Effects of 5-hydroxytryptamine and morphine on the stomach motility in situ.

The effects of 5-hydroxytryptamine and morphine on the stomach motility were determined in in situ experiments. 5-Hydroxytryptamine and morphine inhibited stomach motility of unanaesthetized cats but did produce a slight contraction of the stomach of anaesthetized cats. In unanaesthetized rabbits, 5-hydroxytryptamine caused a contraction, followed by an inhibition of motility, and morphine depressed motility. The 5-hydroxytryptamine-induced contraction is a direct action on smooth muscle and the inhibition of spontaneous movement due to 5-hydroxytryptamine may be, in part, mediated through catecholamine-release and in part, result from paralysis of the receptors for 5-hydroxytryptamine in the cholinergic nerves in the stomach. In anaesthetized rabbits, 5-hydroxytryptamine produced contraction and morphine had no effect. In unanaesthetized guinea pigs, 5-hydroxytryptamine caused a contraction and morphine abolished spontaneous movement of the stomach. In anaestetized guinea-pigs, 5-hydroxytryptamine caused contraction and morphine produced no effect. The 5-hydroxytryptamine-induced contraction of the guinea pig stomach is indirect. From these results it is concluded that the differences in the modes of actions of 5-hydroxytryptamine and morphine on gastric motility are related to differences in species and experimental conditions such as anaesthesia.     

Effect of 5-hydroxytryptamine precursors on morphine analgesia in the formalin test

The 5-hydroxytryptamine (5HT) precursors tryptophan and 5-hydroxytryptophan had no significant effect on the behavior of rats in the formalin test when given by themselves. However, both compounds significantly attenuated the analgesic effect of morphine in the formalin test. The 5HT antagonist methysergide enhanced the antinociceptive effect of morphine but systemic 5HT had no effect. Assays of whole brain and spinal cord indoles revealed different patterns as a result of tryptophan or 5-hydroxytryptophan loading. The effect common to both treatments was an increase in brain 5HT. There was no effect of morphine on any measure. Formalin injection by itself did not alter indole levels in the brain or spinal cord. Our results, taken in conjunction with previous work, suggest that 1) 5HT in the spinal cord does not influence pain perception in the formalin test and 2) 5HT in the brain can antagonize morphine analgesia in the formalin test. We conclude that there may be circumstances in which the use of 5HT precursors for clinical pain management may be contraindicated.     

Interaction between picrotoxin and 5-hydroxytryptamine in the superior cervical ganglion of the cat

1. Electrophysiological techniques were utilized to study the actions of 5-hydroxytryptamine (5-HT) and picrotoxin on the superior cervical ganglion of the cat.2. The intra-arterial administration of 5-HT to the ganglion elicited both depressant and excitatory actions. In low doses (0.01-0.5 mug) the amine produced a depression of ganglionic transmission. In larger doses (2-50 mug) it produced an excitation of ganglion cells (early discharge) and an initial enhancement of transmission, which was followed by depression. Picrotoxin (25-500 mug, i.a.) blocked the initial excitatory effects of 5-HT but did not block the depression. Picrotoxin did not antagonize the excitatory actions of injected cholinomimetic agents or potassium chloride.3. In ganglia conditioned by repetitive stimulation of the preganglionic nerve (30 Hz for 30 s) 5-HT also elicited a late-occurring and very prolonged discharge on certain postganglionic nerves (;spinal') but not on others (external carotid). The late discharge was only partially depressed by picrotoxin.4. Recordings from the surface of the superior cervical ganglion revealed that 5-HT produced three types of ganglionic potentials: (1) an initial transient depolarization which coincided with the early discharge, (2) a late-occurring, prolonged depolarization which coincided with the late discharge, and (3) a hyperpolarization which in some experiments accompanied the depression of transmission. The late depolarization and hyperpolarization were not observed in every experiment. Picrotoxin (25-500 mug) blocked the initial depolarization, but did not block the late depolarization or the hyperpolarization.5. It is concluded the 5-HT can produce three distinct responses in the superior cervical ganglion: a depressant effect and two types of excitation. It seems likely that depression and excitation occur via the activation of different receptors, since picrotoxin selectively blocks the latter. The finding that picrotoxin is a 5-HT antagonist in peripheral ganglia raises the possibility that picrotoxin might also influence tryptaminergic mechanisms in the central nervous system.     

Intestinal effects of 5-hydroxytryptamine and morphine in guinea pigs, dogs, cats and monkeys

Intestinal introluminal pressure was measured in vivo in anesthetized guinea pigs, dogs, cats ad monkeys. In guinea pigs, but not in the other species, the intestinal stimulatory effect of 5-hydroxytryptamine was antagonized by morphine. The 5-HT-blocking action of morphine in intestine seems to be unique to the guinea pig.     

Involvement of the periaqueductal grey matter and spinal 5-hydroxytryptaminergic pathways in morphine analgesia: Effects of lesions and 5-hydroxytryptamine depletion

1 Electrolytic lesions of the periaqueductal grey matter (PAG) were made in rats. The analgesia produced by intraperitoneal injection of morphine (10 and 20 mg/kg), tested by the tail flick and hot plate methods, was substantially reduced in the lesioned rats. Baseline pain thresholds were unaffected by the lesions.

2 The lesion effects were not due to damage to the dorsal raphé nucleus. The extent of histologically determined damage to the dorsal raphé and the resulting decrease in striatal 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations did not correlate with the reduction in morphine analgesia produced by the lesion. Furthermore, microinjections of 5, 6-dihydroxytryptamine (5,6-DHT) into the dorsal raphé nucleus produced a similar fall in 5-HIAA levels but had no effect on morphine analgesia.

3 Selective destruction of the periventricular catecholamine system produced by microinjection of 6-hydroxydopamine (6-OHDA) caused a slight decrease in morphine analgesia, thus raising the possibility that catecholamines may be involved in the action of morphine in the PAG.

4 5,7-Dihydroxytryptamine-induced lesions of the spinal cord 5-hydroxytryptaminergic pathways reduced cord 5-HT concentration by 70% and markedly attenuated morphine analgesia as determined by the tail flick test.

5 These experiments provide additional evidence that the PAG is a major site of action of opiates in producing analgesia. Furthermore, they have demonstrated the probable involvement of spinal 5-hydroxytryptaminergic pathways in the mediation of opiate analgesic effects.

     

Interactions between acetylcholine, 5-hydroxytryptamine, nicotine and morphine on isolated rabbit atria

1. The effects of 5-hydroxytryptamine (5-HT) and morphine on the responses to acetylcholine and nicotine of isolated rabbit atria were studied.2. 5-Hydroxytryptamine (10 mug/ml.) and morphine (20 mug/ml.) blocked the negative chronotropic and inotropic actions of acetylcholine.3. Nicotine (20 mug/ml.) produced stimulation of the atria, which was blocked by dichlorisoprenaline, morphine, 5-HT, bretylium and hemicholinium. Hemicholinium block was reversed by choline.4. In reserpinized preparations, nicotine produced inhibition of atria and this action was also blocked by atropine, 5-HT and morphine. Inhibition induced by nicotine was potentiated by physostigmine.5. 5-Hydroxytryptamine (20 mug/ml.) produced stimulation of atria. This was blocked by bretylium and reduced by hemicholinium. Hemicholinium block was reversed by choline.6. It is concluded that 5-HT in low concentrations acts as a weak agonist at the cholinoceptive receptors and therefore blocks the action of acetylcholine. Furthermore, nicotine and larger doses of 5-HT have actions on ganglionic structures and liberate acetylcholine, which in turn releases catecholamines.     

Interaction of 5-hydroxytryptamine (serotonin) against Aspergillus spp. in vitro

This study examined the direct interaction of serotonin (5-hydroxytryptamine (5-HT)) with Aspergillus species. Accumulation of 5-HT in aspergilli was investigated by immunofluorescence staining and laser confocal scanning microscopy. The influence of 5-HT on fungal ergosterol content, cell membrane integrity, fungal growth and hyphal elongation was determined. 5-HT was localised in the cytoplasm of Aspergillus spp., as 5-HT fluorescent signals appeared after 30min at 4 degrees C and in the presence of inhibitors of oxidative phosphorylation. 5-HT treatment of Aspergillus spp. significantly affected ergosterol synthesis, fungal cell membrane integrity and hyphal elongation (P<0.05). 5-HT treatment for 4h resulted in a lag of re-growth (post-antifungal effect). In conclusion, our findings suggest that 5-HT affects hyphal growth and diminishes fungal cell membrane integrity.     

Role of brain catecholamines and 5-hydroxytryptamine in morphine induced temperature changes in normal and tolerant rats and mice

Summary Morphine (5–20 mg/kg) produced hyperthermia in normal, unrestrained rats. Rats which were chronically treated with morphine became tolerant and physically dependent but did not develop tolerance to the acute hyperthermia. Pretreatment of rats with 6-hydroxydopamine to deplete brain catecholamines potentiated the acute morphine hyperthermia in normal rats but not in tolerant rats. The effect is probably related to brain dopamine. Depletion of brain 5-hydroxytryptamine (5-HT) produced by 5,6-dihydroxytryptamine pretreatment, antagonized the acute morphine hyperthermia in both normal and tolerant rats. Morphine (5–20 mg/kg) produced hypothermia in both normal and morphine tolerant mice. Pretreatment of normal mice with 6-hydroxydopamine depleted brain noradrenaline and dopamine and antagonized the hypothermia. Pretreatment with pargyline and 6-hydroxydopamine caused a greater loss of cerebral dopamine than 6-hydroxydopamine alone and resulted in an acute morphine hyperthermia. Morphine also caused hyperthermia when given to tolerant mice pretreated with 6-hydroxydopamine. Pretreatment of normal mice with 5,6-dihydroxytryptamine totally abolished the acute morphine hypothermia. In tolerant mice treated with 5,6-dihydroxytryptamine morphine caused a rise in temperature. It is concluded that (1) a single dose of morphine given to normal rats shifts a hypothalamic 5-HT: dopamine balance in favour of 5-HT; (2) activation of a 5-HT mechanism causes hyperthermia whereas dopamine mediates hypothermia; (3) rats chronically treated with morphine do not become tolerant to the acute hyperthermia because morphine tolerance has little effect on 5-HT; (4) brain dopamine mechanisms readily develop tolerance to morphine; (5) the hypothermia produced by a single dose of morphine in normal mice is mediated by dopamine and, to a lesser extent, 5-HT mechanisms; (6) the hypothermic mechanisms rapidly develop tolerance to morphine; (7) loss of cerebral dopamine and 5-HT in morphine tolerant mice leads to an acute morphine hyperthermia due to another neurotransmitter.     

Action of 5-hydroxytryptamine on electrical activity of Auerbach's plexus in the ileum of the morphine dependent guinea pig

Guine pigs were made dependent to morphine by a daily s.c. injection of morphine hydrochloride. Half of them were given morphine hydrochloride (50 mg/kg) s.c. 30 min befor sacrifice; these animals were termed ‘morphine-treated’ guinea pigs. The animals in the abstinence syndrome were sacrificed 30 to 40 hr after the last morphine dose. Effective concentrations of 5-hydroxytryptmine on Auerbach's plexus of the guinea pig in the abstinence syndrome was significantly smaller than those on Auerbach's plexus of normal and morphine-treated animals, while the responses to nicotine and caerulein were unchanged. The results suggest that withdrawal of morphine excites the M-receptors in Auerbach's plexus.     

Modulation of neuronal activity in the hippocampus by 5-hydroxytryptamine and 5-hydroxytryptamine1A selective drugs

The interactions between 5-hydroxytryptamine (5-HT), 8-hydroxy-2-(N,N-dipropylamino)-tetralin (8-OH-DPAT), buspirone, 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,2-benzisothiazol-3- (2H)one-1, 1-dioxide-hydrochloride (TVX Q 7821) and ketanserin, and putative 5-HT receptors were analyzed using both radioligand techniques and an in vitro hippocampal slice preparation. The potencies of the drugs were determined at 5-HT1A binding sites labelled by [3H]8-OH-DPAT in hippocampal membranes from the rat. The binding site had similar affinity for 5-HT, 8-OH-DPAT, buspirone and TVX Q 7821, whereas ketanserin was essentially inactive. Physiological effects of these drugs were also examined using an in vitro hippocampal slice preparation. With the exception of ketanserin, application of each drug to the bath modulated the amplitude of the field potential recorded in the pyramidal layer of CA1 evoked by stimulation of Schaffer collaterals. Application of micromolar concentrations of 5-HT produced an initial increase in the population spike followed by a return to near baseline levels within 5 min. By contrast, the amplitude of the population spike was reduced in a dose-dependent manner by micromolar concentrations of 8-OH-DPAT, buspirone and TVX Q 7821, beginning 5 min after application of drug. Ketanserin did not affect the amplitude of the population spike and it did not antagonize the effects of 5-HT, buspirone or TVX Q 7821. Neither buspirone nor 8-OH-DPAT altered the initial increase in population spike induced by 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)     

外周5-羟色胺系统与糖脂代谢平衡研究进展

外周5-羟色胺(5-HT)系统与机体糖脂代谢平衡关系十分密切,本文选取胰岛、肝脏、脂肪组织、骨骼肌4种糖脂代谢敏感的组织和器官来分别阐述5-羟色胺对外周糖脂代谢调控的研究进展.     

Interaction of 5-hydroxytryptamine and ketanserin in rat vas deferens subjected to low frequency field stimulation

The interaction of 5-hydroxytryptamine (5HT) and ketanserin was investigated in isolated rat vas deferens. Ketanserin (10(-7) M) almost completely abolished the phasic and the following rhythmic contractions induced by 5HT, whereas the inhibition by prazosin (10(-6) M) or methysergide (10(-6) M) of 5HT-induced contractions were incomplete. The amplitude of twitch contractions of vas deferens subjected to low frequency (0.1 Hz) field stimulation were substantially unchanged by 5HT (10(-7)-10(-5) M) per se. After pretreatment of the tissue with ketanserin (10(-8)-10(-6) M), 5HT, in a concentration-dependent manner, attenuated the amplitude of twitch contractions. Such attenuation of the amplitude was not observed after pretreatments with methysergide (10(-8)-10(-6) M) or prazosin (10(-7)-10(-5) M). The 5HT-induced inhibition of twitch contractions in the presence of ketanserin was not antagonized by phentolamine, propranolol, methysergide, morphine, promethazine, cimetidine, atropine or indomethacin. It is suggested that 5HT has dual (excitatory and inhibitory) effects upon nerve transmission of rat vas deferens, and only the excitatory effect is suppressed by ketanserin.     

On the role of central nervous system catecholamines and 5-hydroxytryptamine in the nialamide-induced behavioural syndrome

1. Intraperitoneal administration of nialamide, 200 mg/kg, to mice elicited a pronounced increase in motor activity and rectal temperature concomitant with a gradual increase in the concentrations of 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine in the brain.2. In mice treated with L-tryptophan, 300 mg/kg, 1 h before nialamide, the increase in motor activity appeared earlier than after nialamide alone, and the hyperthermia was more pronounced. The increase in 5-HT concentrations in the brain was more pronounced in these animals, whereas the concentrations of NA and dopamine were of the same magnitude as after nialamide alone.3. Treatment with p-chlorophenylalanine methylester-HCl (PCPA), 400 mg/kg, 24 h before nialamide partially antagonized the increase in motor activity and the accumulation of NA and dopamine was not significantly different from that observed after nialamide alone.4. Treatment with PCPA, 800 mg/kg, 72, 48 and 24 h before nialamide, completely antagonized the increase in motor activity and rectal temperature. The accumulation of brain 5-HT was greatly depressed in these animals. The concentrations of dopamine 1, 3 and 6 h and the concentration of NA 6 h after the nialamide injection were significantly lower in the mice given PCPA 800 mg/kg x 3, than in the mice given nialamide alone.5. Administration of DL-5-hydroxytryptophan, 30 mg/kg, 1 h after the nialamide injection, to mice pretreated with PCPA, 800 mg/kg x 3, restored the increase in motor activity and rectal temperature.6. L-Tryptophan, 300 mg/kg, given 1 h before nialamide to mice pretreated with PCPA, 800 mg/kg x 3, elicited a moderate increase in motor activity and a slight increase in the accumulation of 5-HT in the brain when compared to that after PCPA, 800 mg/kg x 3, and nialamide.7. Administration of alpha-methyltyrosine methylester, 200 mg/kg, 2 h before nialamide partially antagonized the increase in motor activity and completely antagonized the increase in rectal temperature elicited by nialamide alone. The accumulation of brain NA and dopamine was inhibited in these animals.8. It is concluded that the excitation in mice, elicited by nialamide, is mediated largely via brain 5-HT, but that also the brain catecholamines seem to contribute to this effect.     

Effects of morphine, physostigmine and raphe nuclei stimulation on 5-hydroxytryptamine release from the cerebral cortex of the cat.

1. The release of 5-hydroxytryptamine (5-HT) from the cerebral cortex and caudate nucleus of brainstem-transected cats and from the cerebral cortex of rats anaesthetized with urethane was determined by radioenzymatic and biological assay. 2. The stimulation of nucleus linearis intermedius of raphe doubles the basal 5-HT release in the caudate nucleus and increases it 3 fold in the cerebral cortex. The effects of the electrical stimulation of the raphe are potentiated by chlorimipramine. 3. Brain 5-HT release is greatly increased by morphine hydrochloride (6 mg/kg i.v.) and by physostigmine (100 microgram/kg i.v.), but not by DL-DOPA (50 mg/kg i.v.). 4. It is suggested that the 5-HT releasing action of physostigmine can contribute to some of its pharmacological effects such as the analgesic effect so far attributed exclusively to its indirect cholinomimetic activity. 5. The 5-HT releasing action of physostigmine seems unrelated to its anticholinesterase activity.     

Urapidil inhibits 5-hydroxytryptamine induced platelet aggregation and 14C-5-hydroxytryptamine uptake in platelets

The effect of urapidil, an a1-antagonist with additional antihypertensive action via central 5HT1A agonism, was determined on platelet aggregation induced by 5HT and adrenaline. The 5HT uptake in human platelets was determined as well. Urapidil inhibited both the 5HT and adrenaline-induced human platelet aggregation and the 5HT uptake by platelets in vitro. The 5HT-induced aggregation was inhibited with a K1 value of 8.8 microM, the adrenaline-induced aggregation with a K1 value of 21.6 microM, and the 5HT uptake non-competitively with a K11 = 11.5 microM and a K12 = 13 microM.     

Interaction between thromboxane A2 and 5-hydroxytryptamine in the radial artery compared to the internal thoracic artery.

The aim of the present study was to investigate if the function of 5-hydroxytryptamine-1B/1D (5-HT1B/1D) receptors in human radial artery (RA) and internal thoracic artery (ITA) can be modified by thromboxane A2 (TXA2) released from the vessel wall in these two arteries that are commonly used in coronary artery bypass grafts. The 5-HT1B/1D agonist sumatriptan contracted the RA with a maximum response of 23.5+/-6.8 mN and a pD2 value of 6.6+/-0.1. The effect of sumatriptan was significantly reduced in the ITA with a maximum of 5.8+/-2.7 mN (P<.05) and a pD2 value of 6.4+/-0.2. The TXA2 receptor antagonist SQ30741 inhibited contractions to sumatriptan in the RA but not in the ITA. It is concluded that the effect mediated by 5-HT1B/1D is augmented by endogenous TXA2 in the RA.     

Uptake of 5-hydroxytryptamine and adrenaline in the liver

A dose of 5-hydroxytryptamine caused a greater contraction of the cat nictitating membrane when injected into the jugular vein than when injected into the portal vein. The difference is attributed to uptake or destruction of 5-hydroxytryptamine by the liver. The effects of portal and jugular injections became equal after administration of the monoamine oxidase inhibitors iproniazid or harmaline. Isoniazid, which does not inhibit monoamine oxidase, did not have this effect. Similarly, the effect of a portal injection of adrenaline was less than the effect of an equal jugular injection of adrenaline. Iproniazid and harmaline increased the effect of a portal injection, but not to equal the effect of a jugular injection. Isoniazid had no effect. Pyrogallol did not alter the ratio between the effects of portal and jugular injections of adrenaline, but increased the responses to both.