naloxone and Diarrhea

In this large population-based cohort, individuals with more-severe obesity, central obesity, or genetic predisposition for obesity are at higher risk of developing severe-COVID-19.. The use of different references for the classification of a high %BF implied a difference in the diagnostic sensitivity of the BMI. Higher cutoff points resulted in greater sensitivity and ability to differentiate individuals with and without obesity.

Topics: Acyclic Monoterpenes; Adipose Tissue; Adolescent; Adult; Aged; Aged, 80 and over; Air Pollutants; Air Pollutants, Occupational; Amino Acid Transport Systems; Analgesics, Opioid; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Arthrobacter; Bacteria; Bacteriological Techniques; Benzaldehydes; Biodegradation, Environmental; Biofilms; Biological Transport; Biomarkers; Biomass; Bioreactors; Body Composition; Body Mass Index; Brassica; Brazil; Buprenorphine; Buprenorphine, Naloxone Drug Combination; Caco-2 Cells; Cadmium; Calcium; Calcium Carbonate; Calcium Channels; Catalysis; Cell Degranulation; Cell Line; Cell Membrane; Chitosan; Chromatography, High Pressure Liquid; Chromium; Cobalt; Cohort Studies; Colony Count, Microbial; Composting; Copper; COVID-19; Cross-Sectional Studies; Cytoplasm; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diarrhea; Diethylhexyl Phthalate; Dose-Response Relationship, Drug; Drug Implants; Drug Stability; Drug Synergism; Electroplating; Endometrial Neoplasms; Endometrium; Environmental Monitoring; Environmental Restoration and Remediation; Estradiol; Estrogens; Feces; Female; Food Microbiology; Food Preservation; Fruit and Vegetable Juices; Gasotransmitters; Gastrointestinal Diseases; Gastrointestinal Microbiome; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; Glutathione; Gold; Graphite; Growth Hormone; Harm Reduction; Hot Temperature; Humans; Hydrocortisone; Hydrogen; Hydrogen Peroxide; Hydrogen Sulfide; Hydrogen-Ion Concentration; Ileum; Imidazoles; Injections, Intraperitoneal; Insecticides; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Intestinal Absorption; Light; Lignin; Liver; Magnetics; Male; Manganese; Mast Cells; Melanoma; Membrane Potentials; Metals; Methadone; Microbial Viability; Microplastics; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Middle Aged; Mitochondrial Swelling; Molecular Dynamics Simulation; Monophenol Monooxygenase; Morocco; Naloxone; Naltrexone; Nanocomposites; Nanomedicine; Nanoparticles; Narcotic Antagonists; Neonicotinoids; Nitric Oxide; Nitro Compounds; Nitrogen; Nitrogen Compounds; Obesity; Obesity, Abdominal; Occupational Exposure; Ontario; Opiate Substitution Treatment; Opioid-Related Disorders; Oryza; Overweight; Oxidative Stress; Oxides; Oxygen; Perception; Photoelectron Spectroscopy; Plants; Plastics; Point Mutation; Polychlorinated Biphenyls; Polycyclic Aromatic Hydrocarbons; Potassium; Premenopause; Prodrugs; Prospective Studies; Protons; Pyrolysis; Qualitative Research; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resins, Synthetic; Rhodamines; Risk Factors; ROC Curve; Salmo salar; SARS-CoV-2; Seawater; Severity of Illness Index; Sewage; Social Media; Soil; Soil Microbiology; Soil Pollutants; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Staining and Labeling; Stainless Steel; Steel; Stress, Physiological; Substance Abuse Treatment Centers; Symporters; T-Lymphocytes; Toluene; Triclosan; Ultraviolet Rays; Waist Circumference; Waste Disposal, Fluid; Wastewater; Water Purification; Welding; X-Ray Diffraction; Young Adult

Topics: Adult; Analgesics, Opioid; Chronic Pain; Constipation; Delayed-Action Preparations; Diarrhea; Drug Combinations; Gastrointestinal Tract; Humans; Naloxone; Nausea; Neoplasms; Oxycodone

Endogenous opioid peptides have been implicated in the regulation of pain perception, behaviour, gastrointestinal activity and other physiological responses. However, the functional role of these peptides in the horse has yet to be elucidated. The opioid antagonist, naloxone, is often administered to infer endogenous opioid effects. In the present study, naloxone (0.75 mg/kg bodyweight) was administered to eight Thoroughbred racehorses and a number of behavioural and autonomic responses were measured. Naloxone produced rapid onset diarrhoea, restlessness, abdominal checking, tachycardia, tachypnoea, paradoxical yawning and diaphoresis. These responses described an acute abdominal distress syndrome similar to spasmodic colic. Results from this study suggest that, in the horse, endogenous opioids: 1) influence behaviour, 2) modify intestinal activity and sensation, and 3) if perturbed, may be involved in pathophysiology of colic.

Topics: Abdominal Pain; Animals; Behavior, Animal; Colic; Defecation; Diarrhea; Gastrointestinal Diseases; Heart Rate; Horse Diseases; Horses; Naloxone; Respiration; Syndrome; Yawning

42 outpatients with chronic diarrhoea of varying origin received individually adapted doses (2--12 mg) of loperamide for a median time of 543 days (range 140--1,159 days). In most cases, the mean daily stool frequency dropped significantly and stool consistency improved clearly; the beneficial effects of the drug were maintained over the entire treatment period. Also, patients with diarrhoea of organic origin tended to react more favourably to loperamide than patients with functional diarrhoea. No drug-related changes in laboratory parameters could be detected and clinical side effects were virtually nil. No morphine-like effect of loperamide could be evidence by means of the pupil diameter changes after naloxone administration.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Diarrhea; Double-Blind Method; Drug Evaluation; Female; Humans; Isotonic Solutions; Loperamide; Male; Middle Aged; Naloxone; Piperidines; Pupil; Sodium Chloride; Time Factors

Topics: Adult; Aged; Amides; Antidiarrheals; Chlorobenzenes; Chronic Disease; Clinical Trials as Topic; Colitis, Ulcerative; Colonic Diseases, Functional; Crohn Disease; Diarrhea; Drug Evaluation; Female; Gastrointestinal Agents; Humans; Isonipecotic Acids; Male; Middle Aged; Naloxone; Nitriles; Piperidines; Placebos; Reflex, Pupillary

Topics: Acetaminophen; Adult; Buprenorphine; Cocaine-Related Disorders; Diagnosis, Differential; Diarrhea; Drug Combinations; Female; Humans; Illicit Drugs; Naloxone; Narcotic Antagonists; Nausea; Opioid-Related Disorders; Oxycodone; Substance Abuse Detection; Vomiting

Irritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and changes in bowel habit. The aim of this study was to characterize the effect of loperamide hydrochloride (LOP) and naloxone hydrochloride (NLX), an opioid agonist and antagonist, respectively, on electrolyte equilibrium in ileal and colonic mucosae and to estimate the possible influence of divergent activity of the endogenous opioid system (EOS) on IBS therapy.. Two mouse lines bidirectionally selected for high (HA) and low (LA) swim stress-induced analgesia associated with high and low EOS activity were used in this study. To assess the effect of LOP and NLX on HA/LA lines in vivo, we used the castor oil-induced diarrhea model. Changes in electrolyte equilibrium were determined on the basis of short-circuit current (ΔI. In vivo, we found that LOP significantly prolonged time to appearance of diarrhea in HA and LA lines. In vitro, LOP and NLX increased ΔI. Individual differences in EOS activity may play a crucial role in the response to the IBS-D therapy, thus some patients may be at an increased risk of side effects such as constipation or diarrhea.

Topics: Analgesics, Opioid; Animals; Castor Oil; Colon; Diarrhea; Ileum; Intestinal Mucosa; Loperamide; Male; Mice; Naloxone; Narcotic Antagonists; Stress, Psychological

Mitragyna speciosa (Korth.) Havil. (M. speciosa) is among the most well-known plants used in ethnic practice of Southeast Asia. It has gained increasing attention as a plant with potential to substitute morphine in addiction treatment program. However, its action on the central nervous system is controversial.. This study investigated the effects of M. speciosa alkaloid extract on naloxone-precipitated morphine withdrawal and neural signaling in the nucleus accumbens (NAc, brain reward center) of mice.. The effects of M. speciosa alkaloid extract and mitragynine, a pure major constituent, on naloxone-precipitated morphine withdrawal were examined. Male Swiss Albino (ICR) mice were rendered dependent on morphine before injection with naloxone, a nonspecific opioid antagonist, to induce morphine withdrawal symptoms. The intensity of naloxone-precipitated morphine withdrawal was assessed from jumping behavior and diarrhea induced during a period of morphine withdrawal. To test possible addictive effect of M. speciosa alkaloid extract, mice were implanted with intracranial electrode into the NAc for local field potential (LFP) recording. Following M. speciosa alkaloid extract (80mg/kg) and morphine (15mg/kg) treatment, LFP power spectra and spontaneous motor activity were analyzed in comparison to control levels.. One-way ANOVA and multiple comparisons revealed that M. speciosa alkaloid extract (80 and 100mg/kg) significantly decreased the number of jumping behavior induced by morphine withdrawal whereas mitragynine did not. Additionally, M. speciosa alkaloid extract significantly decreased dry and wet fecal excretions induced by morphine withdrawal. LFP analysis revealed that morphine significantly decreased alpha (9.7-12Hz) and increased low gamma (30.3-44.9Hz) and high gamma (60.5-95.7Hz) powers in the NAc whereas M. speciosa alkaloid extract did not. Spontaneous motor activity was significantly increased by morphine but not M. speciosa alkaloid extract.. Taken together, M. speciosa alkaloid extract, but not mitragynine, attenuated the severity of naloxone-precipitated morphine withdrawal symptoms. Neural signaling in the NAc and spontaneous motor activity were sensitive to morphine but not M. speciosa alkaloid extract. Therefore, treatment with the M. speciosa alkaloid extract may be useful for opiate addiction treatment program.

Topics: Alkaloids; Analgesics, Opioid; Animals; Behavior, Animal; Diarrhea; Male; Mice, Inbred ICR; Mitragyna; Morphine; Naloxone; Narcotic Antagonists; Nucleus Accumbens; Plant Extracts; Plant Leaves; Secologanin Tryptamine Alkaloids; Substance Withdrawal Syndrome

Irinotecan-induced gut toxicity is mediated in part by Toll-Like receptor 4 (TLR4) signalling. The primary purpose of this preclinical study was to determine whether blocking TLR4 signalling by administering (-)-naloxone, a TLR4 antagonist, would improve irinotecan-induced gut toxicity. Our secondary aim was to determine the impact of (-)-naloxone on tumour growth.. Female Dark Agouti (DA) tumour-bearing rats were randomly assigned to four treatments (n = 6 in each); control, (-)-naloxone (100 mg/kg oral gavage at -2, 24, 48, and 72 h), irinotecan (175 mg/kg intraperitoneal at 0 h), and (-)-naloxone and irinotecan. Body weight and tumour growth were measured daily, and diarrhoea incidence and severity were recorded 4× per day up to 72 h post-treatment.. At 72 h, all rats that received irinotecan lost weight compared to controls (p = 0.03). In addition, rats that received (-)-naloxone and irinotecan lost significantly more weight compared to controls (p < 0.005) than irinotecan only compared to controls (p = 0.001). (-)-Naloxone did not attenuate irinotecan-induced severe diarrhoea at 48 and 72 h. Finally, (-)-naloxone caused increased tumour growth compared to control at 72 h (p < 0.05) and significantly reduced the efficacy of irinotecan (p = 0.001).. (-)-Naloxone in our preclinical model was unable to block irinotecan-induced gut toxicity and decreased the efficacy of irinotecan. As (-)-naloxone-oxycodone combination is used for cancer pain, this may present a potential safety concern for patients receiving (-)-naloxone-oxycodone and irinotecan concurrently and requires further investigation.

Topics: Animals; Camptothecin; Cancer Pain; Diarrhea; Female; Irinotecan; Naloxone; Rats; Toll-Like Receptor 4

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional disorder of the gastrointestinal (GI) tract. The major IBS-D symptoms include diarrhea, abdominal pain and discomfort. High density of opioid receptors (ORs) in the GI tract and their participation in the maintenance of GI homeostasis make ORs ligands an attractive option for developing new anti-IBS-D treatments. The aim of this study was to characterize the effect of methyl-orvinol on the GI motility and secretion and in mouse models mimicking symptoms of IBS-D.. In vitro, the effects of methyl-orvinol on electrical field stimulated smooth muscle contractility and epithelial ion transport were characterized in the mouse colon. In vivo, the following tests were used to determine methyl-orvinol effect on mouse GI motility: colonic bead expulsion, whole GI transit and fecal pellet output. An antinociceptive action of methyl-orvinol was assessed in the mouse model of visceral pain induced by mustard oil.. Methyl-orvinol (10. Methyl-orvinol could become a promising drug candidate in chronic therapy of functional GI diseases such as IBS-D.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Abdominal Pain; Analgesics; Analgesics, Opioid; Animals; Colon; Diarrhea; Disease Models, Animal; Gastrointestinal Motility; Gastrointestinal Transit; Irritable Bowel Syndrome; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Muscle, Smooth; Naloxone; Naltrexone; Receptors, Opioid; Thebaine

The withdrawal syndrome after the cessation of μ-opioid receptor agonists remains an obstacle in the clinical treatment of pain. We recently showed that peripheral opioid receptors play a significant role in the withdrawal signs in morphine-dependent mice. Therefore, the present study was designed to investigate the underlying mechanism of morphine-induced withdrawal symptoms, especially the peripheral oriented body-weight loss that accompanied diarrhea, in mice. Withdrawal signs were precipitated by the injection of naloxone 1 day after the slow-release emulsion administration of morphine. Withdrawal body-weight loss and diarrhea precipitated by naloxone in morphine-dependent mice were significantly suppressed by ritanserin (a 5-HT2 receptor antagonist), olanzapine (5-HT2/D2 receptor antagonist) and fullerene (a free radical scavenger), whereas neither ondansetron (a 5-HT3 receptor antagonist) nor atropine (a muscarine receptor antagonist) significantly suppressed naloxone-precipitated diarrhea. 5-HT3-receptors (but not 5-HT2-receptors) are known to play a significant role in 5-HT-induced diarrhea. Therefore, we also examined the effects of ritanserin and fullerene on 5-HT-induced diarrhea in morphine-dependent mice. Ritaserin significantly suppressed 5-HT-induced diarrhea in morphine-dependent mice, but not saline-treated mice. These results suggest that peripheral 5-HT2-receptor function could be altered in morphine-dependent mice, and the blockade of 5-HT2 receptor or free radical scavengers may be useful for the treatment of opioid-withdrawal diarrhea.

Topics: Animals; Diarrhea; Free Radical Scavengers; Fullerenes; Male; Mice, Inbred ICR; Morphine Dependence; Naloxone; Narcotic Antagonists; Receptors, Serotonin, 5-HT2; Serotonin; Serotonin Receptor Agonists; Substance Withdrawal Syndrome

Ginger (Zingiber officinale Roscoe), a well-known spice plant, has been used traditionally in the treatment of a wide variety of ailments such as opiates withdrawal-induced disorders. However, its influences on opioid tolerance and dependence have not yet been clarified.. Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10 mg/kg, i.p.) twice daily for 8 days. To develop morphine dependence, rats given escalating doses of chronic morphine. To determine the effect of ginger on the development of morphine tolerance and dependence, different doses of ginger were administrated before morphine. The tail-flick and naloxone precipitation tests were used to assess the degree of tolerance and dependence, respectively.. Our results showed that chronic morphine-injected rats displayed tolerance to the analgesic effect of morphine as well as morphine dependence. Ginger (50 and 100 mg/kg) completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with 100 and 150 mg/kg attenuated almost all of the naloxone-induced withdrawal sings which include weight lose, abdominal contraction, diarrhea, petosis, teeth chattering, and jumping. In addition, morphine-induced L-type calcium channel over-expression in spinal cord was reversed by 100 mg/kg ginger.. The data indicate that ginger extract has a potential anti-tolerant/anti-dependence property against chronic usage of morphine.

Topics: Analgesics, Opioid; Animals; Diarrhea; Drug Tolerance; Ethanol; Gene Expression; Male; Morphine; Morphine Dependence; Naloxone; Pain; Plant Extracts; Plant Roots; Rats; Rats, Wistar; RNA, Messenger; Spinal Cord; Substance Withdrawal Syndrome; Zingiber officinale

Δ(9)-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB(1) and CB(2) cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB(1) receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB(1) receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.

Topics: Amidohydrolases; Animals; Arachidonic Acid; Behavior, Animal; Benzodioxoles; Brain Chemistry; Cannabinoid Receptor Modulators; Diarrhea; Dronabinol; Electric Stimulation; Endocannabinoids; Hydrolysis; Ileum; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Monoacylglycerol Lipases; Morphine Dependence; Muscle Contraction; Naloxone; Narcotic Antagonists; Piperidines; Prostaglandins; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Substance Withdrawal Syndrome; Weight Loss

Repeated morphine administration increases extracellular dopamine levels in the nucleus accumbens, which results in behavioral sensitization that can be suppressed by acupuncture at Shenmen (HT7) points. The present study was conducted to investigate the effects of acupuncture at HT7 on morphine withdrawal syndrome as well as to explore the role of GABA receptors in mediating the effects of HT7 acupuncture. We induced morphine withdrawal by injecting naloxone to rats that self-administer morphine and evaluated the effects of acupuncture and/or GABA receptor antagonists on their withdrawal symptoms. Acupuncture at HT7, but not at the control point LI5, significantly decreased symptoms of morphine withdrawal. HT7 inhibition of the withdrawal syndrome was blocked by pretreatment with either the GABA(A) receptor antagonist bicuculline or the GABA(B) antagonist SCH 50911. These findings suggest that the effects of acupuncture on suppression of morphine withdrawal syndrome are mediated, at least in part, through GABA receptors.

Topics: Acupuncture Points; Acupuncture Therapy; Animals; Bicuculline; Diarrhea; GABA-A Receptor Antagonists; GABA-B Receptor Antagonists; Male; Morphine; Morphine Dependence; Morpholines; Muscle Contraction; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, GABA-B; Substance Withdrawal Syndrome; Tremor

Dried fruits of Piper nigrum (black pepper) are commonly used in gastrointestinal disorders. The aim of this study was to rationalize the medicinal use of pepper and its principal alkaloid, piperine, in constipation and diarrhea using in vitro and in vivo assays. When tested in isolated guinea pig ileum, the crude extract of pepper (Pn.Cr) (1–10 mg/mL) and piperine (3–300 μM) caused a concentration-dependent and atropine-sensitive stimulant effect. In rabbit jejunum, Pn.Cr (0.01–3.0 mg/mL) and piperine (30–1,000 μM) relaxed spontaneous contractions, similar to loperamide and nifedipine. The relaxant effect of Pn.Cr and piperine was partially inhibited in the presence of naloxone (1 μM) similar to that of loperamide, suggesting the naloxone-sensitive effect in addition to the Ca(2+) channel blocking (CCB)-like activity, which was evident by its relaxant effect on K+ (80 mM)-induced contractions. The CCB activity was confirmed when pretreatment of the tissue with Pn.Cr (0.03–0.3 mg/mL) or piperine (10–100 μM) caused a rightward shift in the concentration–response curves of Ca(2+), similar to loperamide and nifedipine. In mice, Pn.Cr and piperine exhibited a partially atropine-sensitive laxative effect at lower doses, whereas at higher doses it caused antisecretory and antidiarrheal activities that were partially inhibited in mice pretreated with naloxone (1.5 mg/kg), similar to loperamide. This study illustrates the presence of spasmodic (cholinergic) and antispasmodic (opioid agonist and Ca(2+) antagonist) effects, thus providing the possible explanation for the medicinal use of pepper and piperine in gastrointestinal motility disorders.

Topics: Alkaloids; Animals; Antidiarrheals; Benzodioxoles; Calcium Channel Blockers; Cholinergic Agents; Constipation; Diarrhea; Dose-Response Relationship, Drug; Female; Gastrointestinal Diseases; Guinea Pigs; Ileum; Jejunum; Laxatives; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Naloxone; Phytotherapy; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rabbits; Receptors, Opioid

The study evaluated the adulterants in a specimen of illicit street heroin supplied under strict control by the Pakistan Anti-Narcotic Force. It also examined the effects of Hypericum perforatum L. extracts on the naloxone-induced heroin withdrawal syndrome. The GC-MS analysis of the specimen showed that in addition to heroin (37.8%), the sample also contained caffeine (8.4%), phenobarbitone (12.7%), 6-acetyl codeine (5.3%), 6-acetyl morphine (10.9%) and noscapine (15.8%). Administration of the heroin to rats for 8 days induced physical withdrawal signs of abdominal constriction, diarrhoea and vocalization on touch after naloxone treatment. Aqueous Hypericum perforatum extracts (20 mg/kg twice daily chronically or as a single acute dose 90 min before naloxone) given orally to the heroin dependent rats attenuated abdominal constrictions both acutely and chronically while the hydroethanol and ethanol extracts were only effective in acutely treated animals. Diarrhoea was ameliorated by the hydroethanol and ethanol extracts following acute or chronic heroin treatment while the aqueous extract failed to show any effect. Vocalization on touch during withdrawal was reduced by all the extracts either chronically or acutely with the exception of chronic treatment with hydroethanol extracts. The findings suggest that Hypericum perforatum is capable of reducing the physical signs of opiate withdrawal.

Topics: Animals; Diarrhea; Gas Chromatography-Mass Spectrometry; Heroin; Hypericum; Naloxone; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Vocalization, Animal

Topics: Analgesics, Opioid; Delayed-Action Preparations; Diarrhea; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Oxycodone; Patient Compliance; Practice Patterns, Physicians'; Substance Withdrawal Syndrome

Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.

Topics: Animals; Antidiarrheals; Castor Oil; Diarrhea; Loperamide; Mice; Models, Molecular; Naloxone; Structure-Activity Relationship; Thiazolidinediones

In the present study, we have investigated the effect of nicotine and diazoxide, a potassium channel opener and glibenclamide, a potassium channel (K(ATP)) blocker on naloxone-precipitated physical withdrawal signs, including jumping and diarrhea. Then, the interactions of nicotine with diazoxide and glibenclamide were tested. Mice were rendered dependent on morphine by subcutaneous (s.c.) injections of morphine sulphate 3 times a day for 3 days, and jumping behavior and diarrhea were induced by intraperitoneal (i.p.) administration of naloxone 2 h after the 10th injection of morphine sulphate on day 4. Nicotine was administered 15 min and diazoxide and glibenclamide 30 min before naloxone injection. Nicotine (0.01-1 mg/kg, s.c.) and (0.1-1 mg/kg) reduced withdrawal jumping and diarrhea respectively. Diazoxide (8-64 mg/kg, i.p.) decreased jumping behavior significantly, but had no significant effect on diarrhea. On the other hand glibenclamide (0.25-1 mg/kg i.p.) and (1 mg/kg) augmented jumping and diarrhea respectively. The response of nicotine on jumping or on diarrhea was potentiated by diazoxide and decreased by glibenclamide pretreatment. The isobolographic analysis revealed synergistic interaction between diazoxide and nicotine on decreasing physical withdrawal signs including jumping and diarrhea in morphine-dependent mice. According to these results the interaction of nicotine with the K(ATP) channel opener and blocker in morphine physical withdrawal signs could be explained by direct and indirect effects of nicotine on membrane potassium currents.

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Behavior, Animal; Diarrhea; Diazoxide; Dose-Response Relationship, Drug; Ganglionic Stimulants; Glyburide; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Nicotine; Potassium Channels, Inwardly Rectifying; Substance Withdrawal Syndrome

Much evidence supports the hypothesis that A2A adenosine receptors play an important role in the expression of morphine withdrawal and that the dopaminergic system might also be involved. We have evaluated morphine withdrawal signs in wild-type and A2A receptor knockout mice and shown a significant enhancement in some withdrawal signs in the knockout mice. In addition, micro -opioid and dopamine D2 receptor autoradiography, as well as micro -opioid receptor-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate ([35S]GTPgammaS) autoradiography was carried out in brain sections of withdrawn wild-type and knockout mice. No significant changes in D2 and micro -opioid receptor binding were observed in any of the brain regions analysed. However, a significant increase in the level of micro receptor-stimulated [35S]GTPgammaS binding was observed in the nucleus accumbens of withdrawn knockout mice. These data indicate that the A2A receptor plays a role in opioid withdrawal related to functional receptor activation.

Topics: Analysis of Variance; Animals; Autoradiography; Behavior, Animal; Binding Sites; Brain; Densitometry; Diarrhea; Dose-Response Relationship, Drug; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Male; Mice; Mice, Knockout; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Raclopride; Receptor, Adenosine A2A; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Sulfur Isotopes; Tremor; Tritium; Urine; Weight Loss

The effect of a hot water extract of black tea (Camellia sinensis (L.) O. Kuntze, Theaceae) on upper gastrointestinal transit and on diarrhoea was investigated employing conventional rodent models of diarrhoea. Black tea extract was found to possess antidiarrhoeal activity in all the models of diarrhoea used. Naloxone (0.5 mg/kg i.p.) significantly inhibited the antidiarrhoeal activity of the extract as well as loperamide, thus indicating a role of the opioid system in the antidiarrhoeal activity of the extract.

Topics: Animals; Antidiarrheals; Castor Oil; Diarrhea; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gastrointestinal Motility; Loperamide; Male; Mice; Mice, Inbred BALB C; Naloxone; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Tea

For biotherapeutic agents, there is a lack of information on dose-response relationships and mechanism of action. The present study was designed to address these issues for Saccharomyces boulardii using the rat model of castor oil-induced diarrhea. A single dose of Saccharomyces boulardii at 12 x 10(10) CFU/kg of viable cells given 1 hr before castor oil administration significantly reduced the onset of diarrhea. Repeated ingestion of the yeast, twice daily between 1.2 and 12 x 10(10) CFU/kg for 5 days before castor oil, showed a dose-response relationship. The percentage of rats with diarrhea decreased and a stronger protection was afforded by the repeated treatment. The mechanism of action of Saccharomyces boulardii in this model was investigated with two classes of antagonists, naloxone and L-arginine. The effect of Saccharomyces boulardii was not inhibited by naloxone but was significantly reduced by L-arginine. This last result suggests a novel mechanism of action for Saccharomyces boulardii involving a possible inhibition of nitric oxide production by the yeast.

Topics: Animals; Antidiarrheals; Arginine; Castor Oil; Diarrhea; Dose-Response Relationship, Drug; Fungal Vaccines; Indomethacin; Loperamide; Male; Naloxone; Probiotics; Rats; Rats, Wistar; Saccharomyces; Water-Electrolyte Balance

Although the phenomenon of opioid tolerance and dependence has been widely investigated, neither opioid nor non-opioid mechanisms are completely understood. In view of the modulation of 5-HT transport into presynaptic terminals in the brain by nitric oxide (NO) via cGMP, and the existence of a tonic 5-HTergic inhibition of dopamine release, the present study investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor, and NO modulators L-N(G)-nitroarginine methyl ester (L-NAME; NO synthase inhibitor) and L-Arginine (substrate for nitric oxide synthase) alone or in combination against morphine tolerance and dependence. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg s.c. twice daily) on day 3 and the degree of tolerance was further enhanced on days 9 and 10. The development of tolerance to the antinociceptive effect of morphine was delayed by prior administration of fluoxetine (10 mg/kg i.p, twice daily for 9 days) and L-NAME (10 mg/kg i.p. twice daily for 9 days) alone or in combination. It was accentuated by L-Arginine (50 mg/kg i.p. twice daily for 9 days) alone or in combination with fluoxetine (10 mg/kg i.p. twice daily for 9 days). Similarly, fluoxetine (10 mg/kg i.p.) or L-NAME (10 mg/kg i.p.), when administered acutely on day 10, reversed morphine-induced tolerance. L-Arginine (50 mg/kg i.p.) however, when administered acutely on day 10, accentuated morphine tolerance. Fluoxetine (10 mg/kg i.p. twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg i.p.)-precipitated withdrawal jumps. This suppression of dependence was potentiated by L-NAME (10 mg/kg i.p. twice daily for 9 days) and reversed by L-Arginine (50 mg/kg i.p. twice daily for 9 days), respectively. Acute administration of the respective drugs on day 10 modulated morphine dependence in a similar fashion. L-Arginine also reversed fluoxetine-induced weight loss in morphine-dependent animals. The present study demonstrated that fluoxetine suppressed the dependence and development of tolerance to the antinociceptive effect of morphine. Fluoxetine-induced suppression was potentiated by L-NAME and accentuated by L-Arginine. The results therefore suggest that a complex phenomenon such as morphine tolerance and dependence might involve close interplay of the NO-c GMP/5-HT/DA receptor system. To the best of the authors' knowledge, this is the first report to suggest targeting this cascade for ame

Topics: Animals; Arginine; Body Weight; Cyclic GMP; Depression, Chemical; Diarrhea; Dopamine; Drug Interactions; Drug Tolerance; Female; Fluoxetine; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Selective Serotonin Reuptake Inhibitors; Serotonin; Substance Withdrawal Syndrome

The antidiarrhoeal activity of the seed extract of Albizzia lebbeck (Benth.) was investigated employing conventional rodent models of diarrhoea, i.e. castor oil-induced diarrhoea, upper gastrointestinal transit (u.g.t.) and fluid secretion. It was found that the aqueous methanol extract of Albizzia lebbeck seeds (2.5-5 mg/kg i.p.) possessed antidiarrhoeal activity which strengthens the earlier use of the seeds in the treatment of diarrhoea and dysentery. The antidiarrhoeal dose of the extract was at least 10-30 times less than the LD(50) dose. The extract (2.5-5 mg/kg i.p.) potentiated the antidiarrhoeal activity of loperamide (1 mg/kg i.p.). Nalaxone (0.5 mg/kg i.p.) significantly inhibited the antidiarrhoeal activity of the extract as well as loperamide, thus indicating a role of the opioid system in the antidiarrhoeal activity of the extract.

Topics: Animals; Antidiarrheals; Castor Oil; Diarrhea; Fabaceae; Gastrointestinal Transit; Lethal Dose 50; Loperamide; Mice; Naloxone; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Seeds; Toxicity Tests, Acute

Effects of pretreatment with the selective corticotropin-releasing factor (CRF) subtype 1 (CRF(1)) receptor antagonist, 2-(N-(2-methylthio-4-isopropylphenyl)-N-ethyl-amino-4-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1000) on the behavioral and biochemical changes after naloxone-precipitated morphine withdrawal were examined in ICR mice. Mice were chronically treated with morphine (8-45 mg/kg) for 5 days. Naloxone (3 mg/kg, s.c.) precipitated jumping, diarrhea, and body weight loss in morphine-dependent mice. In addition, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and noradrenaline turnover (MHPG/noradrenaline) levels in the cerebral cortex were increased following naloxone challenge in morphine-dependent mice. However, 5-hydroxytriptamine turnover did not alter the increase following naloxone challenge in morphine-dependent mice. Pretreatment with CRA1000 (20 mg/kg, i.p.) attenuated the incidence of withdrawal signs and naloxone-precipitated increases in noradrenaline turnover. These results suggest that the activation of CRF(1) receptor may play an important role in the elevation of noradrenaline transmission, but not in 5-hydroxytriptamine transmission, in the cerebral cortex, which projects from the locus coeruleus during morphine withdrawal.

Topics: Animals; Behavior, Animal; Brain; Cerebral Cortex; Diarrhea; Male; Mice; Mice, Inbred ICR; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Norepinephrine; Pyridines; Pyrimidines; Receptors, Corticotropin-Releasing Hormone; Substance Withdrawal Syndrome; Time Factors

Laser-Doppler flowmetry was used to study cerebral cortical blood flow responses to morphine and naloxone in morphine-naive and -dependent rats. The experiments were performed in spontaneously breathing anesthetized rats. Morphine (10 mg/kg, i.p.) administration reduced regional cerebral blood flow in control, sham-operated and morphine-dependent rats, but the depressant effect of morphine in morphine-dependent animals was less than that in control and sham-operated groups. While naloxone (0.5 mg/kg, s.c.) had no considerable effect on regional cerebral blood flow in control and sham-operated groups, it increased regional blood flow in morphine dependent ones. The depressant effect of morphine in all groups and the enhancing effect of naloxone in morphine-dependent animals were not seen after local application of lidocaine at the recording site. This study may provide a framework to study the cellular and molecular mechanisms responsible for coupling neuronal electrical activity with regional alterations in blood flow during precipitation of morphine withdrawal.

Topics: Anesthesia; Anesthetics, Local; Animals; Brain; Cerebrovascular Circulation; Diarrhea; Lidocaine; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Weight Loss

Effects of different doses of adenosine receptor agonists and antagonists on naloxone-induced jumping and diarrhea in morphine-dependent mice were studied. The adenosine A1 receptor agonists, N6-cyclohexyladenosine (CHA: 0.1, 0.25 and 0.5 mg kg(-1)) and R-isomer of N6-phenylisopropyladenosine (R-PIA: 0.1, 0.3 and 1 mg kg(-1)), decreased jumping and diarrhea induced by naloxone in morphine-dependent mice. The adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX: 0.3-9 mg kg(-1)), increased jumping but decreased diarrhea. The adenosine A2 receptor agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), decreased jumping and diarrhea. However, the adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX: 0.5 and 1 mg kg(-1)), did not elicit any response in this respect. DPCPX (0.3 and 3 mg kg(-1)), decreased the inhibition of jumping and diarrhea induced by CHA (0.5 mg kg(-1)), while DMPX (0.5 and 1 mg kg(-1)), decreased the inhibition of diarrhea induced by CPCA (0.1 mg kg(-1)). It is concluded that jumping induced by naloxone in morphine-dependent mice may be modified by the adenosine A receptor mechanism(s) and diarrhea induced by the opioid receptor antagonist could be mediated by the adenosine A1 and A2 receptors.

Topics: Adenosine; Analysis of Variance; Animals; Behavior, Animal; Diarrhea; Male; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Substance Withdrawal Syndrome; Theobromine; Xanthines

We investigated the antinociceptive effect of FR140423, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl] pyrazole, in the tail-pinch test in mice, and evaluated the mechanism of action using various opioid receptor antagonists. P.o. and i.t. injection of FR140423 exerted dose-dependent antinociceptive activities with ED50 values of 21 mg/kg and 3.1 microg/mouse, respectively. However, i.c.v. injection of FR140423 did not show an antinociceptive effect. The antinociceptive effects of FR140423 were completely abolished by naloxone and naltrindole but not by naloxonazine, beta-funaltrexamine and nor-binaltorphimine. FR140423 did not affect any opioid receptor binding in mouse spinal membranes at concentrations up to 100 microM in vitro. Naloxone-induced jumping and diarrhea tests for morphine-like physical dependence of FR140423 gave negative results. These results suggest that FR140423 can induce antinociception by acting on the spinal but not the supraspinal site, and that spinal delta-opioid systems indirectly play a role in the antinociception produced by FR140423 in mice.

Topics: Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Binding, Competitive; Diarrhea; Injections, Intraventricular; Injections, Spinal; Male; Membranes; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Pyrazoles; Rats; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord; Sulfoxides

1. We set out to ascertain the role of tachykinins, neurokinin A and substance P, in castor oil-induced diarrhoea in rats as disclosed by the inhibitory effect of the non-peptide NK1- and NK2-receptor antagonists. SR 140333 and SR 48968, respectively. 2. SR 48968 (0.02 to 20 micrograms kg-1, s.c. or p.o.), and the opioid receptor agonist loperamide (1-10 mg kg-1, p.o.), dose-dependently prevented castor oil effects: % inhibition vs castor oil, diarrhoea 0 to 100, increase in faecal mass 7 to 90 and water content 16 to 90. SR 140333 (0.02 to 20 micrograms kg-1, s.c.) and the platelet activating factor antagonist SR 27417 (5 to 500 micrograms kg-1, p.o.) did not prevent the increase in faecal water content, but reduced faecal mass (35 to 66%) and diarrhoea (0 to 57%). 3. The R-enantiomers of tachykinin NK1 and NK2 receptor antagonists, SR 140603 and SR 48605 (both at 2 or 20 micrograms kg-1, s.c.) had no effect other than reducing faecal mass at the highest dose tested. 4. SR 48968 (20 micrograms kg-1, p.o.) but not loperamide (10 mg kg-1, p.o.) given 24 h before castor oil, still slightly but significantly reduced by 30% the increase of faecal mass output; both treatments significantly reduced (30 to 70%) the effect of castor oil on faecal water content, although the incidence of diarrhoea was only slightly less than in controls. 5. In castor oil-treated rats, naloxone (2 mg kg-1, s.c.) completely blocked the antidiarrhoeal action of loperamide (10 mg kg-1, p.o.) but not of SR 48968 (20 micrograms kg-1, p.o.): a similar result was obtained on faecal mass and water content. 6. Castor oil strongly increased the occurrence of manometrically recorded propulsive giant contractions (500 to 1000% over control values) of transverse and distal colon, this effect being significantly prevented (80 to 100%) by SR 48968 and loperamide and partially by SR 140333 (35% distal colon, 70% transverse colon). 7. In castor oil free rats, loperamide but not SR 48968 or SR 140333 significantly reduced by 50% the gastrointestinal transit of a charcoal test meal, as well as 24 h faecal mass output. Consistently, loperamide, unlike the tachykinin receptor antagonists, had a dramatic effect on manometric recordings of intestinal motility, reducing all kinds of colonic contractions. 8. Our findings suggest that castor oil diarrhoea in rats entails activation of NK1 and NK2 receptors by endogenous tachykinins, whose antagonists may have a potential as antidiarrhoeal agents free from t

Topics: Animals; Benzamides; Castor Oil; Colon; Diarrhea; Gastrointestinal Motility; Loperamide; Male; Naloxone; Piperidines; Quinuclidines; Rats; Tachykinins

The severity of naloxone-precipitated withdrawal in rats infused intravenously with morphine at the rates of 2.5, 5 and 10 mg/kg/hr over various time periods was investigated. Plasma morphine concentration reached a constant and rate-dependent level at 1 hr after the start of morphine infusion, and this level was maintained until the termination of infusion. Naloxone (2.0 mg/kg, s.c.) was challenged 18 hr after infusion was stopped, and the withdrawal was evaluated by plasma corticosterone (PCS) increase, diarrhea and body weight loss. The incidence of naloxone-precipitated withdrawal signs was related to both the infusion rate and duration of morphine infusion. The duration of morphine infusion (ET50) needed to elicit naloxone-precipitated PCS increase and diarrhea in 50% of the rats was inversely related to the morphine infusion rates, but the total amount of infused morphine (EA50) that elicited naloxone-precipitated withdrawals in 50% of rats was the same at all infusion rates. These results suggest that the total amount of morphine infused may play an important role in the development of acute physical dependence on morphine rendered by continuous intravenous morphine infusion for 1-8 hr.

Topics: Acute Disease; Analysis of Variance; Animals; Corticosterone; Diarrhea; Infusions, Intravenous; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Time Factors; Weight Loss

A series of thiazolidinones related to loperamide was synthesized and evaluated for antidiarrhoeal activity in mice, using the castor oil test. Of five compounds tested, antidiarrhoeal activity was found only for 2-(p-nitrophenyl)-3-¿3-[(4-(p-chlorophenyl)-4-hydroxy)piperidino]ethyl¿- 1,3-thiazolidin-4-one. The compound was less active than loperamide (ED50 values = 48.7 (24.8-95.6) and 0.91 (0.24-3.40) mg kg-1 respectively), but was also less toxic (LD50 values = 745.9 (545.2-929.8) and 108.9 (85.5-138.7) mg kg-1, respectively). Its antidiarrhoeal activity was counteracted by naloxone. Our results support the hypothesis that this compound, like loperamide, is an opiate-receptor agonist.

Topics: Animals; Antidiarrheals; Castor Oil; Diarrhea; Lethal Dose 50; Loperamide; Male; Mice; Naloxone; Narcotic Antagonists

We have investigated the antitransit effects of free and liposomal morphine in a model of intestinal inflammation. Mice received saline or croton oil orally, 3 h prior to evaluation, and gastrointestinal transit was measured 20 min afterwards. Peak/duration of effects, potency (ED50) and antagonism by naloxone and naloxone methiodide were evaluated. Peak effects occurred 30 and 40 min after administration of morphine and liposomal morphine, respectively. Encapsulated morphine had a more pronounced and prolonged effect than morphine. Comparison of the ED50S demonstrated that the potency of liposomal morphine was 3.5 times higher than that of morphine during inflammation; in addition, inflammation increased the potency of morphine and liposomal morphine, 3 and 9.2 times, respectively. The effects of morphine and liposomal morphine in croton oil-treated mice were reversed by naloxone and naloxone methiodide. The results show that during inflammation, the potency and duration of the antitransit effects of morphine are significantly enhanced by encapsulation.

Topics: Animals; Diarrhea; Dose-Response Relationship, Drug; Drug Carriers; Drug Interactions; Enterocolitis; Gastrointestinal Transit; Liposomes; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Quaternary Ammonium Compounds

The effects of diltiazem, a Ca2+ channel blocker, on naloxone-precipitated and spontaneous morphine withdrawal were studied in male Sprague-Dawley rats. In naloxone-precipitated withdrawal, body weight loss and plasma corticosterone elevation were dose dependently inhibited by diltiazem injected 4 or 2 and 4 h before naloxone, respectively. Three administrations of diltiazem (17, 11 and 5 h before naloxone) did not reduce the above withdrawal signs. Diarrhea was dose dependently inhibited by all schedule of diltiazem treatments. In spontaneous withdrawal, body weight loss and plasma corticosterone elevation were dose dependently inhibited by two (6 and 12 h) or three (6, 12 and 18 h after the last morphine) treatments with diltiazem at 6-h intervals after the last morphine, but not by a single diltiazem injected 18 h after the last morphine.

Topics: Animals; Body Weight; Calcium Channel Blockers; Corticosterone; Diarrhea; Diltiazem; Drug Interactions; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

The effects of buprenorphine on castor-oil-induced diarrhoea, gastrointestinal transit and ethanol-induced gastric lesions in rats were compared to the same effects of morphine. Like morphine, buprenorphine prevented castor-oil-induced diarrhoea. However, it has no effect on gastrointestinal transit per se but prevented the inhibitory action of morphine. While morphine protected against ethanol-induced gastric lesions, buprenorphine aggravated them. It is suggested that different types/subtypes of opioid receptors may be involved in the gastrointestinal actions of buprenorphine.

Topics: Animals; Buprenorphine; Diarrhea; Digestive System; Dose-Response Relationship, Drug; Male; Morphine; Naloxone; Rats; Rats, Wistar

The effects of the normotensive, mainly centrally active nitric oxide synthase (NOS) inhibitor 7-nitro indazole and the hypertensive drug NG-nitro-L-arginine, which blocks both the endothelial and the central NOS, have been examined on naloxone-precipitated withdrawal in morphine-dependent rats. Both drugs attenuated the same withdrawal signs (teeth-chattering, penile licking, diarrhoea, chewing, wet-dog shakes, grooming), while other signs remained unaffected (rearing, jumping, ptosis, rhinorrhoea, irritability on touch). These findings indicate that mainly central (but not endothelial) nitric oxide is involved in the expression of some opioid withdrawal symptoms.

Topics: Amino Acid Oxidoreductases; Animals; Diarrhea; Dose-Response Relationship, Drug; Male; Morphine; Naloxone; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Substance Withdrawal Syndrome

The aim of the study was to evaluate the effects of centrally and peripherally acting opioid antagonists such as naloxone (NX), naloxone methiodide, (+)-naloxone [(+)NX], (-)-a-5,9-diethyl-2'-hydroxy-2 (3-furylmethyl)-6,7-benzomorphan and naltrindole on gastrointestinal (GI) transit in mice with diarrhea associated with intestinal inflammation. Our hypothesis was that diarrhea/inflammation could induce a release of endogenous opioid peptides that would play an inhibitory role in the physiological response to intestinal inflammation; the administration of opioid antagonists would uncover the effects of the endogenous opioid peptides on the gut. Diarrhea associated with inflammation was induced in mice by administration of croton oil (CO) although control animals received saline (SS); GI transit was evaluated with a charcoal meal. The i.p. administration of 0.1 mg/kg NX or NXME, induced a significant increase in GI transit in CO but not in SS-treated animals (P < .005). At the same dose, (+)NX had no effect either in CO or SS groups. The kappa antagonist MR-2266 (1 and 3 mg/kg) had no effect on GI transit in SS or CO animals. However, the delta antagonist naltrindole (3 mg/kg), caused a small but significant (P < .01) increase in GI transit in the CO group. These results suggest that endogenous opioid peptides are released in CO-treated animals and exert an inhibitory control of intestinal motility, which is unmasked by opioid antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Animals; Benzomorphans; Croton Oil; Diarrhea; Enteritis; Gastrointestinal Motility; Male; Mice; Naloxone; Naltrexone; Quaternary Ammonium Compounds; Receptors, Opioid, delta; Receptors, Opioid, kappa

Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (Ki = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (> 200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.

Topics: Animals; Diarrhea; Gastrointestinal Motility; Guinea Pigs; In Vitro Techniques; Intestinal Diseases; Male; Mice; Piperidines; Radioligand Assay; Receptors, Opioid, mu; Structure-Activity Relationship

Previously, we have shown that the development of physical dependence on morphine in mice is inhibited substantially by treatment of mice with the highly selective, nonequilibrium delta-2 opioid receptor antagonist, naltrindole-5'-isothiocyanate. With the availability of the highly selective, nonequilibrium delta-1 opioid receptor antagonist, [D-Ala2,Leu5,Cys6]enkephalin, it was possible, in the present report, to examine the possible involvement of delta-1 opioid receptors in the development of opiate dependence. Mice were made physically dependent on morphine by s.c. implantation of morphine pellets (75-mg free base) for 3 days. The degree of dependence was quantified by determining the ED50 values of naloxone to precipitate withdrawal jumping and diarrhea. Neither sign of opiate withdrawal was affected by chronic treatment of animals with [D-Ala2,Leu5,Cys6]enkephalin during the morphine implant period. The data suggest that delta-1, as opposed to delta-2, opioid receptors are not involved in the development of physical dependence on morphine. This fact takes on added significance because the recently cloned delta opioid receptors appear to be the delta-2 subtype and the present data together with previous findings suggest that the cloned receptors may be proper models for the study of opiate dependence.

Topics: Affinity Labels; Animals; Diarrhea; Enkephalin, Leucine-2-Alanine; Injections, Intraventricular; Injections, Spinal; Isothiocyanates; Male; Mice; Morphine; Naloxone; Naltrexone; Receptors, Opioid, delta; Substance-Related Disorders

The effect of intraperitoneally administered nitric oxide (NO) synthase inhibitors has been examined on the naloxone-precipitated withdrawal syndrome in morphine-dependent mice. L-NAME (30-200 mg/kg) and L-NOARG (7.5-50 mg/kg) induced a significant decrease of naloxone-precipitated withdrawal jumping and diarrhoea. However, L-NMMA (3.5-100 mg/kg), considered as a less potent NO synthase inhibitor, did not significantly affect the withdrawal signs in mice. Although a specificity of NO synthase inhibitors is not fully established, these results indicate that inhibition of NO synthesis in the central nervous system and periphery may significantly affect the morphine withdrawal phenomena. Accordingly, this study suggests an involvement of NO in morphine withdrawal syndrome.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Behavior, Animal; Diarrhea; Male; Mice; Morphine Dependence; Naloxone; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Substance Withdrawal Syndrome

Clinical studies have suggested that patients who take morphine for pain relief do not show a high degree of dependence. The present study examined the development of naloxone-precipitated withdrawal in rats receiving morphine in the presence or absence of formalin-induced pain. Morphine (10 mg/kg, i.p.) or saline was administered for 4 consecutive days 10 min after a subcutaneous injection of 50 microliters of 2.5% formalin or saline into the hind-paw. On the 5th day, rats were injected with naloxone (1 mg/kg, i.p.) and observed for signs of precipitated withdrawal (ptosis, teeth chattering and excretion/diarrhea). Naloxone-precipitated withdrawal symptoms were significantly greater in rats that received morphine in the absence of pain than in rats that received morphine in the presence of pain.

Topics: Animals; Behavior, Animal; Blepharoptosis; Diarrhea; Formaldehyde; Male; Morphine Dependence; Naloxone; Pain; Rats; Substance Withdrawal Syndrome

Involvement of supraspinal and spinal mu opioid receptors in the development degree of morphine dependence was estimated by the ED50 values of naloxone (s.c.) required to precipitate withdrawal jumping and diarrhea 72 hr after morphine-pellet implantation. beta-FNA was administered 4 times (24 hr before, just before, 24 and 48 hr after morphine-pellet implantation) by the i.c.v. or i.t. route. beta-FNA (both i.c.v. and i.t. routes) significantly increased the ED50 values of naloxone for jumping and diarrhea and the increase in the ED50 value of naloxone for jumping was much greater than that for diarrhea. I.c.v. administered beta-FNA was more potent in increasing the ED50 value of naloxone for jumping than i.t. administered beta-FNA. On the other hand, i.c.v. administered beta-FNA was equipotent with i.t. administered beta-FNA in increasing the ED50 value of naloxone for diarrhea. These results suggest that both supraspinal and spinal mu opioid receptors are involved in the development of morphine dependence and that supraspinal mu receptors play a more important role than spinal mu receptors in withdrawal jumping which may reflect an excitation of the central nervous system whereas supraspinal and spinal mu receptors have similar importance in withdrawal diarrhea which may reflect an abnormal function of the autonomic nervous system.

Topics: Animals; Brain; Cerebral Ventricles; Diarrhea; Injections, Intraventricular; Injections, Spinal; Male; Mice; Morphine Dependence; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid, mu; Spinal Cord; Substance Withdrawal Syndrome

It is known that the CXBK inbred strain of mouse is deficient in mu1 opioid receptors, whereas the strain has a delta opioid receptor population that is less consistently altered. In the present study, we compared physical dependence on morphine between CXBK and C57BL/6 mice. Both strains of mice were treated with morphine-admixed food for 5 days. During the treatment, the two strains of mice showed no signs of toxicity. There was no significant difference in morphine intake during the treatment between CXBK and C57BL/6 mice. After the treatment, the withdrawal was precipitated by injecting naloxone (0.01-30 mg/kg, s.c.). CXBK mice showed weight loss, diarrhea and ptosis, but not jumping and body shakes after low dose of naloxone. Whereas, C57BL/6 mice showed weight loss, diarrhea, ptosis, body shakes and jumping. These results suggest that naloxone-precipitated weight loss, diarrhea and ptosis may be mediated by mu2 and/or delta opioid receptor, while naloxone-precipitated jumping and body shakes may be mediated by mu1 opioid receptors.

Topics: Animals; Blepharoptosis; Diarrhea; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Morphine Dependence; Motor Activity; Naloxone; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Weight Loss

The aim of this study was to test whether convergent dependence occurs in vivo. The adenosine A1 receptor agonist N6-[(R)-1-methyl-2-phenylethyl]adenosine (R-PIA), the A2 agonist 2-(phenylamino)adenosine (CV-1808), the nonselective A1, A2 agonist (adenosine-5'-ethylcarboxamide (NECA), and the alpha 2-adrenoceptor agonist clonidine were screened (each at 30, 100, and 300 micrograms/kg, SC) for their ability to alter naloxine-precipitated withdrawal signs in morphine-dependent rats. The results indicate that there is convergent dependence involving opioid and adenosine A1 receptors on those effects expressed by withdrawal diarrhoea, paw-shakes, teeth-chattering, body-shakes, and jumping. Further, dependence expressed by body-shakes involves convergence involving A1 receptors, as well as alpha 2-adrenoceptors; while A1 receptors are involved in dependence expressed by jumping, stimulation of alpha 2-adrenoceptors augments this sign. Adenosine analogues may be of clinical value for detoxification of opiate addicts.

Topics: Adenosine; Animals; Behavior, Animal; Clonidine; Diarrhea; Female; Male; Morphine Dependence; Motor Activity; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

To assess the role of opioid receptors in the spinal cord in regulation of functions of the intestinal mucosa in a secretory model, we evaluated the ability of i.t. administered mu (PL017), delta (DPDPE) and kappa (U50,488H) selective opioid agonists to inhibit diarrhea produced in mice by an injection of prostaglandin E2 (PGE2) (200 micrograms/mouse, i.p.). I.t. PL017 and DPDPE inhibited diarrhea in a dose-related fashion. U50,488H had only minimal antidiarrheal effects. The i.t. doses of PL017 and DPDPE required to inhibit diarrhea were higher than the doses required to produce antinociception and inhibit gastrointestinal transit. Spinally administered PL017 and DPDPE were considerably less potent in the diarrhea model than after i.c.v. administration but far more effective than after peripheral (s.c.) dosing. The antidiarrheal effects of spinally administered opioids were antagonized by concurrently administered naloxone. These data indicate that opioid chemosensitive sites in the spinal cord can modulate diarrhea produced by PGE2, and that the receptor specific opioids, PL017 and DPDPE, and to a lesser extent U50,488H, all possess antidiarrheal activity when administered i.t.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Antidiarrheals; Body Weight; Diarrhea; Dinoprostone; Endorphins; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Gastrointestinal Transit; Male; Mice; Mice, Inbred ICR; Naloxone; Narcotics; Pyrrolidines; Spinal Cord

1. Doses of buprenorphine (0.01, 0.1, 0.5, 1, 5, 10 and 50 mg/kg) were administered to determine buprenorphine's ability to precipitate abstinence symptoms in morphine-dependent mice. 2. When buprenorphine was administered in the fourth day of morphine addiction, the results demonstrate that the administration of the partial agonist opioid produce a bell-shaped dose-response curve. 3. The highest dose (50 mg/kg) was partially inactive while lower doses causing similar percentage than group treated with naloxone with respect to the appearance of the most of the symptoms of abstinence studied (diarrhoea, tremor, shaking-"wet dog shakes"-, jumping and weight loss). 4. Our findings demonstrate the bell-shaped response curve of the antagonist effects of buprenorphine.

Topics: Animals; Behavior, Animal; Buprenorphine; Diarrhea; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred Strains; Morphine Dependence; Naloxone; Substance Withdrawal Syndrome; Tremor

Regional cerebral glucose utilization (RCGU) and behavior during precipitated morphine withdrawal were studied in rats made dependent by either intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of morphine. [14C]2-deoxy-D-glucose autoradiography revealed that RCGU increased in an anatomically related group of limbic and brainstem structures in rats that were in morphine withdrawal precipitated by naloxone administration compared to morphine-dependent controls that were not in precipitated withdrawal. Correlation of RCGU for 24 brain structures comparing i.c.v. vs s.c. morphine-treated rats was highly significant for groups in withdrawal and for controls (r values, 0.958 and 0.971, respectively). Withdrawal behaviors including autonomic signs of withdrawal, withdrawal jumping, and incidence of diarrhea were not different between the two groups in withdrawal (i.c.v. and s.c.). Weight loss during withdrawal increased (P less than 0.05) in rats made dependent by s.c. morphine administration compared to rats that received morphine by the i.c.v. route. Taken together, these results indicate that RCGU changes during morphine withdrawal result solely from effects of chronic morphine in the central nervous system, not in peripheral sites. The increased weight loss of s.c.-treated, morphine-dependent rats in withdrawal suggests an independent peripheral effect perhaps mediated by visceral opiate receptors.

Topics: Animals; Autonomic Nervous System; Autoradiography; Brain; Carbon Radioisotopes; Cerebral Ventricles; Deoxy Sugars; Deoxyglucose; Diarrhea; Infusions, Parenteral; Male; Morphine; Morphine Dependence; Motor Activity; Naloxone; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome; Weight Loss

The effects of systemic administration of morphine (4.0 mg kg-1) and clonidine (2.5-10.0 micrograms kg-1), as well as the peripherally active alpha 2-adrenoceptor agonist oxymetazoline (2.8-11.2 micrograms kg-1), were studied on the migrating myo-electric complexes (MMCs) of the small intestine in conscious, naive rats. Furthermore, the effects of naloxone (1.0 mg kg-1) and the peripherally acting opioid antagonist, methylbromide naloxone (1.0-2.0 mg kg-1) were studied on the MMCs in morphine-dependent animals. Similar doses of clonidine or oxymetazoline inhibited the MMCs of the small intestine, which suggests a peripheral site of action of clonidine. Since naloxone (1.0 mg kg-1) did not antagonize the effect of clonidine, and yohimbine (1.0 mg kg-1) failed to antagonize the effect of morphine on the MMC, the inhibitory effects on intestinal motility of clonidine and morphine are mediated through different receptors. Morphine-dependent rats showed a prolonged interval between activity fronts and decreased propagation velocity of the activity fronts. Both naloxone (1.0 mg kg-1) and methylbromide naloxone (1.0-2.0 mg kg-1) induced intense spiking activity and profuse diarrhoea. Clonidine (5.0-10.0 micrograms kg-1) as well as oxymetazoline (5.6-11.2 micrograms kg-1) given prior to naloxone prevented the intense spiking as well as the concomitant diarrhoea. We conclude that the potent inhibition of small intestinal myoelectric activity by alpha 2-adrenoceptor agonists is mainly executed via peripheral mechanisms. This effect may contribute to their beneficial action in morphine withdrawal diarrhoea, and partly underlie a general antidiarrhoeal action.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Clonidine; Diarrhea; Gastrointestinal Motility; Intestine, Small; Male; Morphine; Morphine Dependence; Naloxone; Oxymetazoline; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

Various alterations of the immune system have recently been reported to attenuate the severity of morphine withdrawal. The effect of the immunosuppressive agent ciclosporine A on the naloxone-induced morphine withdrawal syndrome in the chronically dependent mouse was investigated. Ciclosporine A significantly suppressed stereotyped behaviour such as jumping and forepaw treading while wet shakes were potentiated. Withdrawal diarrhoea was diminished as a consequence of a promotive action of ciclosporine A on the intestine. A ciclosporine derivative, which is devoid of immunosuppressive activity, had no influence on withdrawal signs. The attenuating effect of ciclosporine A was observed at a dose of 20 mg/kg i.p., which is not regarded as immunosuppressive in the mouse. It was also effective in animals lacking an intact immune system as a result of a genetic T-cell defect (nude mouse) or after selective ablation by whole body irradiation. Nude mice and irradiated normal mice developed dependence on morphine to the same extent as normal animals, as could be derived from the severity of their withdrawal signs. These results suggest that an intact immune system is not a necessary prerequisite for ciclosporine A to attenuate morphine withdrawal and that its action may be attributable to mechanisms other than immunosuppression. It is possibly a result of a direct effect of ciclosporine A on the central nervous system structures involved in the behavioural expression of the opiate withdrawal syndrome.

Topics: Animals; Body Temperature Regulation; Body Weight; Cyclosporins; Diarrhea; Female; Immune System; Mice; Mice, Nude; Morphine; Naloxone; Stereotyped Behavior; Substance Withdrawal Syndrome; Time Factors

It has been demonstrated in a murine model that a defined diet (Purina Basal Diet 5755) has immunosuppressive effects similar to cyclosporin A (CsA). It was also shown that CsA treatment in opiate dependent rats can attenuate the severity of opiate withdrawal. In this study, an opiate dependence model was established in Balb/c mice to assess the effects of the 5755 diet and CsA on morphine withdrawal - a CNS mediated phenomenon. Three groups of mice were used; a chow-fed control group (Purina 5008), a chow fed CsA treated group, and a group maintained on the 5755 diet. Morphine dependence was established by subcutaneous implantation of a 100 mg morphine base pellet under ether anesthesia. Seventy-two hours after pellet implantation, withdrawal was precipitated by a single injection of the opiate antagonist naloxone (2 mg/kg ip). Two indicators of withdrawal were assessed; jumping and diarrhea. The data demonstrated that both CsA and the 5755 diet resulted in significant attenuation of withdrawal symptoms with the 5755 diet being the most effective of the two. These findings suggest that immune modulation elicited by the 5755 diet and CsA treatment has a direct impact on the CNS opioid function.

Topics: Animals; Cyclosporins; Diarrhea; Female; Mice; Mice, Inbred BALB C; Morphine Dependence; Motor Activity; Naloxone; Substance Withdrawal Syndrome

Morphine-dependent rats were used to evaluate the effects of the narcotic antagonists, naloxone and nalmefene, and their glucuronide conjugates on the gastrointestinal tract and various parameters of brain-mediated withdrawal. When administered s.c. nalmefene HCl caused a dose-dependent tail skin temperature increase, whereas nalmefene glucuronide was ineffective. Nalmefene precipitated brain-mediated morphine withdrawal at doses as low as 10 micrograms/kg, whereas nalmefene glucuronide was ineffective at doses as high as 1 mg/kg. After p.o. administration of the drugs, naloxone HCl and nalmefene HCl caused diarrhea, withdrawal behavior and tail skin temperature responses by 15 min. In contrast, after p.o. administration of the glucuronide conjugate of either narcotic antagonist, diarrhea was delayed for 75 to 203 min. This latency probably reflects the required transit time to the lower gastrointestinal tract inasmuch as direct colonic administration of either nalmefene or nalmefene glucuronide caused diarrhea within 5 to 8 min. Additionally, the magnitude of brain-mediated withdrawal was smaller and its time of occurrence was delayed and compared to the diarrhea response after p.o. administration of the conjugated forms of the narcotic antagonists. Our calculations indicate that about 0.2 to 0.5% of the dose of the narcotic antagonist administered orally as the glucuronide was absorbed systemically. These results indicate that p.o. administration of the glucuronide conjugates of naloxone and nalmefene results in delivery of the narcotic antagonists to the colon. As such these conjugates may be useful in the prevention or relief of constipation caused by opiate use, without interfering with the central analgesic effects of the narcotics.

Topics: Animals; Colon; Constipation; Diarrhea; Dose-Response Relationship, Drug; Glucuronates; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Skin Temperature; Substance-Related Disorders

Thiorphan and acetorphan, two potent inhibitors of enkephalinase (EC 3.4.24.11 membrane-metalloendopeptidase) significantly reduced the castor oil-induced diarrhea in rats when administered intravenously (or orally, for acetorphan) but not when administered intracerebroventricularly. These effects were more marked during the 90 min period following the castor oil challenge but were still significant up to 4-8 h after the latter. Acetorphan was about 6 times more potent than thiorphan. The antidiarrheal activity of both compounds was completely prevented in rats receiving naloxone subcutaneously but not intracerebroventricularly (in the case of thiorphan). In contrast to loperamide, a peripherally acting opiate receptor agonist, the enkephalinase inhibitors did not significantly reduce gastrointestinal transit as measured in the charcoal meal test. The antidiarrheal activity of enkephalinase inhibitors therefore seems attributable to protection of endogenous opioids, presumably outside the brain, and to reduction of intestinal secretion rather than transit.

Topics: Amino Acids, Sulfur; Animals; Castor Oil; Diarrhea; Drug Interactions; Gastrointestinal Transit; Loperamide; Male; Metalloendopeptidases; Mice; Naloxone; Neprilysin; Rats; Rats, Inbred Strains; Thiorphan; Tiopronin

The effects of two calcium channel blockers (verapamil and flunarizine) were evaluated on the naloxone-precipitated syndrome in morphine-dependent rats. The withdrawal signs in saline-treated rats were mainly diarrhea, body weight loss, jumping and ptosis. On i.p. administration, verapamil and flunarizine prevented diarrhea and body weight loss but not jumping. Verapamil also reduced the incidence of ptosis at the highest dose tested (40 mg/kg). Administered i.c.v., 160 micrograms verapamil reduced the body weight loss and the number of jumps without modifying diarrhea or ptosis. The results show that calcium channel blockers inhibit morphine abstinence syndrome manifestations through both peripheral and central mechanisms.

Topics: Animals; Body Weight; Brain; Calcium Channel Blockers; Clonidine; Diarrhea; Flunarizine; Injections, Intraventricular; Male; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome; Verapamil

We examined the importance of timing with endorphin involvement in shock by giving the opiate receptor antagonist naloxone as a pretreatment in canine endotoxic shock. Dogs anesthetized with pentobarbital (30 mg/kg iv) were given Escherichia coli endotoxin at LD80 doses iv. Naloxone (2 mg/kg plus 2 mg/kg/hr iv, N = 10) started 15 min before endotoxin attenuated the fall in mean arterial pressure, cardiac index, and the first derivative of left ventricular pressure due to endotoxin in comparison with control animals given 0.9% NaCl (N = 10). Naloxone attenuated the endotoxin-induced decrease in superior mesenteric arterial blood flow and the increases in portal venous pressure and pulmonary arterial pressures. Moreover, naloxone pretreatment prevented the characteristic bloody diarrhea and reduced mortality. Our findings implicate endorphins acting on opiate receptors as important mediators of endotoxin-induced cardiovascular failure and bloody diarrhea in canine endotoxemia. These are early manifestations and dictate expeditious use of naloxone in endotoxic shock.

Topics: Animals; Blood Pressure; Diarrhea; Dogs; Endotoxins; Female; Hemodynamics; Male; Naloxone; Shock, Septic

Adult respiratory distress syndrome (ARDS) is a common and serious complication of septic shock. Pulmonary trapping of platelets (PPT) and leukocytes, and release of vasoactive and toxic substances such as prostaglandins, lysozymes and oxygen-radicals have been implicated as mediators of the lung injury. beta-Endorphin is regarded as one of the substances released during shock, and has been shown to cause cell damage similar to that seen with endotoxin, and also PPT. We recently reported that combined treatment with methylprednisolone, ibuprofen and naloxone significantly increased lasting survival in an LD100 canine endotoxin shock model. In the present study the effects of these drugs in various combinations were evaluated as regards blood pressure, hematocrit, peripheral platelet and leukocyte counts, intestinal damage and PPT in the same model. The effects of combined treatment were significantly decreased PPT, rise in blood pressure and abolition of bloody diarrhea. We concluded that ibuprofen and naloxone have additive action and that methylprednisolone has no effect on PPT.

Topics: Animals; Blood Platelets; Blood Pressure; Diarrhea; Dogs; Endotoxins; Escherichia coli; Female; Hematocrit; Ibuprofen; Leukocyte Count; Male; Methylprednisolone; Naloxone; Platelet Count; Respiratory Distress Syndrome; Shock, Septic

Mice were rendered physically dependent by repeated administration of morphine, 25 mg/kg s.c., 5 times daily for 4 days, and on the 5th day, 2 h after the last morphine dose, they were challenged with a s.c. injection of either naloxone, 25 mg/kg, or the peripherally selective opioid antagonist SR 58002 C (N-methyl levallorphan mesilate), 75 mg/kg. Naloxone provoked jumping and diarrhea in all the animals; mice challenged with SR 58002 C presented no significant jumping but a high frequency of withdrawal diarrhea. When naloxone, 12 mg/kg, or SR 58002 C, 50 mg/kg, were given s.c. in combination with repeated morphine as above, mice which had received naloxone with morphine presented virtually no diarrhea or jumping upon naloxone challenge; those repeatedly treated with morphine plus SR 58002 C were substantially protected from naloxone-precipitated diarrhea, but not jumping. These results further support the remarkable selectivity for peripheral opioid receptors of SR 58002 C, even after repeated high-dose treatment, and are strongly consistent with the primary role of a local intestinal mechanism in the development and expression of opioid withdrawal diarrhea in mice. The in vivo dissociation of central and peripheral components of dependence on morphine is illustrated, apparently for the first time.

Topics: Animals; Body Weight; Diarrhea; Levallorphan; Mice; Morphine; Motor Activity; Naloxone; Narcotic Antagonists; Substance Withdrawal Syndrome

Prostaglandins and cyclic adenosine monophosphate have been claimed to play a major role in the morphine withdrawal syndrome, but intestinal secretion has not been ruled out as being responsible, at least in part, for the accompanying diarrhea. Therefore, experiments were performed in which the effect of naloxone-induced morphine withdrawal on jejunal and on colonic fluid transport was assessed in tied-off loops of rat intestine in vivo simultaneously with mucosal cyclic adenosine monophosphate levels or colonic luminal release of prostaglandin E2 or 5-hydroxytryptamine. Naloxone-induced withdrawal reversed fluid absorption to secretion without changing cyclic adenosine monophosphate levels, but markedly enhanced local prostaglandin E2 and 5-hydroxytryptamine release (p less than 0.01). Indomethacin and the 5-hydroxytryptamine receptor antagonist ketanserin prevented withdrawal-induced fluid secretion and the increase in prostaglandin E2 release without influencing the release of 5-hydroxytryptamine. In addition, the alpha 2-adrenergic receptor agonist clonidine promoted absorption during withdrawal, whereas atropine failed to influence fluid transport. These data suggest that naloxone-precipitated intestinal fluid secretion may contribute to diarrhea due to morphine withdrawal and that 5-hydroxytryptamine may play an important role in mediating this secretion through stimulation of local prostaglandin formation.

Topics: Animals; Atropine; Clonidine; Colon; Cyclic AMP; Diarrhea; Dinoprostone; Female; Humans; Indomethacin; Ketanserin; Morphine Dependence; Naloxone; Piperidines; Prostaglandins E; Rats; Rats, Inbred Strains; Serotonin; Substance Withdrawal Syndrome

Topics: Animals; Cholera Toxin; Cyclic AMP; Diarrhea; Enkephalin, Methionine; Intestinal Mucosa; Loperamide; Male; Naloxone; Piperidines; Rats; Water-Electrolyte Balance

Opiates and opioid peptides can alter gastrointestinal motility and delay transit of intraluminal contents. These experiments were designed to characterize the effects of beta-endorphin and [D-Ala2,Met5]enkephalinamide (DALA) on small intestinal transit in the rat. Rats were implanted with a polyethylene cannula in the right lateral cerebral ventricle and a silastic cannula in the proximal duodenum. Drugs were administered via the cerebral cannula or intraperitoneally (i.p.) Interstitial transit was assessed by instilling radiochromium into the duodenum and calculating the geometric center of the distribution of marker in the small intestine. beta-Endorphin and DALA produced a dose-related decrease in intestinal transit when the peptides were given intracerebroventricularly (i.c.v.) however, neither peptide was effective when i.p. [D-Ala2,Leu5]enkephalinamide and dynorphin-(1-13) did not alter intestinal transit. The inhibitory effects of beta-endorphin and DALA were antagonized by pretreatment with naloxone or naltrexone. A quaternary amine containing opiate antagonist. N,N-diallylnormorphinium given i.p. did not alter the response to either peptide but was effective in blocking the antitransit effects of i.p. loperamide, a peripherally acting opioid agonist. In addition, DALA reduced the body weight loss produced by castor oil-induced diarrhea while beta-endorphin had no effect. These results indicate that opioid peptides can alter intestinal motility by an action within the central nervous system. While DALA and beta-endorphin produce quantitatively the same effects on small intestinal motility, qualitatively they may differ in their mechanisms of action.

Topics: Animals; beta-Endorphin; Central Nervous System; Diarrhea; Dynorphins; Endorphins; Female; Gastrointestinal Motility; Intestine, Small; Naloxone; Naltrexone; Rats; Rats, Inbred Strains

Naltrexone methylbromide and naloxone methylbromide, quaternary derivatives of naltrexone and naloxone respectively, are assumed to act peripherally. Both compounds reversed the intestinal stimulating effect of morphine in the dog. Naltrexone methylbromide 5 mg/kg s.c. blocked morphine-induced intestinal spike potentials for 50 min while intravenous doses caused antagonism for only 25 min. The antagonism by the s.c. route approximated that produced by naltrexone 0.2 mg/kg s.c. In morphine-dependent dogs, naltrexone methylbromide did not appear to antagonize morphine centrally in doses ranging from 0.25 to 50 mg/kg s.c. since it did not induce behavioral signs of narcotic withdrawal. Similarly, i.v. naloxone methylbromide was also able to reverse morphine-induced intestinal spike potential in dogs but the protection lasted only 25 min. In rats, naltrexone methylbromide 10 and 30 mg/kg i.p. neither reversed morphine block of PGF2 alpha-induced diarrhea nor antinociception. This suggests a lack of CNS narcotic antagonism in both test. In mice, naltrexone methylbromide, 60-720 mg/kg orally and 3-140 mg/kg i.p. failed to block morphine inhibition of prostaglandin F2 alpha-induced diarrhea. Paradoxically, in this species, 30 mg/kg s.c. of naltrexone methylbromide appeared to cross the blood-brain barrier since this dose reversed morphine-induced antinociception. In conclusion, naltrexone methylbromide effectively antagonizes the acute gut stimulating effect, but not the chronic behavioral effect of morphine administration in dogs. Based upon the antinociception test, naltrexone methylbromide does not cross the blood-brain barrier in rats but may in mice. Morphine inhibits prostaglandin F2 alpha-induced diarrhea by a central mechanism in rodents.

Topics: Animals; Central Nervous System; Diarrhea; Digestive System; Dogs; Female; Humans; Male; Mice; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Rats; Rats, Inbred Strains; Species Specificity; Substance Withdrawal Syndrome

Topics: Animals; Clonidine; Diarrhea; Humans; Male; Morphine Dependence; Naloxone; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Substance Withdrawal Syndrome

The injection of high dose of naloxone 15 minutes after a single injection of morphine in mice was found to produce a jumping response which was behaviorly similar to the jumping response observed during the withdrawal from chronic morphine administration. In addition the jumping response following the acute administration of morphine-naloxone was increased by the injection of atropine and attenuated by oxotremorine. These data are consistent with the reports of effect of these cholinergic drugs on the jumping response which occurred during withdrawal after chronic morphine administration. However, other symptoms associated with opiate withdrawal (hypothermia, weight loss and diarrhea) were not produced by the acute injection of morphine-naloxone. It is therefore suggested that this single injection paradigm is particular to the jumping response rather than a demonstration of the rapid development of opiate dependence.

Topics: Animals; Body Temperature; Body Weight; Diarrhea; Humans; Male; Mice; Morphine; Motor Activity; Naloxone; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Clonidine; Diarrhea; Digestive System; Female; Humans; Morphine Dependence; Naloxone; Neostigmine; Organ Size; Rats; Substance Withdrawal Syndrome

[Met]Enkephalin-Arg6-Phe7 is an opiate-like peptide normally found in the the adrenal gland and brain that has analgesic (antinociceptive) activity when administered directly into the cerebral ventricles of mice. On a molar basis, [Met]-enkephalin-Arg6-Phe7, with a median effective dose (ED50) of 38.5 nmol/mouse, is 8 times more potent than [Met]enkephalin. As with [Met]enkephalin, analgesic activity is blocked by naloxone and intravenous administration does not produce characteristic opiate effects in tests for analgesic, antidiuretic, or antidiarrheal activity. These findings suggest that [Met]enkephalin-Arg6-Phe7 may be at least as important as the enkephalins in the postulated enkephalin system mediating pain and analgesia.

Topics: Analgesics; Animals; Diarrhea; Diuresis; Dose-Response Relationship, Drug; Endorphins; Enkephalin, Methionine; Enkephalins; Injections, Intravenous; Injections, Intraventricular; Male; Mice; Naloxone; Rats

Discontinuation of chronic morphine infusion in rats resulted in the reliable occurrence of withdrawal body shakes. This sign of narcotic withdrawal was dose-dependently reduced by lofexidine (0.04-0.64 mg/kg) and clonidine (0.01-0.16 mg/kg). As with clonidine, the activity of lofexidine was not prevented by naloxone (5 mg/kg). In addition, diarrhea induced by naloxone (5 mg/kg) in morphine dependent rats was also prevented by lofexidine or clonidine pretreatment. These data suggest that lofexidine, like clonidine, may reduce the narcotic withdrawal syndrome in humans.

Topics: Animals; Behavior, Animal; Clonidine; Diarrhea; Dose-Response Relationship, Drug; Humans; Male; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome

The potential role of endogenous opiates in the mediation of the diarrheal actions of prostaglandin-F2 alpha (PGF2 alpha), 5-hydroxytryptophan (5-HTP) and methacholine was investigated. The interaction of the antidiarrheal agents morphine, propantheline bromide and cyproheptadine on the course of PGF2 alpha-induced diarrhea in mice was studied, as were the effects of naloxone on PGF2 alpha-, methacholine-, and 5-hydroxytryptophan-induced diarrhea. The three diarrheal agents, administered intraperitoneally, showed dose-dependent and parallel dose-response curves with the following order of decreasing potency: PGF2 alpha, methacholine and 5-HTP. Naloxone significantly inhibited the diarrhea induced by these agents. The diarrheal action of PGF2 alpha was also significantly attenuated with morphine, propantheline and cyproheptadine. These results suggest that PGF2 alpha, methacholine and 5-HTP induce diarrhea via a common pharmacological mechanism(s) which may involve an interaction with endogenous opiate receptors. However, the antagonism of diarrhea with agents having diverse pharmacological actions would suggest that factors unrelated to an interaction with endogenous opiates may also be involved in the production of diarrhea by the diarrheagenic agents studied.

Topics: 5-Hydroxytryptophan; Animals; Antidiarrheals; Cyproheptadine; Diarrhea; Dose-Response Relationship, Drug; Male; Methacholine Compounds; Mice; Morphine; Naloxone; Propantheline; Prostaglandins F

1 Subcutaneous prostaglandin E2 (2.5 mg/kg) produces profuse diarrhoea in fed rats. 2 Pretreatment of rats with subcutaneous loperamide (1.0 mg/kg) completely prevents prostaglandin-induced diarrhoea. If naloxone is administered prior to loperamide injections the activity of the antidiarrhoeal compound is completely destroyed. 3 These data provide strong evidence that the antidiarrhoeal activity of loperamide is mediated via the opiate receptor.

Topics: Animals; Diarrhea; Loperamide; Male; Naloxone; Piperidines; Prostaglandins E; Rats

Topics: Animals; Diarrhea; Dose-Response Relationship, Drug; Ethanol; Humans; Male; Morphine Dependence; Naloxone; Rats; Substance Withdrawal Syndrome; Time Factors

SC-27166 is the result of continuing efforts to discover selective and orally active antidiarrheal agents. SC-27166, which is chemically unrelated to opiates or neuroleptics, possesses potent constipating and antidiarrheal activity in several animal models. Tolerance to the constipating actions of SC-27166 did not develop in mice. On the other hand, gut tolerance rapidly developed to morphine sulfate and loperamide. The basic mechanism of the antidiarrheal action of SC-27166 is a consequence of increased intestinal circular muscle contractile activity. Supportive pharmacological studies indicated that SC-27166 has equivocal analgesia in mice which is manifested at near toxic dose levels. SC-27166 was also evaluated for potential dependence liability in morphine abstinence-induced jumping in mice. The abstinence-induced jumping was suppressed to a far lesser extent by SC-27166 than by either loperamide or diphenoxylate at equal doses. SC-27166 was also devoid of anticbholinergic activity. When compared with the reference standards morphine and diphenoxylate, these pharmacological studies indicated that SC-27166 has a high degree of separation of undesirable central nervous system actions from its antidiarrheal properties and may have important therapeutic potential.

Topics: Analgesics; Animals; Antidiarrheals; Behavior, Animal; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Constipation; Diarrhea; Diphenoxylate; Diuresis; Dogs; Female; Gastrointestinal Motility; Haplorhini; Humans; Macaca mulatta; Male; Mice; Morphine; Naloxone; Oxadiazoles; Parasympatholytics; Rats; Substance Withdrawal Syndrome

Topics: Administration, Oral; Animals; Behavior, Animal; Body Weight; Diarrhea; Dose-Response Relationship, Drug; Humans; Male; Mice; Morphine; Morphine Dependence; Motor Activity; Naloxone; Posture; Substance Withdrawal Syndrome; Time Factors

Topics: Animals; Behavior, Animal; Diarrhea; Diuresis; Dogs; Drug Interactions; Drug Tolerance; Ethers; Ethylamines; Feces; Gastrointestinal Agents; Guinea Pigs; Haplorhini; Humans; In Vitro Techniques; Indoles; Intestines; Male; Morphine; Naloxone; Rats; Stomach; Substance Withdrawal Syndrome; Time Factors