Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites

The local intestinal component of the constipating action of morphine was assessed through several integrated approaches in an in vivo animal model. The doses of systemically administered morphine reducing to 50% of drug-free controls (ID50) the small intestinal transit of a charcoal meal fed by gavage to overnight fasted rats were 0.04 and 3.8 mg/kg i.p. and p.o. and 0.5 mg/kg either s.c. or i.v., respectively. Transit inhibition with any of these morphine doses occurred within 10 min and was still measurable 20, 30, 45 and 240 min after i.p., i.v., s.c. and p.o. administration, respectively. Morphine given by any of these systemic routes did not reduce significantly transit in rats receiving the putative peripheral antagonist quaternary naloxone (1 mg/kg i.p., 5 min before morphine) that, unlike naloxone, failed to reverse transit inhibition (to about 50% of drug-free controls) induced by 0.08 mg/kg i.c.v. of morphine. Radioassay of thin-layer chromatograms of extracts of central nervous system, plasma, small intestine and small intestinal longitudinal muscle of rats given tritium-labeled morphine and also tested for gastrointestinal transit, showed that morphine concentrations in the longitudinal muscle (with attached myenteric plexus) after i.v., i.p. and s.c. injection fell within a relatively narrow range and were consistent with the appropriate transit scores. Morphine levels in the central nervous system of the same rats were lower than in any other tissue assayed, presented considerable differences depending on administration routes and did not correlate at all with the corresponding intestinal effects. Morphine administered directly into the rat cerebral ventricles effectively inhibits gastrointestinal transit through an opioid-sensitive central nervous system-located action site.(ABSTRACT TRUNCATED AT 250 WORDS)     

Centrally mediated inhibition of small intestinal transit and motility by morphine in the rat

The effects of morphine treatment on small intestinal propulsion and contractile activity were investigated in unanesthetized rats. Intragastrically, s.c. and i.c.v. administered morphine produced dose-related decreases in the transit of a radioactive marker (51Cr) through the small intestine. Morphine was most potent after i.c.v. administration whereas the intragastric route was the least potent. Intracerebroventricular and s.c. morphine also delayed gastric emptying of [3H]polyethylene glycol placed directly into the stomach. Intragastric morphine at doses up to 500 mg/kg did not alter gastric emptying. The antitransit effects of i.c.v. and s.c. morphine were antagonized by prior treatment with naloxone (2 mg/kg s.c.). Changes in small intestinal motility resulting from morphine treatment were measured directly through chronically implanted silastic cannulas. Two cannulas were implanted in each rat, one into the duodenum and the second in the proximal jejunum. Each cannula was perfused with distilled water at a low flow rate (0.04 ml/min) and increases in intraluminal pressure associated with contractions were recorded as changes in outflow resistance. Morphine treatment decreased the frequency of contractions in both areas of the small intestine. Intracerebroventricular morphine again was the more potent route of administration when compared to s.c. morphine. These data indicate that morphine can act within the central nervous system to alter autonomic outflow to the small intestine. The result is an inhibition of motility which accounts for the antitransit effects of opiate-like compounds in the rat.     

Estimation of agonist dissociation constants at central presynaptic alpha-2 autoreceptors in the absence of autoinhibition.

The agonist dissociation constants (KA) and relative efficacies of UK-14304, norepinephrine (NE) and clonidine at presynaptic release-modulating alpha-2 adrenoceptors were determined in rat cerebral cortex slices using the irreversible alpha-2 adrenoceptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (0.8 mg/kg i.p.) to reduce the receptor pool. Eighteen hours after treatment, the slices were incubated with [3H]NE, superfused in the presence of reuptake inhibitor and stimulated electrically with short bursts of 4 pulses delivered at 100 Hz (pseudo-one-pulse; POP) or trains of 36 or 72 pulses delivered at 3 Hz. EEDQ treatment did not affect the overflow of radioactivity evoked by POP, but greatly facilitated overflow at 36 or 72 pulses/3 Hz indicating that the autoinhibition seen under the latter conditions is totally lacking with POP stimulation. KA values determined using 4 pulses/100 Hz were 136, 50 and 625 nM for UK-14304, clonidine and NE, respectively. At 36 or 72 pulses/3 Hz the values were higher by a factor of up to 3. The percentage of receptors active after EEDQ treatment was found to be 5.5 to 8.2% and was not influenced by conditions of stimulation. Receptor reserves were estimated to be about 65% for UK-14304 and NE and 40% for clonidine. The efficacies of UK-14304 and clonidine relative to NE were 1 and 0.5, respectively. The data indicate that KA values for agonists at presynaptic alpha-2 autoreceptors are inevitably underestimated if the released transmitter causes inhibition of release in addition to the drug under investigation.     

Peroxisome proliferator-activated receptor gamma mediates protection against cyclooxygenase-2-induced gut dysfunction in a rodent model of mesenteric ischemia/reperfusion

Cyclooxygenase (COX)-2 has been identified as an important mediator elaborated during ischemia/reperfusion, with pro- and anti-inflammatory properties having been reported. As the role of COX-2 in the small intestine remains unclear, we hypothesized that COX-2 expression would mediate mesenteric ischemia/reperfusion-induced gut injury, inflammation, and impaired transit and that these deleterious effects could be reversed by the selective COX-2 inhibitor, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphanamide (NS-398). Additionally, we sought to determine the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in mediating protection by NS-398 in this model. Rats underwent sham surgery or were pretreated with NS-398 (3, 10, or 30 mg/kg) intraperitoneally 1 h before 60 min of superior mesenteric artery occlusion and 30 min to 6 h of reperfusion. In some experiments, NS-398 (30 mg/kg) was administered postischemia. Ileum was harvested for COX-2 mRNA and protein, PGE2, myeloperoxidase (inflammation), histology (injury), intestinal transit and PPARgamma protein expression, and DNA-binding activity. COX-2 expression and PGE2 production increased after mesenteric ischemia/reperfusion and were associated with gut inflammation, injury, and impaired transit. Inhibition of COX-2 by NS-398 (30 mg/kg, but not 3 or 10 mg/kg) not only reversed the deleterious effects of COX-2, but additionally induced expression and nuclear translocation of PPARgamma. NS-398 given postischemia was equally protective. In conclusion, COX-2 may function as a proinflammatory mediator in a rodent model of mesenteric ischemia/reperfusion. Reversal of gut inflammation, injury, and impaired transit by high-dose NS-398 is associated with PPAR activation, suggesting a potential role for PPAR-gamma in shock-induced gut protection.     

Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents

Marijuana has been reported to be an effective antinauseant and antiemetic in patients receiving cancer chemotherapy. Whether this is due to psychological changes, central antiemetic properties and/or direct effects on gastrointestinal (GI) function is not known. The purpose of these investigations was to determine whether the major constituents of marijuana and the synthetic cannabinoid nabilone have any effects on GI function which can be detected in rodent models of GI transit and motility. Intravenous delta 9-tetrahydrocannabinol (delta 9-THC) slowed the rate of gastric emptying and small intestinal transit in mice and in rats. Delta 9,11-THC, cannabinol and nabilone given i.v. also inhibited small intestinal transit in mice, but were less effective in reducing gastric emptying. Cannabidiol given i.v. had no effect on gastric emptying or intestinal transit. Those cannabinoids which inhibited GI transit did so at doses equal to, or lower, than those reported to produce central nervous system activity. In rats, delta 9-THC produced greater inhibition of gastric emptying and small intestinal transit than large bowel transit, indicating a selectivity for the more proximal sections of the gut. In addition, i.v. delta 9-THC decreased the frequency of both gastric and intestinal contractions without altering intraluminal pressure. Such changes probably reflect a decrease in propulsive activity, without change in basal tone. These data indicate that delta 9-THC, delta 9,11-THC, cannabinol and nabilone (but not cannabidiol) exert an inhibitory effect on GI transit and motility in rats.     

Supplementation and inhibition of nitric oxide synthesis influences bacterial transit time during bacterial translocation in rats

In the obstructed gut, nitric oxide (NO) may influence intestinal barrier function and translocation of bacteria. By using a novel experimental approach, we investigated the effect of supplementation and inhibition of NO synthesis on the time interval necessary for translocation of green fluorescent protein-transfected Escherichia coli (GFP-uv E. coli) in a rat model of small bowel obstruction. In anesthetized Wistar rats, 4 x 10(8) GFP-uv E. coli were administered into a reservoir of terminal ileum formed by ligature. Animals were randomized to receive either i.v. arginine (10 mg/kg), aminoguanidine (300 mg/kg), L-NAME (25 mg/kg), or saline (control). Translocation of GFP-uv E. coli was assessed using intravital video microscopy. Minimal transit time of translocation was measured as time from injection of GFP-uv E. coli into the gut lumen until bacteria were observed in the lamina submucosa and as time from injection of bacteria into the gut lumen until bacteria were observed in the lamina muscularis propria. Minimal transit times were expressed as mean +/- SD. Bacterial translocation into the submucosa and muscularis propria took 36 +/- 7 min and 81 +/- 9 min, respectively in control animals receiving saline. Aminoguanidine and L-NAME caused a marked delay of minimal transit time into the submucosa (63 +/- 5 min and 61 +/- 7 min, respectively; P < 0.05). Arginine significantly accelerated bacterial translocation into the muscularis propria (61 +/- 9 min, P < 0.05). GFP-uv E. coli were detected on frozen sections of small bowel, mesentery, liver, and spleen 2 h after GFP-uv E. coli administration in all animals. A marked upregulation of inducible NO synthase (NOS) in the obstructed bowel segment was demonstrated on immunohistochemistry. The assessment of a newly defined parameter, minimal bacterial transit time, may serve as an additional functional aspect of intestinal barrier function for pathophysiological and pharmacological studies. Aminoguanidine, L-NAME, and arginine were effective in influencing minimal transit time of E. coli during small bowel obstruction.     

Gastrointestinal motor alterations induced by precipitated benzodiazepine withdrawal in rats.

The effects of benzodiazepine withdrawal on intestinal motor activity and propulsion were investigated in two groups of diazepam-dependent rats (15 mg/kg/day for 8 days). Withdrawal was precipitated by injection of two benzodiazepine antagonists (Ro 15.1788 and PK 11.95) acting on central and peripheral-type receptors, respectively. Intestinal motor activity was assessed by implanting electrodes for long-term electromyographic recordings. Gastrointestinal transit was evaluated after gavage by a marker (51CrO4Na2) and radioactivity counting. Both RO 15.1788 (15 mg/kg) and PK 11.195 (5 mg/kg) triggered an abstinence syndrome with behavioral and autonomic signs. At the intestinal level, Ro 15.1788 induced a phase of strong irregular spiking activity (173 +/- 63 min) which remained located in the duodenum. In contrast, PK 11.195 induced a period of propagated myoelectric complexes characterized by phases II and III of high amplitude. The cecal frequency was doubled during the 1st hr after withdrawal induced by the two antagonists. Both Ro 15.1788 and PK 11.195 at this dosage had no effect per se on intestinal motility in vehicle-treated rats. In the second group of rats, gastric emptying was enhanced by 49.4 and 45.6% by Ro 15.1788 and PK 11.195, respectively. In contrast, PK 11.195 was able to accelerate the intestinal transit more than did Ro 15.1788 (geometric center, 5.9 +/- 0.43 and 5.3 +/- 0.49, respectively, vs. 4.1 +/- 0.31 in control rats). Our study shows that precipitated benzodiazepine withdrawal in diazepam-dependent rats induces alterations of the intestinal myoelectrical activity leading to an increase of the gastrointestinal transit. Central and peripheral-type receptors are involved in these effects.     

Intravenous clonidine produces hypoxemia by a peripheral alpha-2 adrenergic mechanism

Intravenous injection of the alpha-2 adrenergic agonists, clonidine and xylazine, have been previously shown to produce hypoxemia in sheep. To characterize this effect further, clonidine and ST-91, a clonidine analog that does not cross the blood-brain barrier, were injected i.v. in 10 conscious ewes. Although both clonidine (3-15 micrograms/kg) and ST-91 (3-30 micrograms/kg) produced arterial hypoxemia, clonidine was more effective (arterial PO2 was 91 +/- 4 mm Hg after saline, 30 +/- 3 mm Hg after 15 micrograms/kg of clonidine and 43 +/- 6 mm Hg after 30 micrograms/kg of ST-91; mean +/- S.E., P less than .0001). ST-91 increased mean arterial blood pressure in a dose-dependent manner (P less than .0001), whereas clonidine did not affect blood pressure. Clonidine-induced hypoxemia was inhibited in a dose-dependent manner by the alpha-2 adrenergic antagonist idazoxan (0.01-1 mg/kg, complete inhibition after 1 mg/kg; P less than .0001), the hydrophilic alpha-2 adrenergic antagonist DG-5128 (0.1-10 mg/kg, 62 +/- 7% inhibition after 10 mg/kg; P less than .0005) and by infusion of prostacyclin (0.15-0.5 microgram/kg/min, 57 +/- 7% inhibition after 0.5 micrograms/kg/min; P less than .05). Hypoxemia was not inhibited by the opiate antagonist naloxone (1 mg/kg), the alpha-1 adrenergic antagonist prazosin (1 mg/kg) or the prostaglandin synthetase inhibitor ibuprofen (12.5 mg/kg). To characterize pulmonary vascular effects, clonidine was injected i.v. in four anesthetized, mechanically ventilated ewes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of ceftriaxone on intestinal transit time

Ceftriaxone reduces gallbladder and ileal contractility. Many studies have shown that ceftriaxone causes biliary sludge and pseudolithiasis. However, its effect on intestinal transit time has not been investigated. This study aimed to investigate the effect of ceftriaxone on intestinal transit time. Sixteen rats were examined in two groups: The study group (group A, n = 8) was administered with 100 mg/kg ceftriaxone intramuscularly for 7 days. The control group (group B, n = 8) was administered with intramuscular distilled water for 7 days. On the seventh day, a mixture of 2 ml barium and saline was given orally to both groups. Barium transit was evaluated using serial digital X-ray images. The stomach was full and the transition into the small intestine loop was observed in all rats at 45 min in both groups. At the 2nd hour, colonic transition was observed in two rats in group A (2/8, 25%) and in seven rats in group B (7/8, 87.5%). At the 4th hour, five (62.5%) rats in group A had transverse colonic transition, and all rats in group B (8/8, 100%) had transverse and/or left colonic transition. At the 6th hour, no rat in group A had rectal transition, and all rats in group B (8/8, 100%) had complete passage of colonic contrast material. Ceftriaxone significantly prolongs the small intestine transit time, large intestine transit time, and total intestinal transit times.     

Cholinergic neurons mediate intestinal propulsion in the rat

Cholinergic influences on intestinal propulsion were determined in vivo in fasted rats by measuring the movement of a nonabsorbable radioactive marker along the intestine following treatment with cholinergic drugs. The marker was instilled directly into the intestine via a previously implanted cannula. The direct effects of cholinergic drugs on intestinal contractions were determined in vitro using isolated segments of duodenum and jejunum. Neostigmine (0.1 mg/kg) produced a marked increase in intestinal transit that was blocked by atropine pretreatment (1.0 mg/kg) but not hexamethonium pretreatment (20 mg/kg). Atropine pretreatment alone significantly delayed transit while hexamethonium treatment alone did not affect intestinal transit. Neostigmine produced a concentration-dependent (0.3-30 microM) increase in contractions in both duodenal and jejunal segments in vitro. Prior incubation of the tissues with atropine (10(-7) M) blocked the neostigmine-induced contractions while prior incubation with hexamethonium (10(-6) M) did not. Contractions produced by substance P were not affected by atropine or hexamethonium. These data indicate that enhancement of cholinergic neurotransmission by neostigmine treatment increased intestinal propulsion and that this effect was mediated at muscarinic cholinergic receptors. Furthermore, inhibition of ongoing cholinergic transmission by atropine treatment reduced intestinal propulsion. The increase in transit produced by neostigmine may result from a stimulation of intestinal contractions. Cholinergic neurons are important mediators of intestinal propulsion in the rat as in other species.     

Mechanism of the clonidine-induced protection against acetylcholinesterase inhibitor toxicity

Clonidine, an alpha-2 adrenergic agonist can inhibit the release of acetylcholine from central and peripheral cholinergic neurons. This study was designed to examine the ability of clonidine to protect animals from the toxic manifestations of cholinesterase poisoning. Physostigmine, a central and peripheral cholinesterase inhibitor produced tremors, and at high doses death, by respiratory paralysis. Mice were injected with physostigmine at a dose (0.75 mg/kg) which evoked tremors in 100% and death in 90% of the animals. Clonidine pretreatment (0.3 mg/kg) increased the onset latency to tremor from 5 to 20 min, increased the onset latency to death from 12 to 24 min and increased the percentage of survivors to 50%. Yohimbine (1 mg/kg) reversed these protective effects of clonidine. The physostigmine-induced accumulation of forebrain and hindbrain acetylcholine also was reduced by 50% in both brain regions in clonidine-pretreated mice. Neostigmine, a selective peripheral cholinesterase inhibitor, induced respiratory paralysis which was not affected by clonidine pretreatment. These findings indicate that central cholinergic neurons involved in the regulation of respiration and fine motor control, but not peripheral motor neurons, are inhibited by clonidine acting on alpha receptors.     

Thoracic epidural clonidine attenuates haemodynamic responses induced by endobronchial intubation

Laryngoscopy and endobronchial intubation usually cause transient hypertension and tachycardia. We investigated whether thoracic epidurally injected 3 microg/kg clonidine attenuates cardiovascular responses to intubation compared with 2 microg/kg fentanyl and 1 mg/kg lidocaine. Epidural catheterization was performed at the T6-T7 or T7-T8 intervertebral space, and saline or clonidine in saline was injected 20 min before anaesthetic induction. Anaesthesia was induced using 5 mg/kg thiopental sodium and 0.1 mg/kg vecuronium. Laryngoscopy and endobronchial intubation were performed 2 min later. Mean blood pressure and heart rate were measured throughout anaesthetic induction. In the control group and the fentanyl group, mean blood pressure and heart rate 3 min after endobronchial intubation were elevated significantly compared with baseline. In the clonidine group, however, mean blood pressure and heart rate did not increase compared with baseline. The control group had higher mean blood pressure and heart rate than the clonidine group 3 min after endobronchial intubation. Thoracic epidural clonidine may attenuate the haemodynamic response to endobronchial intubation.     

The involvement of central noradrenergic systems and corticotropin-releasing factor in defensive-withdrawal behavior in rats

The role of the central noradrenergic systems and corticotropin-releasing factor (CRF) in modulating defensive withdrawal behavior was studied in rats. The apparatus consisted of a small chamber set on one side of a one-meter open field, into which the rat was placed to start the test. When rats were unfamiliar with the apparatus, they displayed species typical defensive withdrawal behavior with long latencies to emerge from and a high proportion of time spent in the small chamber. Intraperitoneal administration of clonidine (0.03 mg/kg), l-propranolol (2.5 micrograms/kg), prazosin (0.1 mg/kg) or chlordiazepoxide (CDP, 5 mg/kg) each significantly decreased the latency to emerge from and the mean time spent in the small chamber (MTIC) and increased the number of chamber entries. When rats were familiar with the apparatus, prior restraint for 20 min significantly increased the latency and MTIC, and decreased the number of chamber entries and rears, but did not alter locomotor activity. Prazosin, clonidine, CDP, l-propranolol and the CRF-antagonist, alpha-helical CRF9-41 (25 micrograms i.c.v.), reversed the restraint-induced increase in the latency and MTIC. CRF (10-100 ng i.c.v.) dose-dependently induced defensive withdrawal behavior in rats familiar with the apparatus; the minimum statistically significant dose was 50 ng. dl-Propranolol (5 mg/kg) and CDP blocked the CRF-induced changes in the latency to emerge and the MTIC; whereas clonidine and prazosin significantly reduced the latency, but had no statistically significant effects on the MTIC. Phenylephrine (25-200 ng i.c.v.) dose-dependently induced defensive withdrawal behavior. This effect of phenylephrine (200 ng) was significantly antagonized by prazosin or alpha-helical CRF9-41 (25 or 50 mg i.c.v.), but not by CDP. Our results suggest that the hyperactivity of the central noradrenergic systems caused by exposure to the novel environment may stimulate the release of CRF, which through some unknown mechanism induces defensive withdrawal behavior in rats. Activation of beta adrenergic receptors may also induce defensive withdrawal.     

Effects of intravenous ketamine on gastrointestinal motility in the dog

Objective The purpose of this trial was to clarify the effets of intravenous ketamine at anaesthetic and sub-anaesthetic dosages on gastrointestinal motility.Design 20 beagles (group 1: 3 mg/ketamine/kg/h,n=10; group 2: 30 mg ketamine/kg/h,n=10), were investigated. Gastric emptying (nuclide gastric emptying studies, liquid and semi-solid test meal), intestinal transit time (Hydrogen breath test with lactulose) and intestinal motor function (perfusion manometry with 8 measuring ports) were determned. As a control condition, the tests were performed on all dogs in the two groups during infusion of physiological saline solution.Results No significant differences in the motility patterns were present between 3 mg ketamine/kg/h and the control condition. For group 2, a moderately significant (p<0.05) increase in the interdigestive motility index was observed for 30 mg k ketamine/kg/h. However, this did not change the transit criteria. There was no significant difference between ketamine and control condition tests with regard to cycle and phase lengths or the propagation rate of the activity front.Conclusions We conclude that ketamine provokes no basic changes in gastrointestinal motility, at either sub-anaesthetic doses. It can there-fore be used to advantage in the continuous postoperative analgesia of intensive care patients, where repeated interventions are necessary and no cardiopulmonary contraindications are present.Parts of this study have been presented on the 6th European Symposium on Gastrointestinal Matility, Barcelona 1992     

Oral papaverine prevents morphine-induced constipation without interfering with analgesia achieved with oral morphine

Long-term administration of morphine for the treatment of chronic pain produces constipation; this requires the use of laxatives, which impair water absorption and upset the electrolyte balance. Morphine-induced constipation is mainly due to inhibition of the propulsive movement of the gastrointestinal tract combined with spastic contraction of smooth circular muscles as a result of drug binding to opioid receptors in the tract. Since papaverine lacks affinity for opioid receptors but relaxes smooth muscle, it seemed possible that oral papaverine might be capable of diminishing constipation without impairing the analgesia achieved with morphine. For this purpose, experiments were carried out on rats: constipation was checked for by measuring the intestinal transit time, and analgesia was assessed by measuring the latency of the tail-flick response to radiant heat or nociceptive activity in single neurons of the thalamus evoked by supramaximal electrical stimulation of afferent C fibres in the sural nerve. Morphine and papaverine were administered by the oral route. Control animals received saline. To measure the intestinal transit time, India ink solution was given orally. Morphine (2.5 and 5 mg/kg orally) prolonged the transit time from approx. 420 min in the controls to more than 600 min, a dose of 2.5 mg/kg producing the maximum effect. Papaverine (0.5, 1, and 2 mg/kg) administered orally together with morphine significantly reduced morphine-induced constipation (Tables 1, 2). Papaverine given alone at a dose of 2 mg/kg caused no change in transit time, while 5 mg/kg significantly increased it (Table 2). The latency of the tail-flick response was increased by oral morphine (2.5 and 5 mg/kg) at 1, 2, and 3 h after administration. Papaverine (0.5, 1 and 2 mg/kg) given in combination with morphine left the antinociceptive effect of morphine unchanged (Figs. 1-3). A study of the nociceptive activity evoked in thalamus neurons of rats under urethane anaesthesia indicated that intestinal absorption of morphine was blocked. Therefore, metoclopramide (0.15 mg/kg) was injected i. v. 10 min before oral administration of morphine or the combination of morphine plus papaverine. Subsequently, morphine produced a dose-dependent depression of evoked nociceptive activity (Fig. 4), the mean effect amounting to 60 % of the control activity and being produced by 2.5 mg/kg (Fig. 5). Since in former experiments on nociceptive activity evoked in thalamus neurones it has been found that the ED(50) of i. v. morphine is 0.05 mg/kg, it is very likely that the presystemic elimination of orally administered morphine is very high and, in addition, that the efficiency of its active metabolite, morphine-6-glucuronide, is rather poor. When morphine 2.5 mg/kg was given together with papaverine 0.5 mg/kg, and morphine 5 mg/kg was administered in combination with papaverine 2 mg/kg, there was no significant reduction in the depressant effect of morphine on nociceptive activity evoked in thalamus neurons (Figs. 6, 7). The results suggest that papaverine given by the oral route may reduce morphine-induced constipation without impairment of the analgesic action of morphine in patients suffering from pain.     

LACK OF PRESYNAPTIC EFFECTS OF KETANSERIN ON CARDIAC NORADRENERGIC NERVE TERMINALS IN THE SHR

The potential cardiac presynaptic effects of ketanserin (K) (0.01-3.00 mg/kg IV) were investigated in pithed SHR in 4 experimental conditions: (a) basal heart rate (HR); (b) HR increased by selective cardiac sympathetic stimulation (SS); (c) HR increased by aminophylline infusion; and (d) HR increased by SS and brought back to basal value by clonidine. Control groups were treated with saline. In the 4 types of experiments, K, starting from 0.3 mg/kg, induced almost identical and dose-dependent decreases in HR (maximal reduction: 45 beats/(min at 3 mg/kg). Thus we conclude: (1) that K is devoid of any presynaptic facilitatory effect on norepinephrine release since it was unable to raise HR in experiment D; (2) that K is devoid of any presynaptic inhibitory effect on norepinephrine release since it lowered HR to the same extent in both experiments B (noradrenergic tachycardia) and (non-noradrenergic tachycardia); and C (3) that the bradycardia which was induced by high doses of K (much above those required to block 5-HT2 and alpha 1-adrenergic receptors) and which was of similar magnitude in the 4 experimental conditions is probably due to a direct, nonspecific depressant effect of K on the sinus node.     

莫索尼定与可乐定对肾性高血压大鼠动脉压及心率作用的比较

背景莫索尼定是高选择性的第二代中枢性降压药,而可乐定是第一代中枢降压药,用于临床治疗高血压,但副作用较多.目的比较莫索尼定与可乐定对肾性高血压大鼠的作用特点.设计随机对照动物实验.单位南通大学医学院药理学教研室.材料实验于2004-09/12在南通医学院完成.选择SD大鼠110只,鼠龄60 d,体质量(180±30)g.方法SD大鼠左侧肾动脉用0.2 mm或0.25 mm内径的银夹狭窄,右侧肾脏不触及,造成二肾一夹型(two-kidney one-clip,2K-IC)肾性高血压模型.①采用尾动脉间接测压法,一次或连续口服给药,分别测定清醒肾性高血压大鼠血压及其心率变化.一次口服给药的降压实验大鼠随机分成5组,每组10只,盐酸莫索尼定1 mg/kg组、3 mg/kg组、10 mg/kg组、盐酸可乐定(1 mg/kg)组作阳性对照、生理盐水组作阴性对照.根据盐酸莫索尼定对血压作用特点,测定给药后1,4,24,48,72 h时间点的血压,分别与给药前或生理盐水作用相比较.连续每天1次口服给药降压实验分组同上,连续给药7 d,1次/d,测定每天给药前、给药后1 h血压及心率的变化,停药后观察3 d.人拟推荐剂量为盐酸莫索尼定0.4 mg/kg左右,按动物体表面积换算,大鼠口服剂量约为0.04 mg/kg左右.②采用颈动脉插管直接测压法测定麻醉肾性高血压大鼠血压及其心率变化以0.2mg/kg的药液灌胃,大鼠随机分5组,每组10只,分别为盐酸莫索尼组、0.13 mg/kg组、0.4 mg/kg组、1.3 mg/kg组、盐酸可乐定0.13 mg/kg组及生理盐水对照组,测定给药前及给药后不同时间的平均动脉压.主要观察指标一次或连续口服给药情况下清醒和麻醉肾性高血压大鼠血压及其心率变化.结果在实验过程中,各组大鼠无脱失,全部进入结果分析.①清醒肾性高血压大鼠一次大剂量口服莫索尼定降压与心率减慢作用呈剂量依赖性,其10倍剂量与可乐定作用相近;连续小剂量口服莫索尼定降压百分率与可乐定相仿,心率减慢作用弱而短暂.②麻醉肾性高血压大鼠,一次口服莫索尼定降压作用与剂量相关;莫索尼定3～10倍剂量与可乐定降压百分率差异无显著性意义(P＞0.05).结论大剂量一次口服给药,莫索尼定对清醒肾性高血压大鼠的降压作用呈剂量依赖性,其10倍剂量与可乐定作用相当;对麻醉肾性高血压大鼠莫索尼定3～10倍剂量与可乐定降压相当.小剂量连续口服给药,莫索尼定和可乐定等剂量对肾性高血压大鼠的降压作用相当.     

Central adenosine signaling plays a key role in centrally mediated hypotension in conscious aortic barodenervated rats

We tested the hypothesis that clonidine-evoked hypotension is dependent on central adenosinergic pathways. Five groups of male, conscious, aortic baroreceptor-denervated (ABD) rats received clonidine (10 microg/kg i.v.) 30 min after i.v. 1) saline, 2) theophylline (10 mg/kg), or 3) 8-(p-sulfophenyl)theophylline (8-SPT) (2.5 mg/kg) or 1 h after i.p. 4) dipyridamole (5 mg/kg) or 5) an equal volume of sesame oil. Blockade of central (theophylline) but not peripheral (8-SPT) adenosine receptors abolished clonidine hypotension. In contrast, dipyridamole substantially enhanced the bradycardic response to clonidine. In additional groups, intracisternal (i.c.) dipyridamole (150 microg) and 8-SPT (10 microg) enhanced and abolished, respectively, clonidine (0.6 microg i.c.)-evoked hypotension. Because clonidine is a mixed I1/alpha2 agonist, we also investigated whether adenosine signaling is linked to the I1 or the alpha2A receptor by administering the selective I1 (rilmenidine, 25 microg) or alpha2A [alpha-methylnorepinephrine (alpha-MNE), 4 microg] agonist 30 min after central adenosine receptor blockade (8-SPT; 10 microg i.c.) or artificial cerebrospinal fluid. The hypotensive response elicited by rilmenidine or alpha-MNE was abolished in 8-SPT-pretreated rats. To delineate the role of the adenosine A2A receptor in clonidine-evoked hypotension, i.c. clonidine (0.6 microg) was administered 30 min after central adenosine receptor A2A blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-epsilon]-1,2,4-triazolo[1,5-c]-pyrimidine (SCH58261); 150 microg i.c.]. The latter virtually abolished the hypotensive and bradycardic responses elicited by clonidine. In conclusion, central adenosine A2A signaling plays a key role in clonidine-evoked hypotension in conscious aortic barodenervated rats.     

Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine

The effects on nociception, blood pressure and heart rate of clonidine administered intrathecally to the lumbar level were determined in conscious rats and in rats anesthetized lightly with pentobarbital. In anesthetized rats, intrathecal (i.t.) clonidine (3.2-32.0 micrograms) inhibited the nociceptive tail-flick reflex and had biphasic effects on blood pressure; lesser doses (1.0-10.0 micrograms) produced depressor effects, whereas a greater dose (32.0 micrograms) produced a marked pressor response. Clonidine also produced biphasic effects on blood pressure in conscious rats, with the dose-response function shifted upward and to the left of that observed in anesthetized rats. The depressor and antinociceptive effects of 3.2 micrograms of clonidine were antagonized by pretreatment with yohimbine (30.0 micrograms i.t.) but not by prazosin (30.0 micrograms i.t.) or by yohimbine (0.1 mg/kg i.v.). Thus, these effects of clonidine are mediated by spinal alpha-2 adrenoceptors. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was accompanied by marked bradycardia, and similar cardiovascular effects were observed when this dose of clonidine was administered either i.v. or to the cervical level of the spinal cord. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was not reduced significantly by i.t. pretreatment with yohimbine (30.0 micrograms) or prazosin (30.0 micrograms), but was diminished significantly by i.v. pretreatment with yohimbine (1.0 mg/kg), prazosin (0.1 mg/kg) or phentolamine (2.0 mg/kg). Neither chlorisondamine (2.5 mg/kg i.v.) or the V1-vasopressin receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(o-methyl)tyrosine]Arg8-vasopressin (10.0 micrograms/kg i.v.) reduced the clonidine-produced pressor response. After i.t. injection of 32.0 micrograms of [3H]clonidine, peak levels of radioactivity in the blood were observed at 2 min and corresponded to a blood concentration of 38.8 ng/ml. Injection of an i.v. bolus dose (2.5 micrograms/kg) sufficient to produce these blood levels resulted in a transient pressor response. These results suggest that after i.t. administration of greater doses of clonidine, sufficient amounts of the drug are rapidly redistributed systemically to produce pressor effects by stimulation of vascular alpha adrenoceptors.     

The effect of coffee on gastric emptying and oro-caecal transit time

BACKGROUND: The consumption of coffee allegedly induces or aggravates gastrointestinal symptoms. In order to investigate the effect of coffee on gastrointestinal motility we studied the effect of coffee on gastric emptying and oro-caecal transit time. METHODS: In a randomised, controlled, cross-over study gastric emptying and oro-caecal transit time were studied in 12 healthy volunteers, using applied potential tomography and lactulose hydrogen breath test, respectively. After 1 day of coffee abstinence and an overnight fast, coffee or the control drink (water) was drunk and 10 min thereafter a liquid nutrient meal was ingested together with lactulose. During 150 min, recordings were made with applied potential tomography and breath samples were taken every 5 min. Lag-phase duration and gastric half-emptying time were determined by two blinded observers. RESULTS: The lag-phase duration after coffee (median 19.8 min, range 6-47 min) was not significantly different from that after water (median 19.3 min, range 11-37.5), nor was the gastric half-emptying time (median 75.7 min, range 56-157.6 vs. median 83.4 min, range 64. 6-148.4). Likewise, coffee had no significant effect on oro-caecal transit time (median 135 min, range 60-270 vs. median 140 min, range 55-270). No significant correlation between any of these parameters and mean daily coffee intake was found. CONCLUSIONS: Coffee does not affect gastric emptying of a liquid meal or small bowel transit.