Effects of Papaver rhoeas extract on the acquisition and expression of morphine-induced conditioned place preference in mice

In the present study, the effects of water-alcohol extract of Papaver rhoeas on the acquisition and expression of morphine-induced conditioned place preference (CPP) in mice were investigated. Subcutaneous (s.c.) administration of morphine (1, 10 and 20 mg/kg) produced place preference. On the other hand, intraperitoneal (i.p.) administration of the plant extract (25, 50 and 100 mg/kg) did not show any effect. Injection of extract (25, 50 and 100 mg/kg, i.p.) 30 min before the morphine administration decreased the acquisition of morphine CPP. Administration of the plant extract (25, 50 and 100 mg/kg, i.p.) 30 min before the test did not change the expression of morphine-induced CPP. It could be concluded that Papaver rhoeas reduced the acquisition but not the expression of morphine-induced conditioned place preference.     

Effects of Papaver rhoeas extract on the expression and development of morphine-dependence in mice

The problem of drug dependence still remains unresolved. In the present study, the effects of water-alcohol extract of Papaver rhoeas on the expression and acquisition of naloxone-induced jumping and diarrhea in morphine-dependent mice were investigated. Administration of three daily doses of morphine (12.5, 25 and 50 mg/kg) for three days in order to develop dependence to morphine caused a significant and dose-dependent increase in the number of jumping and diarrhea when the animals were challenged with naloxone (4 mg/kg). On the other hand, administration with the plant extract (25, 50 and 100 mg/kg) did not show any effect. Injection of extract (25, 50 and 100 mg/kg) 30 min before the naloxone administration in morphine-dependent mice decreased the number of jumping and diarrhea. Administration of extract (25, 50 and 100 mg/kg) 30 min before morphine injection increased the number of jumping but decreased the diarrhea. It could be concluded that the extract of Papaver rhoeas can ameliorate the withdrawal syndrome in morphine-dependent mice. Therefore, the extract might be useful to treatment of withdrawal signs in opioid addicts.     

Antagonistic effects of methanolic extract of Polygala telephioides on morphine responses in mice

The present study was undertaken to investigate the antagonistic effects of the methanolic extract of Polygala telephioides (PT) on morphine responses in mice. Single administration of PT tended to antagonize the morphine-induced analgesia in a hot-plate test. Moreover, PT (300 mg/kg, p.o.) improved the morphine-induced memory impairment in an elevated plus maze test. However, PT alone had no effect on behaviors in the open-field, hot-plate and elevated plus maze tests. We investigated the effects of PT on naloxone-induced jumping (as withdrawal sign) in morphine-dependent mice. To induce dependence, mice were twice daily treated with morphine (10-45 mg/kg, s.c.) for 5 days. Co-administrations of PT (10, 100 and 300 mg/kg, p.o.) during repeated morphine treatments significantly suppressed the naloxone (10 mg/kg, i.p.)-induced jumping. However, the naloxone-induced jumping was not affected by a single large administration of PT on the 5th day. The inhibitory effect of PT on the naloxone-induced jumping was due to the development of dependence rather than expression of withdrawal sign. Moreover, single administration of PT (30 mg/kg, p.o.) decreased the morphine levels in plasma. These results indicate that PT may be useful in facilitating narcotic detoxification.     

Effects of Shilajit on the development of tolerance to morphine in mice

Effects of concomitant administration of Processed Shilajit (PS, 0.1 and 1 mg/kg, i.p.), in Swiss mice were evaluated on the development of tolerance to morphine induced analgesia in the hot plate test. Chronic administration of morphine (10 mg/kg, i.p., b.i.d.) to mice over a duration of 10 days resulted in the development of tolerance to the analgesic effect of morphine. Concomitant administration of PS with morphine, from day 6 to day 10, resulted in a significant inhibition of the development of tolerance to morphine (10 mg/kg, i.p.) induced analgesia. Processed Shilajit per se, in the doses used, did not elicit any significant analgesia in mice; nor did the chronic concomitant administration of Processed Shilajit alter the morphine-induced analgesia. These findings with Processed Shilajit indicate its potential as a prospective modifier of analgesic tolerance to morphine.     

Antinociceptive effect of the essential oil from Cymbopogon citratus in mice

The essential oil (EO) from leaves of Cymbopogon citratus increased the reaction time to thermal stimuli both after oral (25 mg/kg) and intraperitoneal (25–100 mg/kg) administration. EO (50–200 mg/kg, p.o. or i.p.) strongly inhibited the acetic acid-induced writhings in mice. In the formalin test, EO (50 and 200 mg/kg, i.p.) inhibited preferentially the second phase of the response, causing inhibitions of 100 and 48% at 200 mg/kg, i.p. and 100 mg/kg, p.o., respectively. On the other hand, the opioid antagonist naloxone blocked the central antinociceptive effect of EO, suggesting that EO acts both at peripheral and central levels.     

Central Nervous System Activities of Hypericum origanifolium Extract via GABAergic and Opioidergic Mechanisms

Pharmacological effects of hydroalcoholic extract prepared from Hypericum origanifolium Willd. (Guttiferae) on behavioral parameters and pain perceptions of mice were investigated in this study. Depression, anxiety, spontaneous locomotor activity, and motor coordination parameters of mice were assessed by modified forced swimming, hole board, activity cage, and rota‐rod tests, respectively. In addition, antinociceptive effect was evaluated by performing hot‐plate, tail‐clip, and formalin tests. Reboxetine (20 mg/kg), diazepam (1 mg/kg), and morphine (10 mg/kg) were used as reference antidepressant, anxiolytic, and analgesic drugs, respectively. Phytochemical analyses exhibited that chlorogenic acid (2317.12 ppm) and rutin (2108.79 ppm) were the main phenolic compounds in the H. origanifolium extract. The extract (50, 100, and 250 mg/kg) induced significant antidepressant, anxiolytic, and antinociceptive activities following the acute administrations. Anxiolytic effect was antagonized by flumazenil (a benzodiazepine receptor antagonist, 2.5 mg/kg, i.p.) pre‐treatment, which indicated the participation of GABA(A)‐benzodiazepine receptor complex in the activity. Moreover, centrally and peripherally mediated antinociception reversed by naloxone (a non‐selective opioid receptor antagonist, 5 mg/kg, i.p.) pre‐treatment, indicating the involvement of opioid system in the pharmacological action. These findings are the first to indicate the pharmacological effects of the H. origanifolium extract on the emotional state and pain perceptions of mice. Copyright © 2012 John Wiley & Sons, Ltd.     

Acute and chronic toxicity of a lyophilised aqueous extract of Tanacetum vulgare leaves in rodents

AIM OF THE STUDY: The present investigation was carried out to evaluate the safety of an aqueous extract of tansy (Tanacetum vulgare L.) leaves by determining its potential toxicity after acute and chronic administration in rodents. MATERIALS AND METHODS: For the acute study, a lyophilized aqueous extract of tansy leaves was administered to mice in single doses of 0-13 g/kg given by gavage as well as intraperitoneal doses of 0-4.5 g/kg. General behavior adverse effects and mortality were determined for up to 14 days. In the chronic dose study, the extract was administered orally at doses of 0, 100, 300 and 600 mg/kg daily for 90 days to rats. Biochemical and hematological parameters were determined after 30 and 60 days, and then at the end of 90 days of daily administration. RESULTS: In the acute study in mice, the crude aqueous extract of tansy leaves caused dose-dependent general behavior adverse effects and mortality. The no-observed adverse effect levels (NOAEL) of the tansy extract were 7.0 g/kg and 1.0 g/kg, and the lowest-observed adverse effect levels (LOAEL) were 9.0 g/kg and 1.5 g/kg, when given by the oral and intraperitoneal routes, respectively. Mortality increased with increasing doses, with LD(50) of 9.9 g/kg and 2.8 g/kg for the oral and intraperitonal modes of administration, respectively. In the chronic study in rats, daily oral administration of the crude aqueous extract of tansy leaves for up to 90 days did not result in death or significant changes in the biological (except for hypoglycemia) and hematological parameters. CONCLUSIONS: Because of the relatively high NOAEL values in the acute study in mice, and lack of significant effect on biological and hematological parameters in rats after 90 days of daily doses, the tansy extract does not appear to have significant toxicity. In view of the dose of tansy consumed in traditional medicine, there is a wide margin of safety for the therapeutic use of the aqueous extract of Tanacetum vulgare leaves.     

Acute and chronic toxicological studies of Ajuga iva in experimental animals

Ajuga iva (L.) Schreber (AI), is widely used in the Moroccan pharmacopoeia as a panacea (cure-all), and specifically for gastrointestinal disorders and diabetes, and as an anthelmintic. No toxicological investigations have been carried out on this plant. We have previously observed that single oral doses (2-14 g/kg) of a lyophilised aqueous extract of AI (AI-extract) in mice or daily oral administration of 10 mg/kg of AI-extract in rats for 2 weeks did not result in any adverse effects. We have now evaluated AI-extract for its behavioural and pharmaco-toxicological effects after acute and chronic administration by the oral and intraperitoneal routes in rats and mice. No toxicity was observed in mice after single oral doses of as high as 14 g/kg of the AI-extract. However, single intraperitoneal injections of the AI-extract (1500-5500 mg/kg BW) produced a dose-dependent increase in adverse effects in the general behaviour and the mortality rate; the LD50 of acute intraperitoneal dose was 3.6 g/kg. In chronic toxicological studies in rats, the AI-extract (administered orally at daily doses of 100, 300 and 600 mg/kg for 3 months), did not cause any changes in haematological and biochemical parameters, with the exception of a transient rise in platelet counts and a short-term decrease in serum glucose levels. Histopathological examination of the brain, liver and the kidneys at the end of the study (3 months) showed normal architecture suggesting no morphological disturbances.     

Effects of ginseng total saponin on morphine-induced hyperactivity and conditioned place preference in mice

A single or repeated administration of morphine in mice produced hyperactivity, conditioned place preference (CPP) and postsynaptic dopamine (DA) receptor supersensitivity. The hyperactivity induced by morphine was evidenced by measuring the enhanced ambulatory activity using a tilting-type ambulometer. CPP effects were evaluated assessing the increased time spent by the mice to morphine and the inhibition of CPP by the decreased time spent by the mice in the white compartment. Postsynaptic DA receptor supersensitivity in mice displaying a morphine-induced CPP was evidenced by the enhanced response in ambulatory activity to the DA agonist, apomorphine (2 mg/kg, s.c.). The intraperitoneal injection of ginseng total saponin (GTS) from the root of Panax ginseng C.A. Meyer (Araliaceae), prior to and during the morphine treatment in mice inhibited morphine-induced hyperactivity and CPP. GTS inhibited the development of postsynaptic DA receptor supersensitivity. A single dose administration of GTS also inhibited apomorphine-induced climbing behavior, showing the antidopaminergic action of GTS at the postsynaptic DA receptor. These results suggest that the development of morphine-induced CPP may be associated with the enhanced DA receptor sensitivity and that GTS inhibition of the morphine-induced hyperactivity and CPP may be closely related with the inhibition of dopaminergic activation induced by morphine.     

Ginger (Zingiber officinale Roscoe) prevents the development of morphine analgesic tolerance and physical dependence in rats

Ethnopharmacological relevance

Ginger (Zingiber officinale Roscoe), a well-known spice plant, has been used traditionally in the treatment of a wide variety of ailments such as opiates withdrawal-induced disorders. However, its influences on opioid tolerance and dependence have not yet been clarified.

Materials and methods

Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10 mg/kg, i.p.) twice daily for 8 days. To develop morphine dependence, rats given escalating doses of chronic morphine. To determine the effect of ginger on the development of morphine tolerance and dependence, different doses of ginger were administrated before morphine. The tail-flick and naloxone precipitation tests were used to assess the degree of tolerance and dependence, respectively.

Results

Our results showed that chronic morphine-injected rats displayed tolerance to the analgesic effect of morphine as well as morphine dependence. Ginger (50 and 100 mg/kg) completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with 100 and 150 mg/kg attenuated almost all of the naloxone-induced withdrawal sings which include weight lose, abdominal contraction, diarrhea, petosis, teeth chattering, and jumping. In addition, morphine-induced L-type calcium channel over-expression in spinal cord was reversed by 100 mg/kg ginger.

Conclusion

The data indicate that ginger extract has a potential anti-tolerant/anti-dependence property against chronic usage of morphine.     

Effect of crocin on the morphine‐induced antinociception in the formalin test in rats

In this study, the effects of intraperitoneal (i.p.) injection of crocin in the absence and presence of subcutaneous (s.c.) injections of morphine and naloxone were investigated on the formalin test in rats. The formalin test was induced by intra‐plantar (i.pl.) injection of formalin (50 μL, 1%), and the time spent licking and biting of the injected paw was measured for 1 h. Formalin induced a marked biphasic (first phase: 0–5 min and second phase: 15–45 min) pain response. Morphine (1 mg/kg, s.c.) significantly (p < 0.05) suppressed both phases of pain. Naloxone (2 mg/kg, s.c.) alone did not change the intensity of pain, but pretreatment with naloxone (2 mg/kg) significantly (p < 0.05) prevented morphine (1 mg/kg)‐induced antinociception. Crocin at doses of 50, 100 and 200 mg/kg significantly (p < 0.05) attenuated pain. Crocin (100 mg/kg, i.p.) significantly (p < 0.05) increased the morphine (1 mg/kg, s.c.)‐induced antinociception. Naloxone (2 mg/kg) did not reverse the suppressive effect of crocin (100 mg/kg) on pain. Crocin at a dose of 400 mg/kg significantly (p < 0.05) suppressed locomotor activities. These findings indicate that morphine through a naloxone‐sensitive mechanism produced analgesia. Crocin produced a dose‐dependent antinociceptive effect. In addition, crocin increased morphine‐induced antinociception, but naloxone did not change the antinociceptive effect of crocin. Copyright © 2009 John Wiley & Sons, Ltd.     

Evaluation of the antinflammatory and analgesic activity of Sideritis canariensis var. pannosa in mice

The problem of drug dependence still remains unresolved. In the present study the effects of an essential oil of Pimpinella anisum (Umbeliferae) on the expression and acquisition of conditioned place preference (CPP) induced by morphine in mice were investigated. Subcutaneous (s.c.) injections of morphine (2-5 mg/kg) produced place preference in a dose-dependent manner. Furthermore, intraperitoneal (i.p.) injection of the essential oil of P. anisum (0.125-0.5 ml/kg) induced conditioned place aversion (CPA). The mice which have received the essential oil of the P. anisum (0.125-0.5 ml/kg, i.p.) as well as the oil with morphine (5 mg/kg, s.c.) reduced the morphine effect. Administration of the essential oil of P. anisum (0.125-0.5 ml/kg, i.p.) on the test day did not show any effect on morphine action. It appeared that pre-administration with bicuculline (GABA(A) receptor antagonist) (1.5 mg/kg, i.p., 20 min before essential oil) diminished the effect of the essential oil of the P. anisum on morphine which induced CPP, but this result was not found for the GABA(B) receptor antagonist, CGP35348 (200 and 400 mg/kg, i.p., 10 min before essential oil). In conclusion, it appeared that the essential oil of the P. anisum may reduce the morphine effects via a GABAergic mechanism.     

Effects of glycowithanolides from Withania somnifera on morphine-induced inhibition of intestinal motility and tolerance to analgesia in mice

Effects of glycowithanolides (Ws, 10–150 mg/kg, i.p.), consisting of sitoindosides VII-X, in combination with withaferin-A, from Withania somnifera, in Swiss mice were evaluated on (i) morphine-induced inhibition of gastrointestinal tract (GIT) transit and (ii) development of tolerance to morphine-induced analgesia. Pretreatment with Ws significantly reversed the morphine (5 mg/kg, s.c.)-induced inhibition of GIT transit at all doses. Ws (100 mg/kg, i.p., o.d., for 10 days) significantly inhibited the development of tolerance to morphine-induced analgesia. Ws per se did not influence the intestinal motility nor did it produce any perceptible analgesic effect. The present and earlier findings with Ws suggest its potential in alleviating the adverse effects of morphine and the attendant immunodepression.     

Thymoquinone Inhibition of Acquisition and Expression of Alcohol‐Induced Behavioral Sensitization

Repeated low doses of alcohol have been shown to progressively enhance locomotor activity in mice, and this phenomenon is designated as behavioral sensitization. Thymoquinone, a major active component of Nigella sativa oil has been investigated in a number of studies for its neuroprotective effects against a variety of ailments. This study was conducted to explore the therapeutic potential of thymoquinone on the acquisition and expression of alcohol‐induced behavioral sensitization. Mice treated with alcohol (2.2 g/kg/day) or saline for 13 days and subsequently challenged with an acute alcohol dose (2.2 g/kg) 5 days later were orally administered acute doses of thymoquinone (10, 20 and 30 mg/kg). Thymoquinone subacute treatment with all doses throughout alcohol exposure significantly inhibited both the development and expression phases of alcohol behavioral sensitization in a dose‐dependent manner. However, acute treatment with thymoquinone (30 mg/kg) only reversed the expression phase of sensitization. These findings are explained in terms of the known GABA promoting action of thymoquinone in relation to the motive circuit within the limbic component of the basal ganglia. It is concluded that thymoquinone may be a potential therapeutic option for the treatment and prevention of alcohol induced behavioral sensitization. Copyright © 2015 John Wiley & Sons, Ltd.     

Chronic intraperitoneal and oral treatments with hesperidin induce central nervous system effects in mice

Hesperidin (HN) is a flavanone glycoside abundantly found in citrus fruits. This flavonoid mediated central nervous system activity following intraperitoneal (i.p.) acute treatment. The responses of mice after the chronic i.p. (4 and 30 mg/kg/day) or the oral intake administration of this drug (20, 50 and 100 mg/kg/day) were studied by using the holeboard, the plus‐maze and the locomotor activity tests. Hesperidin, chronically administered by the i.p. route, exerted a decrease in the locomotor and exploratory activities, thus evidencing a depressant activity. In turn, the chronic oral intake of this flavonoid induced anxiolytic‐like effects. These varied responses could be attributed to the different routes of administration that could lead to the production of diverse active metabolites. Copyright © 2011 John Wiley & Sons, Ltd.     

Behavioral and pharmaco-toxicological study of Papaver rhoeas L. in mice

A lyophilized ethanolic aqueous extract of Papaver rhoeas petals was evaluated for its behavioral and pharmaco-toxicological effects in mice and its chemical composition was studied using thin layer chromatography (TLC). In this study, chemical analysis by TLC showed that the petals contain some anthocyanins, whereas no alkaloids were detected. The toxicological effect of alcoholic and aqueous plant extract administered intraperitoneally was determined in mice. The toxicological results obtained indicated that 2000 mg/kg is LD10 and 4000 mg/kg is LD50. Behavioral and pharmacological studies of ethanolic and aqueous extract showed that the plant extract reduced locomotory, exploratory and postural behavior of mice. This was evaluated through two specific behavioral tests; a non-familiar environment test (the Staircase test) and a familiar environment test (Free exploratory test). These behavioral and pharmacological effects are more pronounced when the solvent used for extraction is 10% ethanol and is not antagonized by benzodiazepines, opioids, dopaminergic and cholinergic compounds (flumazenil, naloxone, sulpuride and atropine). The plant extract did not induce sleep in mice after treatment with an infrahypnotic dose of pentobarbital. This finding shows that the plant extract has a sedative effect at a 400 mg/kg dosage.     

Antinociceptive activity of the methanolic extract of Kaempferia galanga Linn. in experimental animals

Kaempferia galanga Linn. (Zingiberaceae) presents many chemical constituents of the volatile oil extracted from the rhizome. The rhizome of Kaempferia galanga is used by people in many regions for relieving toothache, abdominal pain, muscular swelling and rheumatism. In this study we investigated the antinociceptive activity in mice and rats using acetic acid-induced writhing, formalin, hot plate and tail-flick tests. The extract at test doses of 50, 100 and 200 mg/kg, p.o. clearly demonstrated antinociceptive activity in all tests. This activity was dose- and time-dependent. The extract administered at 200 mg/kg, p.o. had a stronger antinociceptive effect than aspirin (100 mg/kg, p.o.) but less than morphine (5 mg/kg, s.c.). Naloxone (2 mg/kg, i.p.) abolished the antinociceptive action of both morphine (5 mg/kg, s.c.) and the extract (200 mg/kg, p.o.) in a similar manner. In conclusion, the methanol extract of Kaempferia galanga markedly demonstrated the antinociceptive action in experimental animals. The antinociceptive mechanisms appear to be both peripherally and centrally mediated actions and the opioid receptors are probably involved. Therefore, our studies support the use in traditional medicine of Kaempferia galanga against pain caused by various disorders.     

Effect of Salvia leriifolia leaf extract on morphine dependence in mice

The effect of Salvia leriifolia leaf extract on morphine dependence was investigated in mice. Dependence was induced using subcutaneous injections of morphine daily for 3 days. On day 4, morphine was injected 2 h before the intraperitoneal injection of naloxone. The number of episodes of jumping during the 30 min after injection of naloxone was considered as the intensity of the withdrawal syndrome. The ethanol extract reduced the number of jumping episodes dose-dependently. The extract at a dose of 500 mg/kg was as effective as a dose of 5 mg/kg of diazepam in reducing the number of jumping episodes. The effect of the extract was blocked by aminophylline (20 mg/kg), a non-selective antagonist of adenosine receptors. It is concluded that the ethanol extract of S. leriifolia leaves could diminish the withdrawal syndrome of morphine.     

Acute effects of guarana (Paullinia cupana Mart.) on mouse behaviour in forced swimming and open field tests

Guarana, a herbal extract from the seeds of Paullinia cupana Mart. has been evaluated in comparison with caffeine on mouse behaviour in forced swimming and open field tests. Guarana (25 and 50 mg/kg, p.o.) and caffeine (10 and 20 mg/kg, p.o.) each significantly reduced the duration of immobility in the forced swimming test suggesting an antidepressant-like effect in mice. At these doses, neither substance affected ambulation in the open field test. However, a high dose of guarana (100 mg/kg) and caffeine (30 mg/kg) significantly enhanced the locomotor activity in the open field test. Caffeine, but not guarana, could effectively block an adenosine agonist, cyclopentyl adenosine (CPA)-induced increase in swimming immobility suggesting that mechanism(s) other than the adenosinergic mechanism are involved in the antidepressant-like activity of guarana.     

Pharmacological evaluation of the folklore of Sphenostylis stenocarpa

The pharmacological effects of an aqueous extract of Sphenostylis stenocarpa seed were investigated in albino mice. Acute toxicity testing indicated the LD50 to be 570 mg/kg, i.p. The extract significantly potentiated pentobarbitone-induced sleeping time. Increasing the dose of the extract correspondingly increased the sleeping time up to a dose of 60 mg/kg i.p. The extract did not protect mice from convulsions and death resulting from the administration of strychnine (2 mg/kg, i.p.) or leptazol (100 mg/kg, s.c.).