Different influences of adenosine receptor agonists and antagonists on morphine antinociception in mice

• 1.1. Subcutaneous (s.c.) administration of morphine to mice induced a dose-dependent antinociception.
• 2.2. Pretreatment of animals with adenosine receptor antagonists NECA (5′-N-ethylcarboxamidermadenosine) and l-PIA (N⁶-phenylisopropyladenosine) potentiated, while adenosine agonist CHA (N⁶-cyclohexyladenosine) decreased the morphine response.
• 3.3. Adenosine antagonist theophylline decreased, but adenosine receptor antagonist 8-PT (8-phenyltheophylline) increased the antinociception effect of morphine. Inhibitory effect of CHA on morphine antinociception was also reversed by 8-PT pretreatment.
• 4.4. NECA or l-PIA induced a high degree of antinociceptive effect in animals pretreated with 8-PT.
• 5.5. Dipyridamole pretreatment did not alter the effect of morphine.
• 6.6. It is concluded that A-1 and/or A-2 adenosine receptors are involved in morphine antinociception and the adenosine mechanism(s) may exert a modulatory role in this respect.

     

The effect of N6-cyclohexyladenosine and 5′-N-ethylcarboxamidoadenosine on body temperature in normothermic rabbits.

• 1.1. Thermal responses to IV administration of N⁶-cyclohexyladenosine (CHA; 0.15 mg/ kg), A₁ adenosine receptor agonist, or 5′-N-ethylcarboxamidoadenosine (NECA; 0.15 mg/kg), A₂ adenosine receptor agonist, were investigated in normothermic rabbits at an ambient temperature (Ta) of 20.0±1.0°C.
• 2.2. Although both compounds inhibited metabolic heat production, only NECA produced hypothermia.
• 3.3. NECA showed strong hypotensive activity.
• 4.4. Both compounds produced vasoconstriction of the ear skin vessels and CHA, in addition, slowed down the respiratory rate.
• 5.5. The role of A₁ or A₂ adenosine receptors in the thermoregulatory activity of these compounds is discussed.

     

Effects of chronic lithium pretreatment on apomorphine-induced penile erection

• 1.1. The effects of chronic lithium pretreatment (600 mg/l in drinking rats, 30 days) on penile erection (PE) induced by apomorphine were investigated in rats. This treatment resulted in a serum Li concentration after 30 days of 0.31 ± 0.01 mmol/l.
• 2.2. Subcutaneous (s.c.) administration of mixed Dl/D2 dopamine receptor agonist apomorphine (0.05–0.5 mg/kg) induced PE in a biphasic manner. The maximum effect was obtained with 0.1 mg/kg of the drug while the response decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg.
• 3.3. Pretreatment of animals with 0.0125-0.1 mg/kg of D1 dopamine receptor antagonist SCH 23390 or D2 dopamine receptor antagonist sulpiride (12.5–100 mg/kg) decreased apomorphine-induced PE. Combination of SCH 23390 (0.025 mg/kg) with sulpiride (12.5 mg/kg) caused a stronger inhibitory effect on apomorphine response. This indicates that both D1 and D2 dopamine receptors may be involved in PE induced by apomorphine.
• 4.4. The response induced by apomorphine (0.05-0.5 mg/kg) was decreased in animals pretreated with chronic lithium. The inhibitory effect of sulpiride on apomorphine response, increased in animals pretreated with lithium, in contrast the inhibitory effect of SCH 23390 did not change in this condition. However, a combination of SCH 23390 with sulpiride increased inhibitory effect on apomorphine response in lithium pretreated rats.
• 5.5. It is concluded that chronic lithium inhibits PE induced by dopaminergic mechanism(s).

     

Studies investigating the possible involvement of adenosine in the antisecretory action of morphine

• 1.1. Fluid secretion was induced in the jejunum of anesthetised rats using vasoactive intestinal peptide.
• 2.2. The adenosine antagonist, DPCPX (0.1 μg/kg), suppressed the antisecretory action of morphine (10 μg/kg), but naloxone (80 μg/kg) did not inhibit the antisecretory response of the adenosine agonist, NECA (40 μg/kg), at a dose previously shown to antagonize the antisecretory response of morphine.
• 3.3. NECA (40 (μg/kg) reversed secretion in pithed and reserpine-pretreated (5 μg/kg subcutaneously) rats.
• 4.4. It is proposed that adenosine acts as a mediator of the morphine antisecretory effect at a site distal to the noradrenergic neurons involved in the action of morphine.

     

3-(3-Hydroxyphenyl)-N-(1-Propyl)piperidine elicits convulsant effects in mice

• 1.1. The behaviour and EEG effects of the dopamine and sigma (σ) ligands (+) 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) were studied in mice.
• 2.2. (+) 3-PPP dose-dependently (60–100 mg/kg i.p.) produced behavioural and electrical tonic-clonic seizures.
• 3.3. The incidence of the tonic seizures elicited by 100 mg/kg of the drug was significantly (P < 0.05) prevented by spiperone (0.5 mg/kg i.p.) and haloperidol (0.5 mg/kg i.p.).
• 4.4. The results show an influence on the behavioural and electrical threshold of convulsions by (+) 3-PPP depending on a prevalent interference on dopamine receptors.

     

Preferential decarboxylation of l-threo-3,4-dihydroxyphenylserine in rat renal tissues

• 1.1. Administration of l-threo-3,4-dihydroxyphenylserine (l-threo-DOPS; 3, 10 and 30 mg/kg, i.p.) produced a dose-dependent increase in the tissue levels of both noradrenaline and its deaminated metabolite 3,4-dihydroxyphenylglycol (DOPEG) in the rat jejunum, liver and renal cortex, but not in the left ventricle.
• 2.2. The accumulation of noradrenaline and DOPEG after the administration of l-threo-DOPS (30 mg/kg, i.p.) was also found to be a time-dependent effect, reaching its maximum 15 min after the injection and then declining progressively.
• 3.3. The accumulation of noradrenaline and DOPEG after l-threo-DOPS (30 mg/kg, i.p.) was found to be similar in control and 6-OHDA treated rats and completely prevented by previous treatment with benserazide.
• 4.4. Administration of l-threo-DOPS (30 mg/kg) produced an increase in plasma levels of noradrenaline and DOPEG; this effect was maximum, for both noradrenaline (6.2-fold increase) and DOPEG (3.4-fold increase), at 30 min after the injection of l-threo-DOPS.
• 5.5. The results presented here support the view that most l-threo-DOPS is decarboxylated into noradenaline by non-neuronal AAAD, a reaction occurring predominantly in renal tissues.

     

Analysis of the mechanisms underlying the antinociceptive effect of the extracts of plants from the genus Phyllanthus

• 1.1. We examine some of the mechanisms underlying the analgesic effects of the hydroalcoholic extracts (HE) of Phyllanthus urinaria and P. niruri against formalin-induced nociception in mice. In addition, we also investigate the action of both HEs against capsaicin-mediated pain.
• 2.2. Both prazosin and yohimbine (0.15 mg/kg, i.p.) induced a marked inhibition of the analgesic effect caused by phenylephrine (10 mg/kg, i.p.) and clonidine (0.1 mg/kg, i.p.), respectively, but had no effect on the antinociceptive action caused by HE of P. urinaria (10 mg/kg, i.p.) or P. niruri (30 mg/kg, i.p.).
• 3.3. N^G-nitro-l-arginine (l-NOARG, 75 mg/kg, i.p.) caused marked analgesic effect against the second phase of formalin-induced pain. Treatment of animals with l-arginine (600 mg/kg) completely antagonized the antinociceptive effect of l-NOARG but had no significant effect against the HE of P. urinaria (10 mg/kg, i.p.) or P. niruri (30 mg/kg, i.p.) analgesic properties.
• 4.4. The antinociceptive effects caused by the HEs of P. urinaria (10 mg/kg, i.p.) and P. niruri (30 mg/kg, i.p.) were unaffected by methysergide (5 mg/kg, i.p.), p-chloro-phenylalanine-methyl-ester (100 mg/kg, i.p., once a day for 4 consecutive days) or after previous adrenalectomy of animals.
• 5.5. The HE of P. urinaria and P. niruri given either intraperitoneally (1–30 mg/kg) or orally (25–200 mg/kg) caused marked and dose-related inhibition of capsaicin-induced pain with ID₅₀ of 2.1 and 6.1 mg/kg given intraperitoneally and 39 and 35 mg/kg given orally, respectively.

     

The CCKA receptor antagonist devazepide inhibits the effect of apomorphine on vasopressin release in pigs

• 1.1. A transient increase in plasma vasopressin concentrations represents a physiological correlate of nausea in animals that vomit.
• 2.2. The CCK_A receptor antagonist devazepide has previously been shown to inhibit vasopressin release induced in pigs by intravenous (i.v.) CCK.
• 3.3. This study investigated whether devazepide (70 μg/kg i.v.) would affect vasopressin secretion induced in pigs (n = 6) by the emetic drug apomorphine (25 μg/kg i.v.).
• 4.4. Apomorphine stimulated vasopressin release in the 30 min period following injection; this effect was prevented by prior administration of devazepide.
• 5.5. The results suggest that CCK_A receptor antagonists may have the ability to prevent nausea and/or emesis.

     

Adenosine A1 receptor enhancer,PD 81,723, and cerebral ischemia/reperfusion injury in the gerbil

• 1.1. The adenosine A₁ receptor enhancer, PD 81,723, was tested for its neuroprotective activity in a Mongolian gerbil model of forebrain ischemia/reperfusion cerebral ischemia.
• 2.2. Gerbils were injected with PD 81,723 (1, 10 and 125 mg/kg i.p.) 20 min before a 5-min episode of forebrain ischemia. The extent of ischemic injury was assessed by monitoring the increases in locomotor activity and from the degree of damage to the CA1 hippocampal pyramidal cell layer after 5 days of recovery.
• 3.3. By both criteria, PD 81,723, at all three dose levels, failed to protect against ischemia/reperfusion evoked cerebral injury.

     

Hemodynamic effects of barnidipine hydrochloride in conscious squirrel monkeys

• 1.1. The effects of barnidipine, a new dihydropyridine Ca²⁺ antagonist, on cardiovascular and renin-angiotensin-aldosterone systems were investigated in conscious squirrel monkeys.
• 2.2. Barnidipine (0.3–3 mg/kg p.o.) produced a dose-related decrease in systolic blood pressure. The hypotensive action after 3 mg/kg p.o. lasted more than 8 hr.
• 3.3. Barnidipine increased heart rate, but did not affect the PQ-interval of the electrocardiograph.
• 4.4. Barnidipine (1 and 3 mg/kg p.o.) increased plasma renin activity dose-dependently. However, it had no significant effect on plasma aldosterone concentration.
• 5.5. These results indicate that barnidipine produces a sustained hypotension without affecting atrioventricular conduction time and plasma aldosterone concentration in conscious squirrel monkeys.

     

The influence of various experimental conditions on the expression of naloxone-induced withdrawal symptoms in mice

• 1.1. Physical dependence was induced in mice by repeated injections of increasing doses of morphine for either 4 or 7 days.
• 2.2. Withdrawal symptoms induced by naloxone (1 mg/kg, i.p.) given 3 hr postmorphine were more severe in mice treated for 7 than for 4 days.
• 3.3. In mice that developed a similar degree of dependence, various doses of naloxone (0.1–10 mg/kg) given 3 hr postmorphine produced withdrawal symptoms of different intensities.
• 4.4. Withdrawal jumping was maximal at naloxone (1 mg/kg) but declined with further increases in the dose of the antagonist.
• 5.5. “Wet dog” shakes progressively increased with increasing doses of naloxone (0.1–10 mg/kg).
• 6.6. Variation in the temporal time interval between the last dose of morphine and that of naloxone (1 mg/kg) influenced the intensity of withdrawal symptoms.
• 7.7. In male and female mice that developed a similar degree of dependence, no major differences were observed in the severity of withdrawal symptoms-induced by naloxone (1 mg/kg) given 3 hr postmorphine.

     

Effect of Nω-nitro-l-arginine methyl ester on cardiac haemodynamic responses to adenosine infusion in conscious rats

• 1.1. The aim of the present study was to evaluate the role of NO in the cardiovascular effects of adenosine in conscious rats.
• 2.2. Cardiac index was determinated by thermodilution. In a group of rats, three doses of adenosine were infused (i.v.) at a rate of 150, 300 and 450 μg/kg/min in the absence and in the presence of l-NAME (10 mg/kg). In a second group of rats, the experimental protocol was the same as that of the first group, except an infusion of methoxamine (50 μg/kg/min) was given during the second adenosine administration, instead of L-NAME.
• 3.3. In the absence of l-NAME or methoxamine, adenosine induced a dose-dependent decrease in mean arterial pressure and an increase in vascular conductance although adenosine did not affect cardiac index.
• 4.4. l-NAME administration attenuated the decreasing effect on the mean arterial pressure in response to the two lower doses of adenosine. In the presence of L-NAME, adenosine induced a significant increase in cardiac index from 18.7 ± 1.5 to 29.1 ± 1.9 and 26.2 ± 1.4 ml/min/100 g. Administration of l-NAME significantly attenuated the adenosine-induced increase in vascular conductance.
• 5.5. Methoxamine infusion induced an enhanced response to adenosine infusion. In the presence of methoxamine, adenosine induced a significant greater decrease in mean arterial pressure, and increase in cardiac index and vascular conductance.
• 6.6. These results indicate that part of the cardiovascular effects of adenosine can be mediated by NO, since L-NAME administration partially blocked the adenosine-induced vasodilatation.

     

Cough induced activity of spirapril in rats

• 1.1. We examined the effect of spirapril, a potent angiotensin converting enzyme (ACE) inhibitor, on the number of capsaicin-induced coughs in rats and compared with that of enalapril.
• 2.2. Chronic treatment with enalapril, at doses of 1 and 3 mg/kg, p.o., significantly and dose-dependently enhanced the number of capsaicin-induced coughs.
• 3.3. Chronic treatment with higher dose of spirapril (3 mg/kg, p.o.) also significantly enhanced the number of capsaicin-induced coughs. However, lower dose (1 mg/kg, p.o.) of spirapril had no significant effect on the number of capsaicin-induced coughs.
• 4.4. These results suggest that cough induced activity, one of the most serious side effects associated with chronic treatment with ACE inhibitors, of spirapril is relatively lower than that of enalapril.

     

The analgesic effect of clonixine is not mediated by 5-HT3 subtype receptors

• 1.1. The analgesic effect of clonixinate of L-lysine (Clx) in the nociceptive C-fiber reflex in rat and in the writhing test in mice is reported.
• 2.2. Clx was administered by three routes, i.v., i.t. and i.c.v., inducing a dose-dependent antinociception.
• 3.3. The antinociceptive effect of Clx was 40–45% with respect to the control integration values in the nociceptive C-fiber reflex method.
• 4.4. The writhing test yielded ED50 values (mg/kg) of 12.0 ± 1.3 (i.p.), 1.8 ± 0.2 (i.t.) and 0.9 ± 0.1 (i.c.v.) for Clx administration.
• 5.5. Ondansetron was not able to antagonize the antinociception response of Clx in the algesiometric tests used.
• 6.6. Chlorophenilbiguanide did not produce any significative change in the analgesic effect of Clx in the nociceptive C-fiber reflex method.
• 7.7. It is suggested that the mechanism of action of the central analgesia of Clx is not mediated by 5-HT₃ subtype receptors.

     

Pharmacological analysis of the vasodepressor effect of KRN2391 in pithed rats

• 1.1. The antagonism by glibenclamide of the vasodepressor effects of KRN2391, cromakalim and nitroglycerin was compared in pithed rats with blood pressure supported by an infusion of phenylephrine.
• 2.2. Cumulative administration of KRN2391 (3–300 μg/kg, i.v.), cromakalim (3–300 μg/kg, i.v.) and nitroglycerin (1–300 μg/kg, i.v.) produced dose-dependent decreases in diastolic blood pressure.
• 3.3. In rats given glibenclamide (20 mg/kg, i.v.), the dose-vasodepressor curves for KRN2391 and cromakalim were shifted to the right. However, glibenclamide had no effect on the vasodepressor effect of nitroglycerin.
• 4.4. The ED_{50 mmHg} values increased about 5.9 fold for KRN2391 and 9.5 fold for cromakalim in glibenclamide-treated rats.
• 5.5. These results suggest that the vasodepressor effect of KRN2391 is due to both glibenclamide-sensitive and insensitive mechanisms. This glibenclamide-insensitive effect of KRN2391 is thought to reflect its nitrate action.

     

CI-966, a GABA uptake inhibitor,antagonizes ischemia-induced neuronal degeneration in the Gerbil

• 1.1. Cerebral ischemia of 5 min duration was induced in unanesthetized gerbils by bilateral occlusion of the carotid arteries.
• 2.2. The extent of cerebral damage was assessed by the elevation of motor activity in comparison with pre-ischemic levels and by a histological assessment of the extent of neuronal degeneration of the CAI area of the hippocampus.
• 3.3. The GABA transport inhibitor CI-966 (10 mg/kg i.p.) was tested for cerebroprotective activity in a gerbil stroke model. CI-966 reduced the extent of stroke injury as assessed by locomotor activity and measurement of hippocampal CAI pyramidal cell injury.
• 4.4. It is proposed that enhancement of extracellular GABA levels during ischemia accounts for the cerebroprotective actions of CI-966.

     

Inhibition by ginseng total saponin of the development of morphine reverse tolerance and dopamine receptor supersensitivity in mice

• 1.1. Ginseng total saponin (GTS), 200 mg/kg i.p. 3 hr prior to morphine, inhibited the development of reverse tolerance to the ambulatory-accelerating effect of morphine.
• 2.2. GTS, 200 mg/kg, also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of morphine, 10 mg/kg a day for 7 days.
• 3.3. These results suggest that GTS may be useful for the prevention and therapy of the adverse action of morphine.

     

Involvement of adenosine receptors in mouse thermoregulation

The effects of the activation of adenosine receptors on core body temperature of mice have been studied in the present investigation. Intraperitoneal (i.p.) injection of non-selective adenosine agonists 5'-N ethyl- carboxamide adenosine (NECA; 0.001, 0.01 and 0.05 mg/kg), R-(N(6)-phenylisopropyl)-adenosine (R-PIA; 0.01, 0.1 and 0.25 mg/kg) and selective A(1) adenosine agonist N(6)-cyclohexyladenosine (CHA; 0.1, 0.25 and 0.4 mg/kg) reduced core body temperature. However, R-PIA and CHA were less potent than NECA in reducing the core body temperature. Theophylline (12.5, 25 and 50 mg/kg) blocked the hypothermia of the adenosine agonists. Pre-treatment of animals with selective A(1) adenosine antagonist 8-phenyltheophylline (8-PT; 0.5, 1 and 2 mg/kg) decreased the hypothermic response of CHA but not of NECA and R-PIA. 8-PT potentiated the hypothermia induced by R-PIA. These results suggest that activation of both A(1) and A(2) adenosine receptors decreases core body temperature in mice.     

Gastroprotective activity of the novel proton pump inhibitor lansoprazole in the rat

• 1.1. The protective activity of lansoprazole was evaluated on gastric mucosal lesions induced by intragastric 25% NaCI (1 ml/rat for 1 hr) and by indomethacin (20 mg/kg for 6 hr) in the rat and compared with that of omeprazole.
• 2.2. Lansoprazole (3, 10 and 30 μmol/kg i.g.) dose-dependently prevented the formation of indomethacin-induced lesions, the inhibition being 99% at the highest dose. Omeprazole, 10 μmol/kg i.g., enhanced the damage by indomethacin while higher doses caused a reduction, lesion index being reduced by 98% at 100 μmol/kg.
• 3.3. Histologically in lansoprazole- as well as in omeprazole-pretreated rats, indomethacin-induced necrosis of the mucosa was absent, luminal epithelium being intact.
• 4.4. Lansoprazole (30, 100 and 300 μmol/kg) and omeprazole (30, 100 and 300 μmol/kg) dose-dependently reduced the formation of lesions by hypertonic saline.
• 5.5. Present results indicate that lansoprazole and omeprazole protect the gastric mucosa in different experimental models of gastric ulceration.

     

Antihypertensive and vasorelaxant effects on KRN2391 in spontaneously hypertensive rats

• 1.1. In conscious spontaneously hypertensive rats (SHR), the oral administration of KRN2391 (0.1–3.0 mg/kg) produced a dose-dependent decrease in blood pressure. The antihypertensive effect of KRN2391 was about 2 and 20 times more potent than those of pinacidil and nifedipine, respectively, but about 2 times less potent than that of cromakalim.
• 2.2. During oral administration of KRN2391 (0.5 and 1.0 mg/kg) once daily for 5 weeks, its antihypertensive effect did not diminish in conscious SHR.
• 3.3. In anaesthetized SHR, KRN2391 (3–100 μg/kg, i.v.) produced a decrease in blood pressure in a dose-dependent manner. Its antihypertensive effect was antagonized by glibenclamide (20 mg/kg, i.v.).
• 4.4. In isolated aorta obtained from SHR, KRN2391 (0.01–100 μM) produced a concentration-dependent relaxation. Its concentration-relaxation curve was shifted to the right by glibenclamide (1 μM) and methylene blue (3 μM).
• 5.5. These results indicate that the antihypertensive effect of KRN2391 in SHR is due to its direct action on vascular smooth muscle based on a K⁺ channel opening action and a nitrate action. In addition, KRN2391 is absorbed from the gastrointestinal tract into blood and does not induce tolerance despite possessing some nitrate action.