Decreased colonic mucus in rats with loperamide-induced constipation

Constipation is a risk factor of colorectal cancer. Mucin is a major component of lumenal mucus, which protects the colorectal mucosa against mechanical and chemical damage. The aim of this study was to evaluate mucus production and to quantitate lumen mucus in a rat model of spastic constipation. We induced constipation with loperamide (1.5 mg/kg), and histochemically evaluated mucus production and the thickness of the mucus layer at the fecal surface. We quantitated the mucus attached to the mucosal surface using colonic perfusion with N-acetylcysteine. While more feces remained in the colon, there was less fecal excretion and lower fecal water content in loperamide-administered rats than in control rats. Crypt epithelial cells contained less mucus in constipated rats than in control rats. The mucus layer at the fecal surface was thinner and less mucus was recovered from the mucosal surface in constipated rats than in control rats. Mucus production of crypt epithelial cells and mucus at the fecal and mucosal surface were reduced by loperamide-induced constipation.     

Effects of brewer's yeast cell wall on constipation and defecation in experimentally constipated rats

Brewer's yeast cell wall (BYC) was tested on constipated male Sprague-Dawley rats that had been induced by loperamide (2 mg/kg of body weight). The preventive effect of BYC on constipation was examined and compared with that of a non-fiber diet (NF) as the control. The dose-response of BYC and the effect on defecation by constipated experimental rats were also compared with the characteristics of cellulose diet (CE) group which served as a control. Defecation was observed to be greater by the rats fed with BYC than by those fed with NF or CE. The fecal water content and level of volatile fatty acids (VFA) in the cecal contents were likewise higher in the rats fed with BYC. These results indicate that the administration of BYC was effective for improving defecation and other parameters related to defecation. These favorable effects of BYC supplemented to the diet are attributed to the fermentation ability, water holding capacity and swelling force in the large intestine.     

Effects of Daily Cocaine and Morphine Treatment on Somatodendritic and Terminal Field Dopamine Release

Daily injections of cocaine or morphine into rodents produces behavioral sensitization such that the last daily injection results in a greater motor stimulant effect than the first injection. To evaluate a role for brain dopamine in behavioral sensitization to cocaine and morphine, tissue slices from the ventromedial mesencephalon (containing dopamine cell bodies), the nucleus accumbens, and striatum (dopamine terminal fields) were obtained from rats pretreated with daily cocaine, morphine, or saline 2-3 weeks earlier. When the tissue slices were depolarized by increasing potassium concentration in the superfusate, the release of endogenous dopamine from the ventromedial mesencephalon of cocaine- and morphine-pretreated rats was significantly decreased. In contrast, the release of dopamine from the nucleus accumbens and striatum was either unaltered or slightly enhanced in rats pretreated with cocaine and morphine. When dopamine was released by amphetamine, a significant decrease in dopamine release from the ventromedial mesencephalon of cocaine-pretreated rats was measured. No other significant changes were measured after amphetamine-induced release. It is postulated that the decrease in dopamine release from the ventromedial mesencephalon of cocaine- and morphine-sensitized rats results in less somatodendritic autoreceptor stimulation, and thereby produces an increase in dopamine neuronal activity.     

Bremazocine induces antinociception, but prevents opioid-induced constipation and catatonia in rats and precipitates withdrawal in morphine-dependent rats

Some in vivo agonist and antagonist properties of the putative k-compound bremazocine were characterized in rats. Bremazocine, at doses from 0.015-32 mg/kg i.p., delayed nociceptive reaction on a 55 degrees C hot-plate with a dose-response curve not readily fitting a single straight line; this effect was antagonized by high doses of naloxone. In the same rats bremazocine did not delay the intestinal transit of a charcoal meal fed 5 min earlier and prevented morphine-induced constipation. This antagonism appeared to be opioid-specific and competitive, with apparent pA2 value 8.56. Catatonia induced by etorphine (0.004 mg/kg s.c.) and constipation induced by etorphine (0.004 mg/kg s.c.) and D-Ala2-D-Leu5-enkephalin (0.1 mg/kg i.p.) were completely antagonized by bremazocine (0.03-8 mg/kg i.p.). Antinociception induced by morphine (10 mg/kg i.v.) and etorphine (0.004 mg/kg s.c.) was only partly prevented. Naloxone (1 mg/kg) and bremazocine (0.015-1 mg/kg i.p.) precipitated a withdrawal syndrome, evaluated as jumping frequency, in rats rendered dependent to morphine. These data suggest the involvement of more than one opioid receptor population in bremazocine action in vivo.     

慢性吗啡预处理减弱急性吗啡对伏隔核谷氨酸能突触传递的影响

吗啡长期作用后会产生成瘾(addiction),严重影响其临床应用。前额叶(prefrontal cortex,PFC)投射至伏隔核(nucleus accumbens,NAc)的谷氨酸能突触对奖赏效应有重要的调节作用,但该突触在吗啡成瘾中的具体作用尚不完全清楚。为探讨PFC至NAc的谷氨酸能突触在成瘾形成过程中的具体作用及其机制,本研究利用成年大鼠在体记录的方式,记录电刺激PFC至NAc谷氨酸能传入纤维引起的NAc壳区场兴奋性突触后电位(filed excitatory postsynaptic potential,fEPSP),观察慢性吗啡/盐水预处理后依次急性皮下注射吗啡及腹腔注射纳络酮对fEPSP幅值和配对脉冲比率(paired-pulse ratio,PPR)的影响。结果显示,与基础fEPSP相比,慢性盐水预处理组急性皮下注射吗啡能够增强fEPSP幅值并减小PPR,纳络酮能够反转这种现象。慢性吗啡预处理组急性皮下注射吗啡增强的fEPSP幅度较盐水预处理组减小,纳络酮同样能够反转吗啡作用;吗啡注射后PPR仅有降低的趋势,而纳络酮注射能够显著增高基础PPR。这些结果表明,吗啡首次作用可通过突触前机制增强PFC到NAc的谷氨酸能突触传递,而慢性吗啡预处理后,由吗啡再次作用诱导的突触前谷氨酸能突触传递增强有所减弱,提示NAc中可能存在对成瘾药物的神经适应性现象。     

Morphine analgesia: 2-way cross tolerance between systemic and intracerebral (periaqueductal gray) administrations.

Two-way analgesic cross tolerance was obtained between systematic and intracerebral morphine injections in the periaqueductal gray. When rats were pretreated with intraperitoneal morphine and tested with intracerebral morphine in the periaqueductal gray, a dose-dependent reduction in analgesia as a function of morphine pretreatment level was obtained. Conversely, when rats were pretreated with intracerebral morphine, significant reductions in analgesia were obtained. These results are further confirmation that the periaqueductal gray matter is an important site for morphine analgesia.     

Prevention of HCl-ethanol induced gastric mucosal injury in rats by Garcinia cambogia extract and its possible mechanism of action

Oral pretreatment of rats with G. cambogia fruit extract (1 g/kg body weight/day at interval of 7 and 15 days) protected gastric mucosa against HCl-ethanol induced damage by decreasing the volume and acidity of gastric juice. Increased lipid peroxidation, decreased activity of antioxidant enzymes, altered levels of protein and glycoproteins in the ulcerated mucosa, and gastric juice were maintained at near normal levels in G. cambogia pretreated rats. The results suggest the anti-ulcer activity of G. cambogia by virtue of its ability to decrease acidity and increase mucosal defense.     

Effect of dietary fiber on morphine-induced constipation in rats

Morphine is used to alleviate chronic cancer pain. However, constipation is a major adverse effect that often detracts from the patient's quality of life. In this study, we investigated the effectiveness of dietary fiber on morphine-induced constipation. Rats were fed on a normal diet or one containing either 10% or 20% apple fiber for two weeks before morphine was administered. In the control diet group, the fecal number and dry weight were decreased by treating with morphine in a dose-dependent manner. Moreover, the motility of the small and large intestines was reduced. The fecal number and weight were increased and the colon motility was promoted by dietary fiber, regardless of whether morphine was being administered. The dietary fiber increased the concentration of short-chain fatty acids (SCFAs) in the cecum. These results suggest that dietary fiber has a preventative effect on morphine-induced constipation by increasing SCFAs in the cecum, and thereby promoting colon motility in rats.     

Some effects of morphine on lipid metabolism in normal,tolerant and abstinent rats

The effects of morphine on lipid levels of plasma and liver were studied in rats. The first injection of morphine induced a decrease in free fatty acids (FFA) and an increase in the plasma triglyceride level. No changes in phospholipid, cholesterol or cholesterol ester concentrations were observed. In chronic morphinized rats the plasma FFA level was unchanged one hour following the injection of morphine and tolerance developed to the depressive effect of the drug. In contrast, the rise in plasma triglycerides persisted, but to a lesser extent. In these animals, the plasma levels of FFA and of triglycerides were lower than in normal rats, when blood was sampled 24 hours after the last injection of morphine. In abstinent rats, a reversal of action of morphine was noticed. Nalorphine induced an increase in plasma FFA levels in normal and abstinent rats but not in chronically morphine-treated animals. In the liver no significant changes occured in lipids in either acute or chronically morphinized rats. The effects of morphine on plasma lipid levels might be linked to the action of the drug on the secretory activity of the adrenals and also to the depressive effect of the drug on the lipolytic activity of adipose tissue which was demonstrated in vitro.     

Possible role of cyclic AMP and dopamine in morphine tolerance and physical dependence.

In chronically morphinized rats undergoing naloxone induced withdrawal the cerebellar Cyclic 3′, 5′ adenosine monophosphate (Cyclic AMP) was significantly higher than the controls. The cerebellar dopamine (DA) and norepinephrine (NE) were decreased, elevated or unchanged depending on the duration of morphine treatment. The corpus striatal DA levels during withdrawal were markedly elevated and the striatal cyclic AMP levels were unchanged. The NE levels in the striatal tissue were either elevated or unchanged depending upon the duration of morphine administration. In sharp contrast to the chronically morphinized rats undergoing naloxone induced withdrawal, the rats made morphine dependent over a period of eight weeks showed quite moderate changes in the striatal and cerebellar cyclic AMP and DA levels. Thus alterations in the DA and the cyclic AMP levels in the central nervous system (CNS) may play an important role in the naloxone induced stereotyped morphine withdrawal behavior.     

The effect of Codonopis bulleynana Forest ex Diels on chronically constipated mice

To verify the laxative effect of Codonopsis bulleyana and its effect on intestinal microbiota, a long-term constipation model was established using 3.0?mg/kg loperamide hydrochloride, after which, the long-term constipation model was administered by 0.2?g/ml high-dose Codonopsis bulleyana water extract. The therapeutic effects were observed by measuring defecation amount and feces moisture content. The composition of intestinal microbiota was detected and analyzed using16S rDNA sequencing technology. The results showed that Codonopsis bulleyana water extract can increase stool quantity and promote intestinal tract movement in constipated mice. Obvious changes were shown in intestinal microbiota of chronically constipated mice treated with Codonopsis bulleyana water extract as the proportion of beneficial bacteria increased in the model treated by Codonopsis bulleyana. Codonopsis bulleyana water extract alleviates constipation symptoms caused by loperamide hydrochloride and improves the intestinal microbiota in constipated mice.     

吗啡成瘾大鼠胰腺外分泌的变化

本实验采用急性吗啡成瘾法,观察了吗啡成瘾大鼠在整体胰导管引流和离体胰片灌流条件下,胰腺对ＣＣＫ８刺激的反应。结果如下：（１）吗啡成瘾大鼠对ＣＣＫ８诱导的淀粉酶分泌反应降低;（２）吗啡成瘾大鼠胰腺组织中淀粉酶含量降低。提示吗啡成瘾大鼠胰淀粉酶合成受到抑制。     

Morphine inhibits TRH-induced gastric contractile activity.

This study investigated the effect of centrally and peripherally administered thyrotropin releasing hormone (TRH) on gastric contractile activity of rats 14, 21, 28 and adult (greater than or equal to 50) days (D) of age, and the effect of morphine pretreatment on that response. Rats were anesthetized with urethane, then a tension transducer was implanted on the anterior gastric corpus. Following baseline recording, rats were pretreated with intraperitoneal morphine (2 mg/kg). TRH (5 micrograms) in saline or saline alone (0.6 microliters) was then injected into the cisternum magnum. Additionally, dose response to TRH was examined in 14- and 50-day-old rats. Intracisternal TRH induced a dose-related increase in gastric contractile activity in both 14- and 50-day-old rats. Higher doses of TRH (10 and 30 micrograms) prolonged the response as compared to low doses. Peripheral morphine pretreatment blocked the TRH-induced increase in gastric contractile activity in all age groups although a higher morphine dose (10 mg/kg) was needed to block the effect in 28D rats. Intravenous TRH (5, 10, 30 micrograms) produced an increase in gastric contractile activity in 14D rats which was blocked by vagotomy.     

Dexamethasone blocks morphine-induced hypothermia in restrained rats

Rats restrained in small plexiglass restraining cages responded to morphine, 30mg/kg, with a pronounced $\text{hypo}$thermia. However, when this same dose of morphine was administered to unrestrained freely moving rats a marked $\text{hyper}$thermia resulted. The absolute magnitude and time course for body temperature changes after morphine were similar in both groups. When restrained rats pretreated with dexamethasone were administered morphine the hypothermic response was not only prevented but a subsequent hyperthermia occured. Morphine injected into unrestrained dexamethasone pretreated rats, however, still elicited a hyperthermia although of slightly lesser magnitude. These findings indicate that restraint is a potent modifier of morphine's effects on thermoregulation and that this effect most probably results from a stress-related activation of anterior pituitary hormone release. The possibility that ACTH or ß-endorphin released by the stress of restraint are responsible for this modification is discussed.     

Chronic morphine treatment and withdrawal increase extracellular levels of norepinephrine in the rat bed nucleus of the stria terminalis

Extracellular levels of norepinephrine (NE) and glutamate (Glu) in the ventral bed nucleus of the stria terminalis (vBNST) of saline- and chronic morphine-treated rats, with or without withdrawal, were studied by means of the in vivo microdialysis technique in anesthetized rats. In addition, the tissue concentration of NE was studied at different rostrocaudal levels of the vBNST. Chronic morphine treatment significantly increased extracellular levels of NE, but not Glu, in vBNST. At 48 h after naloxone-induced morphine withdrawal there was a further significant increase in the extracellular levels of NE, but not Glu, in vBNST. The presence of UK 14304, an alpha(2)-adrenergic agonist, induced a significant decrease in NE extracellular levels in all experimental groups. In contrast, UK 14304 induced a significant decrease in Glu extracellular levels only in saline-treated rats. The results also show that the vBNST presents a rostrocaudal gradient of NE and contains 9.4% of total brain NE. The increase in NE extracellular levels in vBNST induced by chronic morphine treatment and the further increase in NE levels 48 h after naloxone-induced morphine withdrawal suggest that NE in vBNST may be involved in the pharmacological effects of chronic morphine and withdrawal.     

Endogenous nitric oxide modulates morphine-induced constipation.

Administration of morphine in mice causes inhibition of the gastrointestinal transit of a charcoal meal. Morphine-induced constipation in mice seems to depend predominantly on action(s) on the central nervous system since N-methyl morphine, a quaternary derivative, inhibits intestinal transit only when administered intracerebroventricularly (i.c.v.). L- but not D-arginine, given intraperitoneally, reversed the constipation induced by both morphine and its quaternary analogue. L-arginine was ineffective when given i.c.v. and did not reverse atropine-induced constipation. These results suggest that L-arginine preferentially modulates opioid-induced constipation through a stereospecific and peripheral action(s). It is possible that the effect of L-arginine is achieved by increasing the amount of nitric oxide released by non-adrenergic, non-cholinergic nerves in the gut. Thus, L-arginine may represent a useful agent for the treatment of undesirable constipation associated with the use of narcotic analgesics.     

Intravenous morphine infusion (IMF) to drug-naive, conscious rats evokes bradycardic, hypotensive effects, but pressor actions are elicited after IMF to rats previously given morphine

Hemodynamic (blood pressure and heart rate) responses of conscious drug-naive rats were studied following intravenous (i.v.) infusion of sterile saline, morphine sulphate, and then naloxone hydrochloride, as well as of other groups previously injected with morphine sulphate. Those groups chronically given morphine sulphate received twice daily injections of morphine sulphate (5 mg/kg, s.c. per injection) for 3 or 6 days before testing with the i.v. infusion of morphine sulphate. Drugs were infused (135 microL/min) through an indwelling femoral venous catheter via a Harvard infusion pump, and blood pressure was recorded from the abdominal aorta via a femoral arterial catheter. Other pretreatment studies were done to determine the receptor mechanisms mediating the blood pressure responses of drug-naive and chronic morphine-treated rats, whereby equimolar doses (0.32 mumol) of specific receptor antagonists were given as a bolus i.v. injection 5 min after saline but before subsequent infusion with morphine sulphate. Intravenous infusion of morphine sulphate (7.5 mg/kg total over 15 min) to drug-native rats caused a transient but precipitous fall in mean arterial pressure and mean heart rate with an associated rise in mean pulse pressure; these effects were blocked in other groups pretreated with atropine. Interestingly, however, rats chronically injected with morphine sulphate for 3 days previously evoked a transient pressor response when subsequently infused i.v. with morphine sulphate, actions that were blocked in other groups when pretreated i.v. with 0.32 mumol of phentolamine, yohimbine, prazosin, or guanethidine. A greater and persistent pressor response occurred following morphine infusion to groups of rats previously injected over 6 days with morphine sulphate, which was associated with tachycardia during the later stages of the 15-min morphine sulphate infusion period. The prolonged pressor and tachycardic responses of this 6-day chronically injected group were completely blocked in another group pretreated i.v. with both phentolamine and propranolol (0.32 mumol). The results suggest that morphine sulphate infusion to conscious, drug-naive rats evokes classical hypotensive effects due to decreases in mean heart rate caused by activation of parasympathetic vagal activity. With 3 or 6 days of chronic morphine sulphate administration beforehand, subsequent i.v. infusion of morphine sulphate evoked pressor actions felt to be caused by a progressive activation of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)     

两种吗啡依赖大鼠模型脑内单胺神经递质水平的比较

目的通过对吗啡诱导的躯体依赖与精神依赖两种大鼠模型脑内单胺类递质水平的比较,探讨其在吗啡依赖形成中的作用。方法采用剂量递增法复制吗啡依赖大鼠模型,然后用纳洛酮催促,引起躯体戒断症状。连续给予吗啡（5mg／kg,ip）6d,引起大鼠产生显著的条件性位置偏爱效应。脑组织去甲肾上腺素（NE）、5-羟色胺（5-HT）和多巴胺（DA）含量采用荧光分光光度法测定。结果吗啡依赖大鼠催促戒断后脑内NE和5-HT水平明显升高,DA水平下降。吗啡在引起大鼠明显位置偏爱的同时,使大鼠脑内DA和5-HT水平显著升高,NE无明显改变。结论吗啡依赖的形成和戒断与脑内单胺神经递质有密切关系,吗啡依赖的躯体戒断症状与NE升高有关,而吗啡诱导的精神依赖则与脑内DA水平升高有关。     

Reduced tolerance to morphine thermoregulatory effects in senescent rats

Age-related differences in the thermoregulatory response to morphine have been shown in rats. To determine if these age-related differences would be reflected in the acquisition of tolerance, we studied morphine tolerance induced by either a single morphine dose or implantation of a morphine pellet. precipitated withdrawal was also analyzed by inducing withdrawal with naloxone in morphine-pelleted rats. Senescent (26 or 27 month old), mature (10 or 11 month old) and young (3 or 4 month old) male Fischer 344 rats were restrained and changes in rectal temperature were monitored for six hours after morphine administration. Only mature and young rats exhibited increased hyperthermic responses to a second low dose of morphine (5 mg/kg s.c.). Only young rats became tolerant after a single higher morphine dose (25 mg/kg s.c.). All age groups showed tolerance three days after morphine pellet implantation. Hypothermia was equivalent in all age groups when withdrawal was induced by naloxone in morphine-pelleted rats. These results indicate that older rats were more resistant to the acquisition of tolerance to the thermic effects of morphine; however; with continued morphine treatment, rats became tolerant regardless of age.