Antinociceptive Effect of the Hydroalcoholic Extract of Bauhinia splendens Stems in Mice

The analgesic effect of the hydroalcoholic extract of the stems of Bauhinia splendens (Leguminosae) has been investigated in chemical and thermal models of nociception in mice. The hydroalcoholic extract of B. splendens, 3–60 mg kg^? intraperitoneally or 50–400 mg kg^? orally, caused dose-related, and long-lasting (up to 3 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 3.2 and 177.6 mg kg^? and maximum inhibition of 95 ± 2 and 61 ± 6%, respectively. In the formalin test, the extract given intraperitoneally (1.60 mg kg^?) or orally (50–400 mg kg^?) caused graded inhibition of both phases of formalin-induced pain, being about 5- to 6-fold more potent in attenuating the second phase of pain. The calculated mean ID50 values for the first and the second phases were 11.5 and 2.5 mg kg^?, respectively, for intraperitoneal administration and > 200 and 70 mg kg^?, respectively, for oral administration; the percentages of maximum inhibition for the first and the second phases were 68 ± 6 and 99 ± 1, respectively, for intraperitoneal administration and 37 ± 6 and 69 ± 9, respectively, for oral administration. However, at the same doses the extract did not significantly affect the oedematogenic response induced by formalin. The treatment of animals with naloxone (5 mg kg^?, i.p.) completely reversed the analgesic effect caused by morphine (5 mg kg^?, s.c), but had no effect against the antinociceptive effect of the hydroalcoholic extract of B. splendens (60 mg kg^?, i.p.) when assessed against acetic acid-induced abdominal constrictions. Furthermore, the extract, in contrast with morphine, had no analgesic effect in the hot-plate test. These data show that the hydroalcoholic extract of B. splendens has significant analgesic action when assessed against several models of pain. The mechanism underlying its analgesic effect still remains unknown, but seems to be unrelated to interaction with opioid systems.     

Potent Antinociceptive Activity of a Hydroalcoholic Extract of Phyllanthus corcovadensis

Abstract— This study analyses the analgesic effect of a hydroalcoholic extract (HE) from Phyllanthus corcovadensis in several models of pain in mice. HE (3–60 mg kg^?1, i.p.) or (100–500 mg kg^?1, p.o.) caused a graded and potent analgesic effect against the abdominal constriction response caused by acetic acid and acetylcholine with an ID50 of about 3 and 100 mg kg^?1, respectively. In the tail-flick model HE (up to 500 mg kg^?1, p.o.) was without effect, while morphine (1–10 mg kg^?1, s.c.) caused a graded increase in pain latency (ID50, 3 mg kg^?1). HE (1–300 mg kg^?1) given both intraperitoneally and orally caused a potent and graded inhibition of the second phase of formalin-induced persistent pain in mice with an ID50 of 1 and 80 mg kg^?1, respectively. In contrast, morphine (1–5 mg kg^?1, s.c.) inhibited both phases of formalin-induced pain with an ID50 of 2·5 mg kg^?1. Indomethacin (1–10 mg kg^?1, i.p.) only inhibited the second phase of formalin-induced pain with an ID50 of about 3 mg kg^?1. The analgesic effect of indomethacin, but not that caused by morphine and HE was accompanied by a graded inhibition of formalin-induced mouse paw oedema. In addition, HE up to 1 g kg^?1 failed to prevent carrageenan- and dextran-induced rat hindpaw oedema. It is concluded that HE exhibits a potent antinociceptive profile, either when given intraperitoneally or orally. The mechanisms that underly its analgesic effect are unclear at present, but appear to be unrelated to inhibition of synthesis of arachidonic acid via cyclo-oxygenase or to activation of opioid receptors.     

Chemical and Pharmacological Studies of Phyllanthus caroliniensis in Mice

The aim of this study was to isolate and characterize the constituents of the hydroalcoholic extract (HE) of the leaves, stems and roots from P. caroliniensis, and also to evaluate the preliminary antinociceptive action of the HE and purified compounds in mice. Phytosterols, quercetin, gallic acid ethyl ester and geraniin were identified in P. caroliniensis on the basis of ¹H and ¹³C NMR spectral data and by mixed co-TLC and co-HPLC injection with authentic samples. The HE of P. caroliniensis (10-100 mg kg^?1, i.p.) inhibited, in a dose-related manner, acetic acid-induced abdominal constrictions in mice, with a mean ID50 value of 23.7 mg kg^?1. In the formalin test, the HE given intraperitoneally (1-30 mg kg^?1) or orally (25-600 mg kg^?1) caused graded inhibitions of both the neurogenic (first phase) and the inflammatory response (late phase) of formalin-induced licking. The HE was 54-fold more effective in inhibiting the late phase than it was in inhibiting the first phase of the formalin test, with mean ID50 values of 3.6 and 196.4 mg kg^?1, respectively. The HE failed, however, to affect the oedematogenic response associated with the late phase of formalin-induced pain. In addition, the reference drug, aspirin, given intraperitoneally (1-100 mg kg^?1) or orally (100-600 mg kg^?1), caused significant inhibition of the late but not the first phase of the formalin test. Pharmacological analysis also revealed that quercetin, gallic acid ethyl ester and a semi-purified fraction of flavonoids (1-100 mg kg^?1, i.p.) exhibited graded and significant antinociception against acetic acid-induced abdominal constriction. The mean ID50 values (mg kg^?1) for these effects were: 18.8, 34.7 and 5.3, respectively. It is concluded that quercetin, gallic acid ethyl ester and some as yet unidentified flavonoids might account for the antinociceptive action reported for the HE of P. caroliniensis.     

Analgesic Effects of Callus Culture Extracts from Selected Species of Phyllanthus in Mice

Abstract— The aim of this study was to evaluate the analgesic effect of the methanolic extract from callus culture of Phyllanthus tenellus, P. corcovadensis and P. niruri in several models of pain in mice. The extracts (medium containing 2,4-dichlorophenoxyacetic acid) of P. corcovadensis, P. niruri and P. tenellus (3–90 mg kg^?1, i.p.) caused graded inhibition of abdominal constrictions induced by acetic acid (0·6%), with ID50 (i.e. dose that reduced response of control by 50%) values of about 30, 19 and >30 mg kg^?1, respectively. The extract of callus of Phyllanthus obtained in indole-3-butyric acid and indole-3-acetic acid media (3–90 mg kg^?1, i.p.) caused a similar analgesic effect. In the formalin test, the extract of P. tenellus obtained in indole butyric acid medium (3–100 mg kg^?1, i.p.) inhibited only the second phase of formalin-induced pain with an ID50 value of about 100 mg kg^?1. Both the indole acetic acid and indole butyric acid methanolic extracts of P. tenellus and P. corcovadensis (10–100 mg kg^?1, i.p.) dose-dependently inhibited both phases of formalin-induced pain (ID50 values for the second phase were approx. 100 and 52 mg kg^?1, respectively). However, the extract of callus from Phyllanthus failed to affect formalin-induced paw oedema, as well as the response to radiant heat in the tail-flick test. In addition, the analgesic effect of morphine, but not the analgesic effects caused by Phyllanthus callus extract, was fully antagonized by naloxone. Preliminary phytochemical analysis revealed the presence of several compounds having no apparent relationship with alkaloids or flavonoids but showing the presence of phenols. These results indicate that, similar to previous reported data from the extract of P. corcovadensis, the methanolic extracts of callus culture of P. niruri, P. corcovadensis and P. tenellus exhibit potent analgesic properties against neurogenic and inflammatory pain that seem to be unrelated to the activation of opioid mechanisms.     

Central and Cardiovascular Effects of the Alcoholic Extract of the Leaves of Carica papaya

Abstract

The central effects of an alcoholic extract of Carica papaya leaf were investigated in male rats. The extract (≥ 10 mg kg^?1, i.p.) induced a dose-dependent sedative effect. The extract (≥ 5 mg kg, i.p.) also induced central muscle relaxation. The behavioral effects of the extract were associated with an initial desynchronization of the electroencephalogram (EEG) and an increased activity of the electromyogram (EMG). This was followed by a deactivating pattern in the optic chiasma while the EMG activity was diminished. The extract at doses ≥50 mg kg^?1 (i.p.) completely protected the rats against pentylenetetrazol-induced seizures, while doses of 5 mg kg^?1 (i.p.) gave 50% protection. The extract at doses of 100 and 200 mg kg^?1 (i.p.) also gave 100% protection against maximal electroshock-induced convulsions.     

Differential effects of adrenaline and noradrenaline on the hepatic expression of immediate early genes in mice

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Further Studies on the Antinociceptive Action of the Hydroalcoholic Extracts from Plants of the Genus,Phyllanthus

The analgesic effects of the hydroalcoholic extracts (HEs) of Phyllanthus urinaria, P. tenellus, P. niruri and P. sellowianus have been investigated in several models of nociception in mice. The HE of four species of Phyllanthus (1–90 mg kg^?1, i.p.) caused a dose-related inhibition of acetic acid-induced abdominal constriction in mice with ID50 values of 5·4, 8·5, 18·2 and 53·0 mg kg^?1 and maximal inhibition (%) of 80 ± 2, 67 ± 8, 63 ± 8 and 50 ± 4 for P. urinaria, P. niruri, P. tenellus and P. sellowianus, respectively. In the formalin test, the HE of all Phyllanthus species (0·3–60 mg kg^?1, i.p.) caused graded inhibition of both phases of formalin-induced pain, but they were, however, more potent in relation to the second phase of the pain. The ID50 values (mg kg^?1) for the first phase were 20·0, 23·0, > 60, and > 60 for the P. urinaria, P. tenellus, P. niruri and P. sellowianus, respectively, and percentages of maximal inhibition were 63 ± 2, 70 ± 2,41 ± 3 and 46 ± 4, respectively. The ID50 values (mg kg^?1) for the second phase were 0·71, 4·87, 7·7, 33·0, with maximal inhibition (%) of 91 ± 6, 97 ± 3, 97 ± 3 and 92 ± 6, respectively. Given orally, the HEs of species of Phyllanthus caused a significant antinociceptive profile, but they were about one-tenth to one-twentieth as potent when given intraperitoneally. However, the HEs of Phyllanthus failed to affect formalin-induced paw oedema and did not interfere with the performance of animals in the rota-rod test. Naloxone (5 mg kg^?1) completely reversed the analgesic effect caused by morphine (5 mg kg^?1), but had no effect against the analgesic effect of the HE of Phyllanthus. Furthermore, the HEs of Phyllanthus in contrast to morphine had no analgesic effect in either tail-flick or hot-plate tests. Taken together, these findings confirm and extend our previous results and indicate that all studied HE of species of plant belonging to the genus Phyllanthus exhibit potent and long-lasting antinociceptive activity in several models of pain, including the neurogenic algesic component of the formalin test. The mechanism underlying their analgesic profile is presently unknown.     

Natural Products: Anti-hyperalgesic Effect of an Ethanolic Extract of Propolis in Mice and Rats

Propolis, or bee glue, which contains a complex mixture of secondary metabolites, has long been used in many countries for the management of several diseases. The purpose of this study was to evaluate, by means of several pharmacological models, the anti-hyperalgesic effect of propolis collected in the south of Brazil. The abdominal constrictions induced in mice by intraperitoneal injection of acetic acid (0.6%), kaolin (50 mg kg^?1) or zymosan (40 mg kg^?1) were inhibited to different extents by an extract of propolis (1–60 mg kg^?1) administered intraperitoneally 30 min earlier; mean ID50 (concentrations resulting in 50% inhibition) values were 2.7, 10.8 and 10.7 mg kg^?1, respectively, and maximum inhibition was 58 ± 5, 57 ± 10 and 51 ± 5%, respectively. Given orally (25–200 mg kg^?1, 1 h previously) propolis also inhibited the abdominal constrictions induced by acetic acid (maximum inhibition 43 ±5%). When injected intraperitoneally (3–60 mg kg^?1, 30 min previously), propolis attenuated both the neurogenic (first phase) and inflammatory (second phase) pain responses and paw oedema caused by intraplantar injection of formalin (2.5%); maximum inhibition was 32 ±5, 43 ±6 and 19 ±2%, respectively. Oral administration of propolis (25–200 mg kg^?1, 1 h previously) inhibited both phases and reduced the oedema formation associated with the second phase of the formalin test (maximum inhibition 22±5, 33 ±6 and 26±3%) and extract of propolis (3–30 mg kg^?1 i.p. or 25–100 mg kg^?1 p.o., respectively 30 min and 1 h previously) significantly inhibited capsaicin-induced pain with maximum inhibition of 39±8 and 41 ±8%, respectively. When assessed in the Randall–Sellito test of pain, the extract of propolis (3–30 mg kg^?1, i.p., 30 min previously) significantly reversed the hyperalgesia induced by intraplantar injection of bradykinin (3 nmol per paw) in rats (P < 0.01). In contrast with morphine the extract of propolis (. 100 mg kg^?1, 30 min previously) was ineffective when assessed in the tail-flick and hot-plate thermal assays. Naloxone (5 mg kg^?1 i.p.) reversed (P < 0.01) the effect of morphine (5 mg kg^?1 s.c.) by 70 and 94% respectively in the first and second phases of the formalin test, but did not interfere with the analgesic effect of propolis (10 mg kg^?1 i.p., 30 min previously). These results show that ethanolic extract of propolis, given systemically, has significant anti-hyperalgesic action when assessed in chemical, but not thermal, models of nociception in mice and rats. Its analgesic action seems to be unrelated to release or activation of the opioid system.     

The mechanism of the hypothermic effect of amantadine in rats and mice

Amantadine (25–100 mg kg^?1, i.p.) given to rats at an ambient temperature of 4°, or mice at 21°, caused a marked fall in rectal temperature. Prior administration of pimozide (1–2 mg kg^?1, s.c.) did not block hypothermia due to amantadine in rats or mice; in contrast, hypothermia due to apomorphine (2 mg kg^?1, i.p.) and piribedil (10–40 mg kg^?1, i.p.) in rats was blocked by pimozide pretreatment. Amphetamine (5 mg kg^?1, i.p.) given 2 h after reserpine (2 mg kg^?1, i.p.) caused a reversal of the hypothermic effect of reserpine in mice, but a reversal was not obtained with amantadine (50 mg kg^?1, i.p.). Direct injection of amantadine (4–8 mg kg^?1) into the cerebral ventricles (i.c.v.) of mice caused marked hypothermia which was not blocked by pimozide, but intravenous injection of the same dose of amantadine did not cause hypothermia. Rimantadine, a congener of amantadine but without anti-parkinsonian activity, also caused pimozide insensitive hypothermia in mice at doses of 50 mg kg^?1, intraperitoneally or 2–4 mg kg^?1, intracerebroventricularly. The main conclusion drawn from these results is that in causing hypothermia amantadine acts in the cns but not on dopamine receptors.     

Behavioural Profile of Two Potential Antidepressant Pyridazine Derivatives Including Arylpiperazinyl Moieties in Their Structure,in Mice

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PCI3), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125·8 and 429-6mg kg^?1. Only at intraperitoneal doses of 100mg kg^?1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5–20 mg kg^?1, i.p.) reduced the duration of immobility of mice in the forced swimming test, antagonized reserpine (2–5 mg kg^?1, i.p.)-induced ptosis, and potentiated reserpine (2–5 mg kg^?1, i.p.)-induced hypothermia. PC4 and PCI3 (20mg kg^?1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg^?1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg^?1, s.c). At 200 mg kg^?1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg^?1, s.c), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg^?1, i.p.) in mice pretreated with pargyline (100mg kg^?1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg^?1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg^?1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (50 < ED50 < 5-5mg kg^?1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg^?1, i.p.). These antinociceptive effects were not significantly diminished by naloxone (1 mg kg^?1, i.p.). Furthermore, acute intraperitoneal administration of both compounds (20 mg kg^?1 for PC4 and 5mg kg^?1 for PC13) potentiated morphine (7–5 mg kg^?1, s.c.) analgesia in the hot-plate test. Thus, these results suggest that PC4 and PC 13 possess potential antidepressant effects related to different aminergic mechanisms, especially at the 5-HT₂ receptor level.     

Chronic Administration Does Not Alter the Pharmacokinetic Profile of l-Dopa in the Rat

Abstract— Chronic administration of l-dopa (200 mg kg^?1 day^?1 for 12 months) plus carbidopa (25 mg kg^?1 day^?1) or carbidopa (25 mg kg^?1 day^?1) alone did not alter the t½, AUC_0–∞ k₁₀, k₁₂, k₂₁, CL_p or Vd_ss of l-dopa following intra-aortic (i.a.) administration (50 mg kg^?1) alone or after carbidopa (25 mg kg^?1, i.p.) pretreatment, or the t½, AUC_0–∞, t_max or the bioavailability (F) of l-dopa (50 mg kg^?1) administered orally, alone or after acute pretreatment with carbidopa (25 mg kg^?1 i.p.). The peripheral metabolism of l-dopa was unaltered by chronic administration of l-dopa plus carbidopa or carbidopa alone as measured by unaltered AUC_{0·360 min} for 3-O-methyldopa, dopamine, DOPAC or homovanillic acid in the plasma of rats following acute administration of l-dopa (50 mg kg^?1, p.o. or i.a.) alone or following pretreatment with carbidopa, and unaltered hepatic dopa decarboxylase activity.     

Glibenclamide Antagonizes the Inhibitory Effect of Morphine on Gall Bladder Emptying

Egg yolk-induced gall-bladder emptying in mice was used to investigate the effect of glibenclamide and minoxidil (ATP-dependent K⁺-channel modulators) on biliary tract effects of morphine. The inhibitory effect of morphine (1–4 mg kg^?l, i.p.) on egg yolk-induced gall-bladder emptying was completely blocked by pretreatment with naloxone (2 mg kg^?l, i.p.) or glibenclamide (0.65 mg kg^?l, i.p.) whereas, pretreatment with minoxidil (0.65 mg kg^?1, i.p.) did not modify the inhibitory effect of morphine on gall-bladder emptying. Our results suggest that biliary-tract actions of morphine are mediated through glibenclamide-sensitive K⁺ channels similar to those involved in the analgesic action of morphine.     

Comparative study of the antagonism of bemegride and picrotoxin on behavioural depressant effects of diazepam in rats and mice

Experiments carried out on rats and mice showed that bemegride and diazepam acted as antagonists. Bemegride (at doses ranging from 4 to 16 mg.kg^?1 i.p.) counteracted diazepam (8 mg.kg^?1 i.p.)-induced hypokinesia and amnesic-like activity, diazepam (4 mg.kg^?1 i.p.)-induced motor inco-ordination and diazepam (2 mg.kg^?1 i.p.)-induced reduced grip strength. A GABA receptor blocking agent, picrotoxin (2–4 mg.kg^?1 i.p.) also markedly antagonized all (except for hypokinesia) these diazepam effects. Diazepam (1. 2, 4, 8 mg.kg^?1 i.p.) exerted similar dose-related antagonisms on bemegride (24 mg.kg^?1 i.p.) and on picrotoxin (8 mg.kg^?1 i.p.)-induced seizures. Both antagonisms were observed at lower doses than were required for strychnine (6 mg.kg^?1 i.p.)-induced seizures inhibition. Picrotoxin/ diazepam antagonism seems to further support the possibility of a gabaminergic mechanism of action of benzodiazepines depressant effects. Bemegride/diazepam antagonism is discussed in terms of a possible inhibitory role of bemegride on gabaminergic transmission.     

Mechanisms involved in the antinociception caused by ethanolic extract obtained from the leaves of Melissa officinalis (lemon balm) in mice

The present study examined the antinociceptive effect of the ethanolic extract from Melissa officinalis L. and of the rosmarinic acid in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. The extract (3-1000 mg/kg), given orally (p.o.) 1 h prior to testing, produced dose-dependent inhibition of acetic acid-induced visceral pain, with ID50 value of 241.9 mg/kg. In the formalin test, the extract (30-1000 mg/kg, p.o.) also caused significant inhibition of both, the early (neurogenic pain) and the late (inflammatory pain), phases of formalin-induced licking. The extract (10-1000 mg/kg, p.o.) also caused significant and dose-dependent inhibition of glutamate-induced pain, with ID50 value of 198.5 mg/kg. Furthermore, the rosmarinic acid (0.3-3 mg/kg), given p.o. 1 h prior, produced dose-related inhibition of glutamate-induced pain, with ID50 value of 2.64 mg/kg. The antinociception caused by the extract (100 mg/kg, p.o.) in the glutamate test was significantly attenuated by intraperitoneal (i.p.) treatment of mice with atropine (1 mg/kg), mecamylamine (2 mg/kg) or l-arginine (40 mg/kg). In contrast, the extract (100 mg/kg, p.o.) antinociception was not affected by i.p. treatment with naloxone (1 mg/kg) or d-arginine (40 mg/kg). It was also not associated with non-specific effects, such as muscle relaxation or sedation. Collectively, the present results suggest that the extract produced dose-related antinociception in several models of chemical pain through mechanisms that involved cholinergic systems (i.e. through muscarinic and nicotinic acetylcholine receptors) and the l-arginine-nitric oxide pathway. In addition, the rosmarinic acid contained in this plant appears to contribute for the antinociceptive property of the extract. Moreover, the antinociceptive action demonstrated in the present study supports, at least partly, the ethnomedical uses of this plant.     

Dexamethasone Reduces the Behavioural Effects Induced by Baclofen in Mice

The present study examines the influence of dexamethasone on the behavioural effects induced by baclofen in mice. The behaviour elements considered were locomotor activity, motor co-ordination, catalepsy, stereotyped behaviour and antinociception. Baclofen (1·0–4·0–6·0 mg kg^?1, i.p.) induced a significant reduction of all behavioural elements studied and an antinociceptive effect was recorded. Dexamethasone alone (0·1–0·5–1·0 mg kg^?1, i.p.) did not induce significant changes in the behaviour elements considered. On the other hand, when the steroid was injected immediately before baclofen a significant reduction of baclofen's behavioural effects was found. Our results suggest a possible link between glucocorticoid and the GABA-ergic system.     

Effect of Bay K 8644 on the synthesis and metabolism of dopamine and 5-hydroxytryptamine in various brain areas of the rat

Abstract— The effects of Bay K 8644 (1,2 and 4 mg kg^?1, i.p.) on the synthesis and metabolism of dopamine and 5-hydroxytryptamine (5-HT) in rat brain after m-hydroxybenzylhydrazine administration were studied. Bay K 8644 (2 and 4 mg kg^?1, i.p.) caused an increase in the synthesis of both dopamine in the striatum and 5-HT in the midbrain and striatum, measured as the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan, respectively. Moreover, Bay K 8644 at the dose of 4 mg kg^?1 increased the turnover of dopamine in the striatum and of 5-HT in midbrain and striatum. These neurochemical changes were antagonized by the calcium channel antagonist nimodipine (10 mg kg^?1, i.p.). It is concluded that dihydropyridine receptors may mediate the brain region-specific changes in the dopaminergic and 5-HT-ergic neurotransmission which occur following activation of neuronal calcium channels.     

Antinociceptive profile of the natural cholinesterase inhibitor huperzine A

The antinociceptive effect of huperzine A, a novel cholinesterase inhibitor, was investigated in the mouse hot‐plate and abdominal constriction tests. Huperzine A induced a dose‐dependent antinociception (70–110 μg kg^–1 i.p.) which was prevented by scopolamine (0.1 mg kg^–1 i.p.) and S‐(–)‐ET 126 (0.01 μg per mouse i.c.v.), but not by naloxone (1 mg kg^–1 i.p.), mecamylamine (2 mg kg^–1 i.p.), α‐methyl‐p‐tyrosine (100 mg kg^–1 i.p.), or CGP 35348 (100 mg kg^–1 i.p.). A dose‐dependent inhibition of the antinociception induced by huperzine A (110 μg kg^–1 i.p.) was observed after inactivation of the M₁ gene by an antisense oligodeoxyribonucleotide (aODN). This effect was detected 24 h after the last intracerebroventricular injection of aODN. Time‐course experiments revealed that, after the end of the aODN treatment, sensitivity to analgesic drugs progressively appeared, reaching the normal range at 96 h. Huperzine A, at the maximal effective doses, did not produce any alteration of mice motor coordination, as revealed by rota‐rod experiments. These results indicate that huperzine A is endowed by muscarinic antinociceptive properties mediated by the activation of central M₁ muscarinic receptor subtype. Drug Dev. Res. 54:19–26, 2001. © 2001 Wiley‐Liss, Inc.     

An α-adrenoceptor-mediated mechanism of hypoactivity induced by β-amyrin palmitate

Abstract— Inhibitory effects of β-amyrin palmitate in locomotor activity of mice were studied by combining this compound with α-adrenergic agonists or antagonists and a dopaminergic agonist. β-Amyrin palmitate (2·5, 5·0 and 10·0 mg kg^?1, i.p.) decreased locomotor activity of mice in a dose-dependent manner. It enhanced hypoactivity of mice treated with clonidine (0·025 mg kg^?1, i.p.) and antagonized hyperactivity produced by phenylephrine (40 μg, i.c.v.). The inhibitory action of β-amyrin palmitate was not affected by yohimbine (1·5 mg kg^?1, i.p.), but was potentiated by prazosin (0·75 mg kg^?1, i.p.). When combined with a dopaminergic agonist, apomorphine (2·0 mg kg^?1, i.p.), β-amyrin palmitate (5·0 and 10·0 mg kg^?1, i.p.) did not affect locomotor stimulation produced by apomorphine. These results suggest that β-amyrin palmitate might inhibit α₁-adrenoceptors.     

Rolipram inhibits airway microvascular leakage induced by platelet-activating factor,histamine and bradykinin in guinea-pigs

Abstract— Rolipram (0·1–1000 μg kg^?1, i.v.) reduced the increase in microvascular permeability induced by platelet-activating factor (PAF; 50 ng kg^?1, i.v.) at different sites of the guinea-pig airways. Rolipram (1–100μg kg^?1, i.v.) inhibited histamine (30μg kg^?1, i.v.)-and bradykinin (0·3 μg kg, i.v.)-induced airway microvascular leakage. These effects of rolipram were obtained at doses which inhibit histamine (7–20 μg kg^?1 min^?1)-induced bronchoconstriction (IC50 = 3 ± 1 μg kg, i.v.) without depressing arterial blood pressure in the guinea-pig. Aminophylline (50 mg kg^?1) did not change the effect of PAF. The anti-exudative effect of rolipram is of potential therapeutic value in asthma.     

Buprenorphine-cocaine Interactions in Mice: Effect on Locomotor Activity and Hole-dipping Behaviour

Abstract— The effect of cocaine and the mixed μ-opioid partial agonist/κ-antagonist buprenorphine on locomotor activity and hole-dipping behaviour was investigated in mice. The drugs were given alone and in combination. Cocaine (7·5, 15, 30 mg kg^?1, i.p.) significantly increased locomotion in a dose-related manner in the hour following injection. The two highest doses also increased hole-dipping although this response was not consistently seen. Buprenorphine (0·5, 5 mg kg^?1, i.p.) produced an increase in locomotion which occurred 30–60 min after injection but did not alter hole-dipping behaviour. A lower dose (0·05 mg kg^?1) had no effect on either parameter. The locomotion induced by cocaine (15 mg kg^?1, i.p.) was not modified by buprenorphine (0·05, 0·5, 1, 5 mg kg^?1, i.p.; 5 min pretreatment). However, hole-dipping was almost completely abolished in animals given combinations of cocaine and buprenorphine (0·05–5 mg kg^?1, i.p.), although neither drug decreased hole-dipping when given alone. This observation, which was not simply due to the emergence of stereotyped behaviour, suggests an interaction between buprenorphine and cocaine.