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.     

Mechanisms Involved in the Antinociceptive Effect in Mice of the Hydroalcoholic Extract of Siphocampylus verticillatus

The antinociception caused by the hydroalcoholic extract of Siphocampylus verticillatus (Campanulaceae) has been investigated in chemical and thermal models of nociception in mice. We have also assessed some of the mechanisms underlying the antinociceptive effect of the extract. The hydroalcoholic extract of S. verticillatus (60–1000 mg kg^?1, i.p. or p.o.) produced dose-related, significant and long-lasting (6 to 8 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 204 and ～1000 mg kg^?1, respectively. In the formalin test, the extract (100–1000 mg kg^?1), given either intraperitoneally or orally, resulted in graded inhibition of both phases of formalin-induced pain, being about 2- to 4-fold more potent in attenuating the second phase of the pain. The calculated mean ID50 (mg kg^?1) values for the earlier and the later phases were: 491 and 186 and 640 and 441, respectively. In addition, the extract (60–1000 mg kg^?1, i.p. or p.o.) caused marked and dose-related inhibition of capsaicin-induced neurogenic pain with mean ID50 values of 420 and 485 mg kg^?1, respectively. The hydroalcoholic extract, at the same doses, did not significantly affect the performance of animals in the rota-rod test, nor did it have any analgesic effect in the tail-flick or hot-plate tests. The treatment of animals with naloxone (5 mg kg^?1, s.c.) significantly reversed the analgesic effect of both morphine (5 mg kg^?1, s.c.) and the extract (300 mg kg^?1, i.p.) when assessed against acetic acid-induced abdominal constrictions. The treatment of animals with l-arginine (600 mg kg^?1, i.p.) significantly attenuated the antinociceptive effects of N^G-nitro-l-arginine (l-NOARG) (75 mg kg^?1, i.p.), of the hydroalcoholic extract (600 mg kg^?1, i.p.) or of morphine (5 mgkg^?1, s.c.), when analysed against the formalin test. In addition, adrenalectomy of animals 7 days before the tests significantly reversed the antinociception caused by the hydroalcoholic extract (300 mg kg^?1, i.p.) in the formalin-induced pain. These data show that the hydroalcoholic extract of S. verticillatus has significant and long-lasting oral antinociception when assessed against both neurogenic and inflammatory models of nociception in mice. The precise mechanism responsible for the analgesic effect of the extract still remains unclear, but a great part of this effect seems to be partly related to an opioid-like action and involvement of the l-arginine-nitric oxide pathway. Finally, the antinociception caused by the hydroalcoholic extract of S. verticillatus is modulated by adrenal hormones.     

Antinociceptive Effect of some Amaryllidaceae Plants in Mice

The antinociceptive effects of ethanolic extracts of Pancratium maritimum L., Narcissus tazetta subspecies tazetta and Leucojum aestivum L. bulbs have been investigated in mice using the p-benzoquinone-induced abdominal constriction and hot-plate tests. In the p-benzoquinone-induced abdominal constriction test the ethanolic extracts of P. maritimum (300, 600 or 1200 mg lg^?, s.c.) and N. tazetta subsp. tazetta (5, 50, 100 or 200 mg kg^?, s.c.) caused dose-dependent inhibition of abdominal constrictions whereas a fluctuating response was obtained from ethanolic extracts of L. aestivum (2.5–500 mg kg^?, s.c). In the hot-plate test P. maritimum and L. aestivum caused a significant increase of latency only at the highest concentrations used (1200 mg kg^? and 500 mg kg^?, i.p., respectively). However, at these concentrations they also caused significant toxic effects. In contrast with P. maritimum and L aestivum, N. tazetta subsp. tazetta (5–500 mg kg^?, i.p.) extracts had no antinociceptive effect in this test. These findings indicate that the antinociceptive effect of Amaryllidaceae plants differs depending on the model of nociception investigated.     

857-860Anti-inflammatory Effect of Magnolol,Isolated from Magnolia officinalis,on A23187-induced Pleurisy in Mice

In the present study, A23187-induced pleurisy in mice was used to investigate the anti-inflammatory effect of magnolol, a phenolic compound isolated from Chinese medicine Hou p'u (cortex of Magnolia officinalis). A23187-induced protein leakage was reduced by magnolol (10mgkg^?1, i.p.), indomethacin (10mgkg^?1, i.p.) and BW755C (30mgkg^?1, i.p.). A23187-induced polymorphonuclear (PMN) leucocyte infiltration in the pleural cavity was suppressed by magnolol and BW755C, while enhanced by indomethacin. Like BW755C, magnolol reduced both prostaglandin E₂ (PGE₂) and leukotriene B₄ (LTB₄) levels in the pleural fluid of A23187-induced pleurisy, while indomethacin reduced PGE₂ but increased LTB₄ formation. In the rat isolated peripheral neutrophil suspension, magnolol (3.7 μM) and BW755C (10 μM) also suppressed the A23187-induced thromboxane B₂ (TXB₂) and LTB₄ formation. These results suggest that magnolol, like BW755C, might be a dual cyclo-oxygenase and lipoxygenase inhibitor. The inhibitory effect of magnolol on the A23187-induced pleurisy is proposed to be, at least partly, dependent on the reduction of the formation of eicosanoids mediators in the inflammatory site.     

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.     

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.     

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

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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.     

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.     

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.     

Pharmacological characterization of the inhibitory effect of (R)-α-methylhistamine on sympathetic cardiopressor responses in the pithed guinea-pig

1 The effect of (R)-α-methylhistamine (R-α-mHA), a selective histamine H₃-receptor agonist, on increases in blood pressure and heart rate mediated by activation of the sympathetic nervous system induced by electrical stimulation of the spinal cord, was characterized in the vagotomized, pithed guinea-pig. 2 The frequency-dependent nature of (R)-α-mHA's effect on sympathetic cardiopressor responses was studied at frequencies between 1 and 20 Hz. (R)-α-mHA (10–100 μg kg^?1, i.v.) produced a dose-dependent inhibition of the stimulated increase in both blood pressure (BP) and heart rate (HR). The inhibition was inversely related to frequency and maximum inhibition (BP, 61% at 1 Hz; HR, 50% at 1 Hz) was seen with 100 μg kg^?1 of (R)-α-mHA. Treatment with the H₃ receptor inactive stereoisomer, (S)-α-methylhistamine (300 αg kg^?1, i.v.) did not inhibit the neurogenic sympathetic cardiopressor responses. 3 Pretreatment with thioperamide (1 mg kg^?1, i.v.), a histamine H₃ receptor antagonist, blocked (R) -α-mHA's inhibitory effect on stimulation-induced sympathetic cardiopressor responses. 4 Combined pretreatment with the H₃-receptor antagonist cimetidine (3 mg kg^?1, i.v.) and the H₁-receptor antagonist chlorpheniramine (0.3 mg kg^?1, i.v.) did not attenuate (R) -α-mHA's inhibitory effects. 5 (R) -α-mHA (100 μg kg^?1) had no effect on the hypertensive or tachycardia effects induced by adrenaline (1 and 3 μg kg^?1, i.v.). 6 Treatment with a combination of prazosin (1 mgkg^?1, i.v.) and yohimbine (1.5 mg kg^?1, i.v.) to block α₁ and α₂-adrenoceptors, abolished the sympathetic hypertension without affecting the inhibition of sympathetic tachycardia induced by (R) -α-mHA. Conversely, pretreatment with the β-adrenoceptor antagonist propranolol (1 mg kg^?1, i.v.), which blocked the sympathetic tachycardia, did not block (R)-α-mHA's inhibition of sympathetic hypertensive responses. 7 In adrenalectomized guinea-pigs, (R) -α-mHA (100μg kg^?1, i.v.) also produced a frequency-dependent inhibition of sympathetic hypertensive cardiopressor responses that was not significantly different from intact animals. 8 These results demonstrate that (R) -α-mHA produces a frequency-dependent inhibition of the cardiopressor responses due to activation of the sympathetic innervation to the resistance vessels and the heart. These effects of (R)-α-mHA are mediated by a prejunctional inhibitory H₃-receptor mechanism, and an intact CNS is not needed to elicit these effects. The most likely site of action is on the postganglionic sympathetic neuroeffector junction whereas a site in the adrenal medulla, unlike the sympathetic ganglia can be excluded. Furthermore, the inhibitory modulation of the sympathetic tachycardia responses with (R)-α-mHA is not affected by α₁- and α₂-adrenoceptor blockade.     

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.     

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.     

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.     

Antinociceptive effect of novel trihalomethyl-substituted pyrazoline methyl esters in formalin and hot-plate tests in mice

The aim of the present study was to evaluate the antinociceptive potential of four novel pyrazoline methyl ester compounds on chemical and thermal models of pain in mice. The following 5-trihalomethylated-4,5-dihydro-1H-pyrazole methyl ester compounds were tested: 3-methyl-5-trifluoromethyl-(MPF3), 4-methyl-5-trifluoromethyl-(MPF4), 3-methyl-5-trichloromethyl-(MPCl3) and 4-methyl-5-trichloromethyl-(MPCl4). MPF3, MPF4, MPCl3 and MPCl4 (0.03-1.0 mmol/kg) given intraperitoneally decreased neurogenic and inflammatory phases of nociception in the formalin test. Moreover, MPF3, MPF4, MPCl3, MPCl4 (0.1-1.0 mmol/kg) and dipyrone (1.5 mmol/kg) also produced a dose-dependent antinociceptive effect in the hot-plate test. However, MPF3, MPF4, MPCl3 and MPCl4 did not impair motor coordination in the rotarod test or spontaneous locomotion in the open field test. The antinociceptive effect of MPF4 (1.0 mmol/kg, i.p.) was reversed by the opioid receptor antagonist naloxone (2 mg/kg, i.p.), but not by the alpha(2)-adrenergic receptor antagonist yohimbine (0.15 mg/kg, i.p.) or by p-chlorophenylalanine ethyl ester (PCPA, 300 mg/kg, i.p.) treatment. In contrast to morphine (5 mg/kg, i.p.), MPF4 given daily for up to 8 days did not generate a tolerance to its antinociceptive effect. However, similar to morphine (11 mg/kg, i.p.), MPF4 reduced gastrointestinal transit in mice. Taken together these results demonstrate that these novel pyrazoline methyl esters tested may be promising prototypes of additional mild analgesics.     

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.     

Synthesis of Thiazolotriazine Derivatives and Their Antinociceptive Effects in Mice

A series of 2-(4-arylpiperazin-1-yl-methyl)-4-methyl-1-oxo-5,6,8,8a-tetrahydro-thiazolo[3,4-d] [1,2,4]triazines was prepared and tested for antinociceptive activity. The compounds were prepared by the Mannich reaction from the corresponding 2-unsubstituted thiazolotriazines. When administered intraperitoneally most were found to have potent analgesic activity in the mouse during tests of phenylbenzoquinone-induced abdominal constriction; ED50 values (doses resulting in half the maximum effect) ranged from 10 to 87 mg kg^?1. Derivatives with a 3-chloro- or 4-fluorophenylpiperazinylmethyl side-chain in the 2-position of the bicyclic system were, when administered intraperitoneally at doses greater than 25 mg kg^?1, also effective in the hot-plate test without associated sedative effects. The compounds have a large therapeutic index; intraperitoneal LD50 values (doses which result in the death of half the animals) were > 700 mg kg^?1. Naloxone attenuated the analgesic activity of the 3-chloro derivative, suggesting the participation of μ-receptors in the antinociceptive effects of this drug. In addition, a non-opioid mechanism, probably related to enhancement of the release of 5-hydroxytryptamine and noradrenaline, or inhibition of the neuronal re-uptake of these compounds, has been evinced to explain the analgesic properties of the 3-chloro or 4-fluoro derivatives. These results provide evidence for the involvement of noradrenergic and 5-hydroxytryptaminergic pathways in the analgesic activity of 3 and 4. Because of their potential effectiveness, the 3-chloro- or 4-fluorophenylpiperazinylmethyl derivatives might be suitable for treatment of a wide variety of painful conditions and could be attractive reserve agents for patients dissatisfied with opioids.     

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.     

The preclinical antipsychotic evaluation of HRP 913, a novel benzisoxazole derivative

HRP 913 {1-[3-(6-fluoro-1,2-benzisoxazole-3-yl)propyl]-4-(2-oxo-1-benzimidazolinyl)} piperidine demonstrated preclinical antipsychotic activity with features that may provide a clinical advantage over current therapy. It was effective in blocking amphetamine stereotypy in rats (ED₅₀ = 0.4 mg/kg, i.p.), amphetamine circling in SN-lesioned rats (ED₅₀ = 0.3 mg/kg, i.p.), apomorphine stereotypy in rats (ED₅₀ = 0.8 mg/kg, i.p.), but not apomorphine circling in SN-lesioned rats (up to 10 mg/kg, i.p.). It also blocked Sidman avoidance in rats (ED₅₀ = 0.17 mg/kg, i.p.) and monkeys (ED₅₀ = 0.2 mg/kg, p.o.) and blocked intracranial self-stimulation in rats (0.09 mg/kg, i.p.). A unique biphasic effect on catalepsy was found. Monkey EPS studies demonstrate a potential for EPS that is lower than some existing clinical standards. HRP 913 displaced ³H-spiroperidol from rat striatal sites (IC₅₀ = 6.0 × 10^?9 M) and inhibited WB-4101 binding (IC₅₀ = 2.6 × 10^?8 M) with only slight effect on QNB binding. HRP 913 does not appear to have marked α-blocking properties in vivo. HRP 913 is a potent dopamine antagonist and is predicted to have less side effects than current therapy.     

Antinociceptive effect of methanol extract of Capparis ovata in mice

Context: Capparis ovata Desf. (Capparaceae) grows widely in Turkey. Flower buds and fruits of the plant are used in folk medicine for their analgesic, antirheumatismal, and diuretic effects.

Objective: This study evaluated the possible antinociceptive effect of the methanol extract of C. ovata (CME) in mice.

Materials: The antinociceptive effect of methanol extract, prepared with the C. ovata flower buds, was studied at the doses of 50, 100, and 200?mg/kg (i.p.) using tail-immersion, hot-plate, and writhing tests in mice. Morphine sulfate (5?mg/kg; i.p.) and dipyrone (100?mg/kg; i.p.) were used as reference analgesic agents. Naloxone (5?mg/kg; i.p.) was also tested.

Results: It was observed that the C. ovata extract had a significant antinociceptive effect in these tests. In the hot-plate and tail-immersion test results, the doses of 50, 100, and 200?mg/kg increased the percentage of the maximum possible effect (MPE%) value for nociception significantly according to the control value (P?<?0.001). All doses of the extract decreased the number of acetic acid-induced abdominal constrictions in mice when compared with control group (P?<?0.001). These effects were inhibited by pretreatment with naloxone.

Discussion and conclusion: Based on the results obtained, it can be concluded that CME is a potentially antinociceptive agent which acts as both at the peripheral and central levels.