naloxone and Cholestasis

Primary biliary cirrhosis (PBC), autoimmune cholangitis (AIC = AMA-negative PBC) and primary sclerosing cholangitis (PSC) are autoimmune cholestatic liver diseases. Overlap syndromes combine characteristics of cholestatic liver diseases and autoimmune hepatitis. In PBC, alkaline phosphatase and gamma-glutamyl transferase are elevated, to a lesser degree aminotransferases. Histology shows bile duct lesions. Anti-mitochondrial antibodies are typical. Ursodeoxycholic acid (UDC) is established therapy that slows or even stops the disease progression, at least in early stages of the disease. In non-responders immunosuppression is recommended. PSC is mostly associated with chronic inflammatory bowel diseases. P-ANCA are frequent. Bile duct lesions revealed by retrograde cholangiography are characteristic. UDC is given as therapy. Bile duct strictures or bacterial cholangitis may be late sequelae and should be treated by antibiotics or bile-duct dilatation. Cirrhosis may ultimately develop in PBC and PCS. In progressed PBC or PSC liver transplantation is indicated.

Topics: Anti-Bacterial Agents; Antibodies, Antineutrophil Cytoplasmic; Anticholesteremic Agents; Antipruritics; Autoimmune Diseases; Bile Ducts; Cholagogues and Choleretics; Cholangiography; Cholangitis; Cholangitis, Sclerosing; Cholestasis; Cholestyramine Resin; Clinical Enzyme Tests; Diagnosis, Differential; Hepatitis, Autoimmune; Humans; Immunosuppression Therapy; Inflammatory Bowel Diseases; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Transplantation; Naloxone; Naltrexone; Narcotic Antagonists; Ondansetron; Plasmapheresis; Ursodeoxycholic Acid

Increased opioidergic neurotransmission in the brain appears to contribute to the pruritus that complicates cholestasis and certain non-cholestatic chronic liver diseases. Opiate antagonists have been shown to decrease scratching activity in patients with the pruritus of cholestasis. Initiation of oral administration of an orally bioavailable opiate antagonist may precipitate a florid opioid-withdrawal-like reaction in patients with pruritus complicating cholestasis. Such reactions can be minimized, or avoided completely, by cautiously infusing naloxone before giving small oral doses of an orally bioavailable opiate antagonist. The infusion rate of naloxone should initially be very low; it should be increased gradually and stopped when a rate known to be associated with opioid antagonist effects has been attained. Oral therapy with an opiate antagonist can then be initiated.

Topics: Administration, Oral; Cholestasis; Humans; Naloxone; Narcotic Antagonists; Narcotics; Pruritus; Substance Withdrawal Syndrome

Topics: Animals; Cholestasis; Humans; Macaca fascicularis; Naloxone; Narcotic Antagonists; Opioid Peptides; Pruritus; Rats; Receptors, Opioid

To determine whether endogenous opioids contribute to the pruritus of cholestasis by studying the effect of the opiate antagonist naloxone on the perception of pruritus and on scratching activity in patients with this form of pruritus.. Double-blind, placebo-controlled, crossover trial with four periods.. Clinical research referral center.. 29 pruritic patients with liver diseases of various causes.. Each patient received as many as two naloxone and two placebo solution infusions consecutively in random order. Each infusion lasted 24 hours.. During the infusions, visual analog scores of pruritus were recorded every 4 hours while patients were awake; scratching activity independent of limb movements was recorded continuously.. One patient had a mild reaction consistent with a naloxone-precipitated syndrome similar to opiate withdrawal. A significant 24-hour rhythm of scratching activity was seen in 7 of 11 patients for whom complete 96-hour data were collected. The mean of a visual analog score of the perception of pruritus (maximum, 10.0) recorded during naloxone infusions was 0.582 lower than that recorded during placebo infusions (95% CI, 0.176 to 0.988; P < 0.01). Furthermore, the ratio of the geometric mean hourly scratching activity during naloxone infusions to that during placebo infusions was 0.727 (CI, 0.612 to 0.842; P < 0.001) and was greater than 1.0 in only five patients.. Naloxone administration is associated with amelioration of the perception of pruritus and reduction of scratching activity in cholestatic patients. Because of the opioid receptor specificity of the action of naloxone, these findings support the hypothesis that a mechanism underlying the pruritus of cholestasis is modulated by endogenous opioids and suggest that opiate antagonists may have a role in the management of this complication of cholestasis.

Topics: Adult; Aged; Cholestasis; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Motor Activity; Naloxone; Pruritus; Treatment Outcome

The involvement of the opioidergic system on anxiolytic and antinociceptive responses induced by cholestasis was investigated in cholestatic and addicted mice. Elevated plus-maze and tail-flick devices were used to assess anxiety and pain levels, respectively. The data indicated that induction of cholestasis and injection of opioid drugs including morphine and tramadol enhanced %OAT and %OAE but naloxone reduced %OAT and %OAE in the sham-operated and bile duct ligation (BDL) mice. Induction of cholestasis and addiction to morphine and tramadol prolonged tail-flick latency, which was reversed by naloxone. Coadministration of morphine and tramadol enhanced anxiolytic and analgesic effects in the sham-operated and BDL mice. It seems (a) cholestasis and addiction affect anxiety and pain behaviors, (b) μ-opioid receptors play a key role in anxiolytic and analgesic effects induced by cholestasis, and (c) cotreatment with morphine and tramadol augmented the effectiveness of them for induction of anxiolytic and analgesic effects both in cholestatic and addicted mice.

Topics: Analgesics, Opioid; Animals; Anti-Anxiety Agents; Cholestasis; Dose-Response Relationship, Drug; Mice; Morphine; Naloxone; Pain; Receptors, Opioid, mu; Tramadol

Patients with cholestatic liver diseases, such as primary biliary cirrhosis, usually suffer from pruritus. However, the pathogenesis of cholestatic pruritus is unclear, and there is no current effective treatment for it. In order to find a treatment for the condition, an appropriate mouse model should be developed. Therefore, here, we established a surgically-induced mouse model of cholestatic pruritus. The bile duct was ligated in order to block bile secretion from the anterior, right, and left lobes, with the exception of the caudate lobe. Serum levels of total bile acid increased after bile duct ligation (BDL). The spontaneous hind paw scratching was also increased in BDL mice. Spontaneous scratching was reduced in BDL mice by naloxone (µ-opioid receptor antagonist), U-50,488H (κ-opioid receptor agonist), and clonidine (α2-adrenoceptor agonist). Azelastine (H

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic alpha-2 Receptor Agonists; Animals; Antipruritics; Bile Ducts; Cholestasis; Clonidine; Disease Models, Animal; Ligation; Liver; Male; Mice, Inbred ICR; Naloxone; Narcotic Antagonists; Pruritus; Receptors, Opioid, kappa

Increased activity of the endogenous opioid system in cholestasis results in analgesia. GABAA receptors have been ascribed both pronociceptive and antinociceptive roles in pain modulation. Considering the elevated endogenous opioid tone in cholestasis and the existence of close interaction between the GABAergic and opioidergic systems in pain control, the involvement of GABAA receptors in modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated using muscimol and bicuculline as selective GABAA receptor agonist and antagonist respectively. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct between them. Cholestatic rats had increased tail-flick latencies (TFLs) compared to non-cholestatic rats. Administration of muscimol (0.2 and 0.4 mg/kg, s.c.) and bicuculline (0.5 and 1mg/kg, s.c.) to the cholestatic groups significantly increased and decreased respectively TFLs compared to the saline treated cholestatic group. Muscimol antinociception in cholestatic animals was attenuated by co-administration of naloxone or bicuculline. Furthermore, the combination of bicuculline and naloxone completely reversed the increased TFLs of cholestatic rats back to the level of unoperated animals. Muscimol and bicuculline injections into non-cholestatic animals did not alter TFLs. At the doses used here, none of the drugs impaired motor coordination, as revealed by the rotarod test. This study shows the involvement of GABAA receptors in pain modulation during cholestasis in rats.

Topics: Acute Pain; Animals; Bicuculline; Cholestasis; Disease Models, Animal; Muscimol; Naloxone; Rats; Receptors, GABA-A; Rotarod Performance Test

Bile duct ligation (BDL) is an animal model used in cholestatic disease research. Both opioidergic and nitrergic systems are known to be involved in cholestasis. The aim of this study was to investigate the possible interaction between these two systems in BDL-induced memory formation and exploratory behaviors in mice. Male mice weighing 25-30 g were divided into nonoperated controls, sham-operated, and BDL groups. One-trial step-down and hole-board paradigms were used to assess memory acquisition and exploratory behaviors, respectively. Cholestasis did not alter memory acquisition while increasing exploratory behaviors 7 days after BDL. A pretraining intraperitoneal injection of L-arginine (50, 100, and 200 mg/kg), L-NG-nitroarginine methyl ester (L-NAME) (5, 10, 20, and 40 mg/kg), or naloxone (0.125, 0.25, and 0.5 mg/kg) did not alter memory acquisition or exploratory behaviors, whereas morphine (5 and 7.5 mg/kg) decreased memory acquisition in sham-operated animals. Moreover, although injection of L-NAME and naloxone exerted no effect on memory acquisition in the 7 days post-BDL mice, L-arginine (100 and 200 mg/kg) and morphine (2.5, 5, and 7.5 mg/kg) injection reduced it. In contrast, L-NAME and naloxone, but not morphine or L-arginine, reduced the BDL-induced exploratory behaviors. Coadministration of subthreshold doses of morphine (1.25 mg/kg) and L-arginine (50 mg/kg) caused a memory deficit in 7 days post-BDL mice. However, the memory deficit induced by the effective doses of morphine (2.5 mg/kg) or L-arginine (200 mg/kg) in these mice was restored by the administration of either naloxone (0.5 mg/kg) or L-NAME (40 mg/kg). In addition, naloxone and L-NAME reduced the exploratory behaviors in L-arginine-pretreated mice but not in morphine-pretreated mice. We conclude that there appears to be a synergistic effect between opioidergic and nitrergic systems on memory acquisition and exploratory behaviors in cholestatic mice.

Topics: Analgesics, Opioid; Animals; Arginine; Avoidance Learning; Cholestasis; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Exploratory Behavior; Ligation; Male; Memory Disorders; Mice; Morphine; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide

There are several studies carried out to test the effect of cholestasis on memory impairment and anxiolytic-like behaviors. Some previous studies have shown that cholestasis alters the activity of opioidergic and dopaminergic systems. The aim of the present study is however to investigate the role of mu opioid, D₁ and D₂ dopamine ventral hippocampal (CA₃) receptors upon cholestasis-induced anxiolytic-like behaviors in hole-board task. Male mice weighing 25-30 g were used. Cholestasis was induced by ligation of the main bile duct. Our data indicated that cholestasis can induce anxiolytic-like response. Furthermore, the results showed that the intra-CA₃ injection of naloxone, a mu receptor antagonist at 0.25 and 0.5 µg/mouse, SCH23390, a D₁ dopamine receptor antagonist or sulpiride, as a D₂ dopamine receptor antagonist, 5 min before testing, reversed the cholestasis-induced anxiolytic-like behaviors seven days after bile duct ligation (BDL). Unlike the higher dose of SCH23390 (0.5 µg/mouse) which induced anxiogenic-like behaviors, other doses of the above drugs did not alter the exploratory behaviors in examined mice. Based on our findings, co-administration of the subthreshold dose of naloxone (0.125 µg/mouse), SCH23390 or sulpiride, and SCH23390 with sulpiride, neither altered exploratory behaviors in animals nor reversed the cholestasis-induced anxiolytic-like behaviors, seven days post BDL. Current results demonstrated firstly, the anxiolytic-like behaviors are evident in cholestatic mice seven days post BDL; secondly, there are plausible mechanisms governing the involvement of the CA₃ opioidergic and dopaminergic systems in this phenomenon and thirdly, there seem to be no interaction between these systems.

Topics: Animals; Anxiety; Behavior, Animal; Benzazepines; CA3 Region, Hippocampal; Cholestasis; Exploratory Behavior; Male; Mice; Naloxone; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Opioid, mu; Sulpiride

Topics: Aged, 80 and over; Cholestasis; Comorbidity; Humans; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pruritus; Quality of Life; Quaternary Ammonium Compounds

Bile duct ligation (BDL) induces primary biliary cirrhosis characterized by cholestasis, impaired liver function and cognition including impairment of memory formation and anxiety-like behaviors. Endogenous opioid and acetylcholine levels are elevated in animal model of cholestasis. In addition, there is no data about the effects of interaction opioidergic and cholinergic systems of dorsal hippocampus (CA1) on amnesia-induced by cholestasis. Male mice weighing 25-35 g were used in this study. Cholestasis was induced by the ligation of the common bile duct. One-trial step-down and hole-board paradigms were used for the assessment of memory retrieval and anxiety-like behaviors respectively. All drugs injected intra-CA1. The data showed that cholestasis (24 days after BDL) decreased memory retrieval. Sole intra-CA1 injection of higher dose of mecamylamine (0.125, 0.25, 0.5 and 1 μg/mice) and scopolamine (0.125, 0.25, 0.5 1 and 2 μg/mice) but not all doses of naloxone (0.0125, 0.025 and 0.05 μg/mice) decreased memory retrieval in the sham operated BDL. The ineffective doses of naloxone (0.025 and 0.05 μg/mice), mecamylamine (0.5 μg/mice) and scopolamine (0.5 μg/mice) restored cholestasis-induced amnesia 24 days after BDL. Further, all cross co-administration ineffective doses of naloxone (0.0125 μg/mice), mecamylamine (0.125 μg/mice) and scopolamine (0.125 μg/mice) reversed cholestasis-induced amnesia. All doses of the drugs have no effect on exploratory behaviors. The data strongly revealed that synergistic effect between opioidergic and cholinergic systems of CA1 on the modulation of cholestasis-induced amnesia.

Topics: Amnesia; Animals; Animals, Outbred Strains; CA1 Region, Hippocampal; Cholestasis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exploratory Behavior; Male; Mecamylamine; Mental Recall; Mice; Microinjections; Muscarinic Antagonists; Naloxone; Narcotic Antagonists; Nicotinic Antagonists; Receptors, Opioid; Scopolamine

Several investigations have indicated that cholestasis decreases opioid receptor expression in the brain following increased opioidergic neurotransmission. The opioidergic system plays an important role in regulation of reward circuits that may be produced via dopamine-dependent mechanisms. It has been suggested that the dopaminergic system of the nucleus accumbens is necessary in conditioned place preference (CPP). The aim of this study is, therefore, to test if cholestasis can alter the reward system and the involvement of opioidergic and dopaminergic systems in this phenomenon. . We used CPP and hole-board paradigms to measure the reward effect and exploratory behaviors, respectively, in mice. Cholestasis was induced by ligation of the main bile duct, using two ligatures and transecting the duct between them (BDL mice). . The data showed that morphine (1 and 2 mg/kg), sulpiride (80 mg/kg) and SKF38393 (20 mg/kg) produced CPP, while naloxone (1 mg/kg) and SCH23390 (1mg/kg) produced conditioned place aversion (CPA), whereas quinpirole had no effect in sham-operated mice. However, morphine (2 mg/kg, i.p.), sulpiride (40 mg/kg) and? SKF38393 (10 mg/kg) induced CPP in BDL mice compared to sham-operated mice. Naloxone- or SCH23390-induced CPA was reduced in BDL mice compared with the respective sham-operated mice. Quinpirole tended to induce aversion in BDL mice which was, however, not significant. In addition, quinpirole 1 mg/kg) and SCH23390 (1 mg/kg) increased head-dip exploratory behavior, whereas naloxone (2 mg/kg) caused a decrease in head-dip exploratory behavior in sham-operated mice. Morphine (2 mg/kg), SCH23390 (1 mg/kg) and quinpirole (0.25 and 0.5 mg/kg) induced anxiogenic-like behavior in BDL mice. . It can be concluded that cholestasis differentially alters the reward effects of opioidergic and dopaminergic agents.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Analgesics, Opioid; Analysis of Variance; Animals; Behavior, Animal; Benzazepines; Cholestasis; Dopamine Agents; Exploratory Behavior; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Quinpirole; Reward; Sulpiride

Cholestasis is associated with analgesia. The histamine H(2) receptors control pain perception. The involvement of histamine H(2) receptors on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using zolantidine and cimetidine as two H(2) receptor antagonists and dimaprit as a selective H(2) receptor agonist. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct at the midpoint between them. A significant increase in tail-flick latencies was observed in cholestatic rats compared to non-cholestatic rats. Administration of zolantidine (10, 20 and 40 mg/kg) and cimetidine (25, 50 and 100 mg/kg) in the cholestatic group significantly increased tail-flick latencies while dimaprit (10 and 20 mg/kg) injection in the cholestatic group decreased tail-flick latencies compared to the saline treated cholestatic group. Antinociception produced by injection of zolantidine and cimetidine in cholestatic rats was attenuated by co-administration of naloxone. Drug injection in non-cholestatic rats did not alter tail-flick latencies compared to the saline treated rats at any of the doses. At the doses used here, none of the drugs impaired motor coordination as revealed by the rota rod test. These data show that the histamine H(2) receptor system may be involved in the regulation of nociception during cholestasis. According to the hypothesis that increasing the nociception threshold in cholestasis may lead to a decrease in the perception of pruritus, the provision of the drugs that increase the threshold to nociception may be a novel approach to the treatment of cholestatic pruritus.

Topics: Analgesia; Animals; Benzothiazoles; Cholestasis; Cimetidine; Dimaprit; Disease Models, Animal; Histamine H2 Antagonists; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Pain Perception; Phenoxypropanolamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H2; Rotarod Performance Test

Cholestasis is associated with endotoxinemia and elevated serum levels of bile acids, cholesterol, bile salts and opioids. Opioid systems have been reported to modulate anxiety. In the present study, the possible involvement of opioidergic system on anxiolytic-like behaviors induced by cholestasis was investigated. Cholestasis was induced in male Wistar rats by ligation of the main bile duct using two ligatures and transecting the duct at the midpoint between them. A standard elevated plus-maze was used to determine anxiety levels in animals. The data indicated that there is an increase, 13 days (but not 10 days) after bile duct ligation, in the percentage of open arm time (%OAT) and open arm entries (%OAE) but not locomotor activity, grooming, rearing and defecation, showing anxiolytic-like effects of cholestasis. Intraperitoneal (i.p.) injection of a subthreshold dose of morphine (4 mg/kg), 15 min before testing 10 days after bile duct ligation, showed an increase in %OAT and %OAE, suggesting an anxiolytic-like effect for the drug. Furthermore, injection of subthreshold doses of naloxone (0.4 and 0.6 mg/kg, i.p.), 15 min before testing 13 days after bile duct ligation, decreased %OAT and %OAE. This indicates that naloxone blocks anxiolytic-like behaviors induced by cholestasis. Also, injection of a subthreshold dose of naloxone (0.4 mg/kg, i.p.), 15 min before the injection of a subthreshold dose of morphine (4 mg/kg, i.p.), 10 days after bile duct ligation, decreased %OAT and %OAE but not other behaviors. In conclusion, the results show the involvement of opioidergic system in anxiolytic-like behaviors induced by cholestasis.

Topics: Analgesics, Opioid; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Bile Ducts; Body Weight; Cholestasis; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Morphine; Naloxone; Rats; Rats, Wistar; Time Factors

Cholestasis is associated with changes including analgesia. The histaminergic system regulates pain perception. The involvement of histamine H(3) receptors in modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using immepip and thioperamide as selective H(3) receptor agonist and antagonist respectively. Cholestasis was induced by ligation of main bile duct using two ligatures and transsection the duct between them. Cholestatic rats had increased tail-flick latencies (TFLs) compared to non-cholestatics. Administration of immepip (5 and 30mg/kg) and thioperamide (10 and 20mg/kg) to the cholestatic groups significantly increased and decreased TFLs compared to the saline treated cholestatic group. Immepip antinociception in cholestatic animals was attenuated by co-administration of naloxone. Immepip and thioperamide injections into non-cholestatic animals did not alter TFLs. At the doses used here, none of the drugs impaired motor coordination, as revealed by the rotarod test. The present data show that the histamine H(3) receptor system may be involved in the regulation of nociception during cholestasis in rats.

Topics: Animals; Behavior, Animal; Bile Ducts; Cholestasis; Histamine Agonists; Histamine H3 Antagonists; Imidazoles; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Piperidines; Postural Balance; Rats; Rats, Wistar; Reaction Time; Receptors, Histamine H3

Topics: Aged; Bone Neoplasms; Carcinoma, Bronchogenic; Cholestasis; Humans; Lung Neoplasms; Male; Naloxone; Narcotic Antagonists; Nociceptors; Pruritus

Cholestasis is associated with increased activity of the endogenous opioid system that results in analgesia. Endocannabinoid system can reduce pain sensitivity. Considering the interaction that has been shown between the endogenous opioid and endocannabinoid systems in nociception processing, we studied the effect of AM404, an endocannabinoid transport inhibitor, on modulation of nociception in cholestasis, a model of elevated endogenous opioid tone. Cholestasis was induced by ligation of the main bile duct using two ligatures and transection of the duct at the midpoint between them. A significant increase (P<0.01) in TF was observed in cholestatic rats compared to unoperated and sham rats. AM404 (10 mg/kg, i.p.) significantly increased TFL at 5, 30 min but not 60 min after injection in cholestatic animals compared to the vehicle treated cholestatic group (P<0.05, P<0.001, respectively). AM404 injection to unoperated and sham rats did not alter baseline TFL. The effect of AM404 in cholestatic rats was blocked by co-administration of a CB(1) receptor antagonist, AM251 (1 mg/kg, i.p.) but not by the CB2 receptor antagonist, SR144528 (1 mg/kg, i.p.). Naloxone injection blocked the antinociception induced by cholestasis in bile duct ligated group. Antinociception produced by injection of AM404 in cholestatics was also attenuated by co-administration of naloxone. These data show that AM404 potentiates antinociception induced by cholestasis and indicate that there are possible interactions between opioid and cannabinoid systems in this experimental model of elevated endogenous opioid tone. The inhibitory effects of AM404 in this model are mediated by cannabinoid CB(1) and not CB(2) receptors.

Topics: Animals; Arachidonic Acids; Biological Transport; Camphanes; Cannabinoid Receptor Modulators; Cholestasis; Endocannabinoids; Male; Naloxone; Opioid Peptides; Pain; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Topics: Administration, Topical; Aged; Analgesics, Opioid; Buprenorphine; Cholestasis; Chronic Disease; Drug Combinations; Female; Humans; Injections, Intravenous; Naloxone; Narcotic Antagonists; Neoplasms; Pain; Pain Measurement; Palliative Care; Pruritus; Treatment Outcome

Severe pruritus is a frequent complication of cholestasis. Both serotonin and opioids play an important role in the development of this symptom. Guidelines to provide rational management of pruritus of cholestasis do not exist. We describe a patient with complex and malignant course of pruritus. She responded to several measures proposed (among other naltrexone), but rapidly became tolerant to them. Buprenorphine with an ultra low dose of naloxone was able to control her symptoms without development of tolerance until her death.

Topics: Aged; Buprenorphine; Cholestasis; Colonic Neoplasms; Drug Therapy, Combination; Fatal Outcome; Female; Humans; Liver Neoplasms; Naloxone; Narcotic Antagonists; Pruritus

Cholestasis is associated with elevated plasma level of endogenous opioid peptides. Naloxone-precipitated withdrawal syndrome has been described in a mouse model of acute cholestasis. Thus we aimed at determining whether central noradrenergic hyperactivity is involved in manifestation of naloxone-precipitated withdrawal syndrome in mice with obstructive cholestasis. Acute cholestasis was induced by bile duct resection in mice and physical dependence was observed by precipitating a withdrawal syndrome with naloxone (2 mg/kg, intraperitoneally) 5 days after induction of cholestasis. Administration of clonidine (0.1 mg/kg, intraperitoneally), an alpha2-adrenoceptor agonist, 15 min. before naloxone injection significantly alleviates withdrawal severity in cholestatic mice. However, pretreatment of animals with yohimbine (3 mg/kg, intraperitoneally), an alpha2-adrenoceptor antagonist, 15 min. before clonidine blocked this ameliorative effect of clonidine. The results of this study support the evidence for involvement of the alpha2-adrenoceptors in the withdrawal syndrome of cholestasis in a mouse model.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Cholestasis; Clonidine; Disease Models, Animal; Male; Mice; Naloxone; Narcotic Antagonists; Opioid Peptides; Substance Withdrawal Syndrome; Yohimbine

We compared indomethacin-induced gastric damage in three groups of rats-bile duct-ligated, sham-operated, and unoperated-and evaluated the role of the opioid system by blocking the effects of endogenous opioids with naloxone. Indomethacin was administered orally in a dose-dependent manner at 10, 30, and 45 mg/ kg. Naloxone was administered intraperitoneally in several doses of 0.5 and 1 mg/kg, starting 30 min before indomethacin (10mg/kg) administration and continued every 30 min. The animals were killed 4h after indomethacin administration. Indomethacin induced more severe gastric damage in bile duct-ligated rats than in sham and unoperated animals, and administration of naloxone (1 mg/kg) every 30 min inhibited the potentiation of indomethacin-induced gastric damage in bile duct-ligated rats, but not in the control groups (sham-operated and unoperated rats). Plasma indomethacin level was also measured, by fluorometry, but showed no significant difference between the groups. Endogenous opioids have been reported to accumulate in plasma of cholestatic animals, and, considering the results of this study, we suggest the opioid system plays an important pathophysiologic role in the pathogenesis of peptic ulcers in cholestatic subjects.

Topics: Animals; Cholestasis; Dose-Response Relationship, Drug; Gastric Mucosa; Indomethacin; Male; Naloxone; Narcotic Antagonists; Rats; Stomach Ulcer

The existence of an opioid central pathway that may regulate bile secretion was explored by studying the effect of the intracisternal (i.c.) administration of the opiate D-Ala2-Met-enkephalinamide (DAME) on bile secretion in anesthetized male rats. The i.c. administration of DAME was associated with a dose-related decrease in bile flow that ranged from 12% to 41%, which was prevented by the opiate antagonist naloxone. Bicarbonate secretion into bile decreased significantly after i.c. DAME. Chemical adrenergic denervation and cholinergic pharmacological blockade with atropine did not prevent the DAME-induced decrease in bile flow. The data support the existence of an opioid-mediated pathway that starts in the brain and that contributes to the regulation of bile secretion.

Topics: Animals; Bile; Blood Pressure; Cholestasis; Cholinergic Antagonists; Enkephalin, Methionine; Gallbladder; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley

Cholestasis liver disease is associated with clinical and experimental findings consistent with increased opioidergic neuromodulation, increased plasma total activity, and elevated plasma enkephalin concentrations. The effect of the nitric oxide (NO) synthase inhibitor, L-nitro-arginine (L-NA, 0.03, 0.1, 0.3, 1 mg/kg), and the nitric oxide precursor, L-Arg (30 mg/kg), on antinociception induced by bile duct resection or sham operation, as well as on opioid dependence, was examined in male albino Swiss mice. Repeated (5 days) administration of L-NA attenuated signs of dependence, as assessed by naloxone (5 mg/kg)-precipitated withdrawal, and decreased the antinociception; however, L-Arg potentiated withdrawal signs and increased the antinociception. The results of this study support the involvement of the L-arginine/nitric oxide pathway in the opioidergic-dependent manifestation of cholestasis in an animal model.

Topics: Acute Disease; Animals; Arginine; Behavior, Animal; Bile Ducts; Cholestasis; Enzyme Inhibitors; Male; Mice; Naloxone; Narcotic Antagonists; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Reaction Time; Substance Withdrawal Syndrome

Following the naloxone administration in bile duct resected animals, striking opioid withdrawal signs are observed due to increased opioidergic tone. Pretreatment of animals with L-nitro arginine, a nitric oxide synthase inhibitor, reduces the naloxone-precipitated withdrawal signs as well as increase the antinociception. The results of this study support evidence for the involvement of the L-arg-nitric oxide pathway in opioidergic-dependent manifestation of cholestasis in an animal model.

Topics: Analgesia; Animals; Behavior, Animal; Cholestasis; Male; Mice; Naloxone; Narcotic Antagonists; Nitroarginine; Opioid Peptides; Pain Measurement; Substance Withdrawal Syndrome

Topics: Central Nervous System; Cholestasis; Humans; Naloxone; Narcotic Antagonists; Opioid Peptides; Pruritus

Clinical observations have suggested that cholestasis is associated with increased neurotransmission mediated by the opioid system in the central nervous system. As opiate agonists (e.g. morphine) mediate analgesia, increased opioidergic tone in cholestasis should be associated with a decreased response to pain. To test this hypothesis, the response of rats with acute cholestasis to a nociceptive stimulus was measured by the use of the tail-flick test, an extensively validated assay for measuring opiate-induced antinociception. Five and 7 days after bile-duct resection, the mean tail-flick latency was longer than before surgery (p < 0.05), whereas the corresponding means for unoperated and sham-resected controls were not significantly different from their respective baseline values. The increase in the mean tail-flick latency in the bile-duct resection group was reversed by (-)-naloxone (1 mg/kg subcutaneously), but not by its enantiomer (+)-naloxone (10 mg/kg subcutaneously) (p < 0.001). The stereoselective reversal of antinociception in cholestasis by naloxone indicates that this phenomenon is opioid-receptor mediated. In contrast, prolongation of the mean TFL found in the rat model of thioacetamide-induced acute hepatocellular necrosis was not reversed by (-)-naloxone, indicating that antinociception in this model is not opioid mediated. These findings provide support for the hypothesis that cholestasis is associated with increased opioidergic tone.

Topics: Animals; Cholestasis; Male; Naloxone; Nociceptors; Pain Threshold; Pruritus; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Synaptic Transmission

Changes of antioxidant activity of dalargin in the liver after naloxone (100 micrograms/kg) administration were examined in experiment on 144 rats with cholestasis. It was found that dalargin inhibited the activity of xanthine oxidase by 32-37% in different time periods after the injection. Dalargin and naloxone, when used in combination, had no effect on the enzyme activity. Glutathione-S-transferase activity rose by 38.0% and 21.8% on hour 1 and 3 after the injection, respectively, while simultaneous injection of dalargin and naloxone induced no changes in the enzyme activity after 1 hour, though decreased it by 36.8% and 26.4% on hour 3 and 5, respectively. Dalargin inhibited lipid peroxidation by 29-35%, simultaneous injection of dalargin and naloxone raised lipid peroxidation by 109.2%, 80.7% and 25.7% after 1, 3 and 5 hours, respectively. Dalargin injection elucidated a marked tendency to lowering of blood release of the liver-specific enzymes histidase and urokaninase in line with enhancement of their activity in the liver. A combined injection of dalargin and naloxone promoted high release of histidase and urokaninase in blood and did not change histidase activity in the liver in all cases. Urokanidase activity elevated in 5 hours. It was noticed that dalargin raised leu-enkephalin levels in the liver 3.5-fold 1 h after the injection. The reduced dalargin antioxidant effect coupled with naloxone pretreatment demonstrated indirect action of the neuropeptide on the liver via neuron receptors of the liver.

Topics: Animals; Antioxidants; Cholestasis; Drug Therapy, Combination; Enkephalin, Leucine-2-Alanine; Liver; Male; Naloxone; Rats; Sympatholytics; Time Factors

It is widely known that narcotics, such as morphine, cause spasm of the sphincter of Oddi, increasing pressure in the common bile duct. This pharmacologic effect has been applied to hepatobiliary scintigraphy in patients with chronic cholecystitis or cholestasis to reducing the time required for a diagnostic study. However, this feature of narcotics could result in delayed or nonvisualization of the small bowel, simulating a distal common bile duct obstruction, in patients requiring parenteral narcotic analgesics who must undergo hepatobiliary scintigraphy. We report on three patients where administration of intravenous naloxone hydrochloride (Narcan), a narcotic antagonist, was helpful in distinguishing narcotic-induced spasm of the sphincter of Oddi from true obstruction of the common bile duct.

Topics: Adult; Analgesics, Opioid; Biliary Tract; Cholestasis; Common Bile Duct; Diagnosis, Differential; Female; Humans; Liver; Male; Middle Aged; Naloxone; Radionuclide Imaging