and peripheral analgesic effects, as is evident from increase in reaction time in hot plate and tail flick tests, inhibition in writhing counts in acetic acid-induced writhing test, inhibition of licking time in formalin-induced hind paw licking, increased pain threshold in paw withdrawal latency in carrageenan-induced hyperalgesia and increased paw withdrawal threshold in post-surgical pain.
The results of the present study demonstrate marked antinociceptive effects of SRE.
PMCID: PMC3469954  PMID: 23087512
Carrageenan; hot plate; post-surgical pain; resin; Shorea robusta; tail flick
15.  Antinociception Effect and Mechanisms of Campanula Punctata Extract in the Mouse 
In the present study, the antinociceptive profiles of Campanula punctata extract were examined in ICR mice. The Campanula punctata contain a large dose of saponin. Campanula punctata extract administered orally (200 mg/kg) showed an antinociceptive effect as measured by the tail-flick and hot-plate tests. In addition, Campanula punctata extract attenuated the writhing numbers in the acetic acid-induced writhing test. Furthermore, the cumulative nociceptive response time for intrathecal (i.t.) injection of substance P (0.7 µg) was diminished by Campanula punctata extract. Intraperitoneal (i.p.) pretreatment with yohimbine (α2-adrenergic receptor antagonist) attenuated antinociceptive effect induced by Campanula punctata extract in the writhing test. However, naloxone (opioid receptor antagonist) or methysergide (5-HT serotonergic receptor antagonist) did not affect antinociception induced by Campanula punctata extract in the writhing test. Our results suggest that Campanula punctata extract shows an antinociceptive property in various pain models. Furthermore, this antinociceptive effect of Campanula punctata extract may be mediated by α2-adrenergic receptor, but not opioidergic and serotonergic receptors.
PMCID: PMC2997413  PMID: 21165326
Campanula punctata; Anti-nociception; Inflammatory pain; α2 adrenoceptor
16.  Effect of Agrimonia pilosa Ledeb Extract on the Antinociception and Mechanisms in Mouse 
In the present study, the antinociceptive profiles of Agrimonia pilosa Ledeb extract were examined in ICR mice. Agrimonia pilosa Ledeb extract administered orally (200 mg/kg) showed an antinociceptive effect as measured by the tail-flick and hot-plate tests. In addition, Agrimonia pilosa Ledeb extract attenuated the writhing numbers in the acetic acid-induced writhing test. Furthermore, the cumulative nociceptive response time for intrathecal (i.t.) injection of substance P (0.7 µg) was diminished by Agrimonia pilosa Ledeb extract. Intraperitoneal (i.p.) pretreatment with yohimbine (α2-adrenergic receptor antagonist) attenuated antinociceptive effect induced by Agrimonia pilosa Ledeb extract in the writhing test. However, naloxone (opioid receptor antagonist) or methysergide (5-HT serotonergic receptor antagonist) did not affect antinociception induced by Agrimonia pilosa Ledeb extract in the writhing test. Our results suggest that Agrimonia pilosa Ledeb extract shows an antinociceptive property in various pain models. Furthermore, this antinociceptive effect of Agrimonia pilosa Ledeb extract may be mediated by α2-adrenergic receptor, but not opioidergic and serotonergic receptors.
PMCID: PMC3339287  PMID: 22563257
Agrimonia pilosa Ledeb; Anti-nociception; Inflammatory pain; α2 adrenoceptor
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
18.  Antinociceptive and Anti-inflammatory Effects of Pistacia vera LeafExtract in Mice 
Pistacia vera L., a member of Anacardiaceae family, has been used for sedation and analgesia in traditional medicine. In this study, the antinociceptive and anti-inflammatory effects as well as acute toxicity of the aqueous and ethanolic extracts of P. vera leaves were investigated in mice. The antinociceptive activity was studied using hot plate and writhing tests. The effect of the extracts against acute inflammation was determined using xylene-induced ear edema and the activity of the extracts, against chronic inflammation, was assessed using the cotton pellet test. The LD50 values of the infusion and maceration extracts were 0.8 g/Kg and 0.79 g/Kg, respectively. The aqueous and ethanolic maceration extracts of the P. vera leaves at the doses of 0.4 g/Kg and 0.5 g/Kg (IP), respectively, showed antinociceptive effects. The pretreatment of naloxone (2 mg/Kg, SC) inhibited the activities of extracts in hot plate test, but naloxone at the same dose could not inhibit the antinociceptive activity in writhing test. The extracts also showed anti-inflammatory effects in acute and chronic anti-inflammatory tests. The ethanolic extract was as effective as diclofenac in both inflammatory tests. The aqueous and ethanolic extracts of P. vera leaves demonstrated central and peripheral antinociceptive activities dose-dependently and the central effect may be mediated by opioid system. The extracts also demonstrated anti-inflammatory effects against acute and chronic inflammation.
PMCID: PMC3813078  PMID: 24250418
Pistacia vera; Antinociceptive; Anti-inflammatory; Hot plate test; Writhing test; Xylene-induced ear edema; Cotton pellet test.
19.  Antinociceptive and Antipyretic Activities of Amaranthus Viridis Linn in Different Experimental Models 
Methanolic extract of whole plant of Amaranthus viridis L (MEAV), was screened for antinociceptive activity using acetic acid induced writhing test, hot plate test and tail immersion test in mice. In a similar way a screening exercise was carried out to determine the antipyretic potential of the extract using yeast induced pyrexia method in rats. Administration of the extracts was applied to both laboratory animals at the doses of 200 and 400 mg/kg body weight, respectively. The results of the statistical analysis showed that MEAV had significant (p<0.01) dose dependent antinociceptive and antipyretic properties at 200 and 400 mg/kg. Hence present investigation reveals the antinociceptive and antipyretic activities of methanolic extract of Amaranthus viridis.
PMCID: PMC3558137  PMID: 23408482
Analgesics; Animals; Dose response relationship; Methanol; Plant extracts
20.  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
21.  Pharmacological Proprieties of the Ethanol Extract of Muehlenbeckia platyclada (F. Muell.) Meisn. Leaves 
Antinociceptive and anti-inflammatory activities of the Muehlenbeckia platyclada leaves’ ethanol extract were investigated in animal models. The extract (p.o.) reduced the number of abdominal contortions induced by acetic acid by 21.57% (400 mg/kg). After intraplantar injection of formalin, a dose of 400 mg/kg (p.o.) inhibited the time spent paw licking in the first phase (26.43%), while the second phase was inhibited by 10.90 and 36.65% at the doses of 200 and 400 mg/kg, respectively. The extract (p.o.) increased the reaction time on a hot plate at a dose of 400 mg/kg (32.68 and 40.30%) after 60 and 90 minutes of treatment, respectively. The paw edema was reduced by extract (p.o.) at doses of 100 (15.46 and 16.67%), 200 (22.68 and 25.64%) and 400 mg/kg (29.50 and 37.33%) after 3 to 4 h of carrageenan application, respectively. Doses of 100, 200 and 400 mg/kg (p.o.), administered 4 h after the carrageenan injection, reduced the exudate volume (11.28, 21.54 and 45.13%), while leukocyte migration was reduced by 21.21 and 29.70% at the doses of 200 and 400 mg/kg, respectively. These results indicate that the ethanol extract from M. platyclada may constitute a potential target for the discovery of new molecules with antinociceptive and anti-inflammatory activities that can be explored for their therapeutic use.
PMCID: PMC2996782  PMID: 21152311
Muehlenbeckia platyclada; Polygonaceae; antinociceptive activity; anti-inflammatory activity
22.  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
23.  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
24.  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
25.  Antioxidant, Antinociceptive and Anti-inflammatory Activities of Ethanolic Extract of Leaves of Alocasia indica (Schott.) 
Extracts obtained from the leaves of various Alocasia species have been used in India as folk remedy for the treatment of various inflammatory ailments including rheumatism and bruise. The ethanolic extract of leaves of Alocasia indica Schott. was evaluated by using different in vitro antioxidant models of screening like scavenging of 1, 1-diphenyl-2-picryl hydrazyl (DPPH) radical, nitric oxide radical, superoxide anion radical, and hydroxyl radical. The antinociceptive activity was tested by acetic acid-induced writhing response, hot plate method, and tail flick method in albino rats. The anti-inflammatory potential of gels of ethanolic extract has been determined by using carrageenan-induced paw edema assay, formalin-induced paw edema assay, arachidonic acid-induced ear edema assay, and xylene-induced ear edema assay. The extract showed remarkable antioxidant activity in all models, comparable to the standard reference drug ascorbic acid. The ethanolic extract of Alocasia indica and its gels produced dose-dependent antinociceptive and anti-inflammatory activity, respectively. This finding suggests that ethanolic extract of A. indica possess potent antinociceptive and anti-inflammatory activity possibly due to its free radical scavenging properties.
PMCID: PMC3021687  PMID: 21264115
Alocasia indica Schott; antioxidant; antinociceptive; anti-inflammatory; ascorbic acid; diclofenac

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