Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of naltrexone on tolerance/dependence, as well as alterations in cellular immune function induced by morphine administration, were determined. Mice were rendered tolerant to and physically dependent on morphine by subcutaneous implantation of pellets containing 75 mg of morphine. Implantation of naltrexone pellets (10 mg) blocked the development of tolerance to the analgesic action of morphine, as well as the development of physical dependence. Morphine suppressed lymphoid organ weights and cellularities, and this suppression was blocked by naltrexone. B-Cell proliferation was suppressed in morphine-tolerant but not in morphine-abstinent mice, and this suppression was exacerbated by naltrexone. Morphine tolerance and abstinence were associated with suppression of IL-2 production, which was completely blocked by naltrexone. NK cell activity was not significantly affected by either morphine or naltrexone exposure. The results suggest that the effects of morphine on the immune system are at least partially mediated through opioid receptors.
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PMID:Effects of naltrexone on morphine-induced tolerance and physical dependence and changes in cellular immune function in mice. 749 98

The development of morphine physical dependence in the contrasting brain states of the nonhibernating (NH) vs. the hibernating (H) condition was measured in the ground squirrel hibernator Citellus lateralis. Morphine was infused continuously into the lateral ventricle (3.44, 6.88 and 13.75 micrograms/hr for periods of 1, 3 and 6 days) in NH and H animals, followed by measurement of the naloxone (1 mg/kg s.c.) evoked abstinence syndrome during the NH state (i.e., H animals were tested after arousal to the NH state). The results showed that morphine treatment during the NH state resulted in significant naloxone-evoked abstinence and an overall dose- and duration-related increase in the strength of the abstinence syndrome. By contrast, morphine treatment during hibernation resulted in significantly reduced abstinence compared with that observed after treatment during the NH state, with no significant morphine dose-response or duration-response trends evident. However, H-state morphine treatment did produce a dose-related reduction of hibernation bout duration. The reduction in the strength of dependence during the H state was associated with a qualitative change in the abstinence syndrome, as revealed by exploratory factor analysis. This change was reflected by an approximate reversal of the rank order of abstinence signs. These results demonstrate that hibernation-related changes in central nervous system function significantly reduce the liability for and change the character of the development of morphine dependence.
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PMID:Quantitative and qualitative aspects of the hibernation-related reduction of morphine physical dependence in the ground squirrel (Citellus lateralis). 756 81

Due to the claim that lithium (Li+) reduces morphine self-administration in dependent rats, the effects of acute and chronic Li+ treatments on naloxone-precipitated withdrawal syndrome and physical dependence development to morphine in mice chronically treated with morphine, were evaluated. Morphine dependency was induced by the ingestion of morphine through drinking water in increasing doses for 10 days. Physical dependence to morphine was observed by precipitating an abstinence syndrome with naloxone (2 mg/kg, i.p.). In the acute experiments, Li+ (1 and 10 mg/kg, i.p.) was administered 1 hr prior to challenge with naloxone to morphine-dependent mice whereas for chronic studies, mice received morphine concomitant with Li+ (1200 mg/l) as drinking fluid for 10 days. Results obtained indicate that acute Li+ administration significantly reduced the withdrawal signs, and we were unable to induce some degree of morphine dependency in co-administration of Li+ to mice receiving chronic morphine treatment as compared to chronic morphine administration alone. The present study revealed that even in mice with very much lower serum Li+ levels than the commonly accepted therapeutic range there was a significant reduction in the withdrawal signs. It has been shown that Li+ and morphine have diverse effects on the transmembrane signal control systems. The interaction of Li+ and morphine might be through these systems.
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PMID:Inhibition of the morphine withdrawal syndrome and the development of physical dependence by lithium in mice. 762 60

We examined the locomotor-enhancing action of mu-opioid receptor agonists, such as morphine and [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO), and physical dependence on morphine in diabetic and nondiabetic mice. Morphine (5-20 mg/kg, s.c.) and DAMGO (1-4 nmol, i.c.v.) had a dose-dependent locomotor-enhancing effect in both nondiabetic and diabetic mice. The locomotor-enhancing effects of morphine and DAMGO were significantly less in diabetic mice than in nondiabetic mice, and were significantly reduced after pretreatment with either beta-funaltrexamine (20 mg/kg, s.c.), a selective mu-opioid receptor antagonist, or naloxonazine (35 mg/kg, s.c.), a selective mu1-opioid receptor antagonist. Both diabetic and nondiabetic mice were chronically treated with morphine (8-45 mg/kg, s.c.) for 5 days. During this treatment, neither diabetic nor nondiabetic mice showed any signs of toxicity. After morphine treatment, withdrawal was precipitated by injection of naloxone (0.3-10 mg/kg, s.c.). Several withdrawal signs, such as weight loss, diarrhea, ptosis, jumping and body shakes, were observed after naloxone challenge in morphine-dependent nondiabetic mice. Although morphine-dependent diabetic mice showed greater weight loss than nondiabetic mice, the incidence of jumping and body shakes after naloxone challenge in diabetic mice were lower than that in nondiabetic mice. These results suggest that diabetic mice are selectively hyporesponsive to mu1-opioid receptor-mediated locomotor enhancement. Furthermore, diabetes may affect mu1-opioid receptor-mediated naloxone-precipitated signs of withdrawal from physical dependence on morphine.
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PMID:Modification of mu-opioid agonist-induced locomotor activity and development of morphine dependence by diabetes. 763 31

The kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) was recently shown to potentiate certain overt withdrawal signs in morphine-dependent rats. The present study sought to further assess this phenomenon by examining the influence of nor-BNI treatment upon the conditioned place aversion associated with the naloxone-precipitated withdrawal syndrome. In addition, in vivo microdialysis studies were conducted in morphine-dependent rats to determine whether nor-BNI treatment can modify withdrawal-induced changes in basal dopamine (DA) release within the mesolimbic system. Rats were pretreated with either saline or a single dose of nor-BNI and then received ascending doses of morphine for 10 days. A withdrawal syndrome was then precipitated by the administration of naloxone (1 mg/kg SC). In rats which received chronic morphine injections, administration of naloxone produced a characteristic withdrawal syndrome and a marked aversion for an environment previously associated with naloxone-precipitated withdrawal. Nor-BNI treatment potentiated most overt signs of physical dependence. This treatment also resulted in a greater withdrawal-induced place aversion. Morphine-dependent rats exhibited a marked reduction in basal mesolimbic DA release. An even greater decrease in basal DA release was observed in nor-BNI treated rats. These results suggest that endogenous kappa-systems are important in the modulation of mesolimbic DA release and the accompanying place aversion which occurs during opiate withdrawal.
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PMID:Endogenous kappa-opioid systems in opiate withdrawal: role in aversion and accompanying changes in mesolimbic dopamine release. 786 83

Opiate withdrawal is a common occurrence in human opiate addicts that is no life threatening but is hypothesized to be a significant factor which may contribute to drug taking behavior in these opiate dependent individuals. The purpose of this study was to compare the time course for the development of tolerance, dependence and abstinence using a rat model. Rats were made dependent by implantation of 2 morphine pellets s.c. (75 mg morphine base). Morphine implanted rats exhibited analgesia as measured in a tail-dip assay, for up to 12 h post-implant after which the development of tolerance resulted in tail-flick latencies returning to the level of control rats. Withdrawal was evaluated by injection of the opiate antagonist, naloxone (1 mg/kg s.c.). Rating of the abstinence syndrome revealed significant withdrawal signs by 3 h post-implant which became increasingly intense up to 24 h post-implant. Withdrawal could be precipitated for at least 13 days post-implant, while by 18 days post-implant almost no abstinence signs were observed. Plasma morphine levels following implantation of 2 pellets remained relatively stable from 3-12 days post-implantation. These results further extend the characterization of opiate abstinence following subcutaneous pellet implantation. These results also suggest that opiate abstinence develops within the first 24 h and follows the time course of the development of tolerance. The characterization of the evolution of opiate tolerance, physical dependence and abstinence under similar experimental conditions is critical to the design of future studies to examine the neural bases for these phenomena.
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PMID:Prolonged tolerance, dependence and abstinence following subcutaneous morphine pellet implantation in the rat. 801 48

Female B6C3F1 mice were rendered tolerant-dependent on morphine by a combination of injections and pellet implantation. Mice were injected with morphine sulfate (20 mg/kg, s.c.) twice a day on day 1. On day 2, they were implanted s.c. with a 75 mg morphine pellet for 3 days. On day 5, the pellets were either left intact (tolerant) or removed 8 h prior (abstinent) to carrying out the immune function tests. A high degree of tolerance to the analgesic and hypothermic effect of morphine developed as a result of this procedure. Similarly, physical dependence also developed as evidenced by the signs of the abrupt and naltrexone-precipitated abstinence syndrome. Implantation with morphine pellets resulted in a profound, statistically significant reduction in spleen and thymus weight and cellularities, with the greatest degree of reduction noted in abstinent animals. Morphine tolerance was associated with suppressed B-cell proliferation following in vitro stimulation, as well as interleukin-2 (IL-2) and interleukin-4 production by T-cells. NK cell activity was significantly reduced in morphine-tolerant, but not in morphine-abstinent, mice following a 24 h incubation in the presence or absence of IL-2. In comparison, the in vitro induction of cytotoxic T-cells was significantly depressed in morphine-abstinent, but not morphine-tolerant, animals. Exposure to morphine apparently had limited effect on macrophage function as assessed by production of tumor necrosis factor. These studies demonstrate a differential effect on immune effector and regulatory mechanisms in morphine tolerance and abstinence processes.
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PMID:Effects of morphine tolerance and abstinence on cellular immune function. 803 70

We investigated if continuous activation of opioid receptors by their endogenous ligands could lead to the development of physical dependence. Catheters were implanted for chronic i.v. drug administration in rats and connected to an infusion pump. On the fifth day of perfusion, the severity of naloxone (5 mg/kg s.c.)-precipitated withdrawal was evaluated. Large behavioral changes and body weight losses were observed in rats chronically treated with morphine (0.17 mg/120 microliters/h). In contrast, only one withdrawal symptom (tremor) was significant in rats treated with the mixed inhibitor of enkephalin-degrading enzymes, RB 101 (1.20 mg/120 microliters/h). Morphine and RB 101 were perfused at doses which give same analgesic responses 6 h after the start of perfusion. This lack of physical dependence after drastic conditions of administration emphasizes the potential clinical interest of systemically active mixed inhibitors as new analgesics.
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PMID:Assessment of physical dependence after continuous perfusion into the rat jugular vein of the mixed inhibitor of enkephalin-degrading enzymes, RB 101. 820 Apr 22

Morphine was administered intracerebroventricularly to normal or recombinant inbred CXBK (mu-opioid receptor deficient) mice and antinociception was determined against two different stimuli. Morphine-induced antinociception against acetylcholine was strain-dependent, whereas against endothelin-1 it was not. The antinociception was mediated via opioid mu receptors (blocked by beta-FNA, but not naltrindole, ICI 174,864 or nor-BNI) through separate pathways, one naloxonazine-sensitive and the other naloxonazine-insensitive. Taken together, these results appear to demonstrate supraspinal morphine-induced antinociception through distinct subtypes of the mu opioid receptor, supporting the possibility of novel subtype-selective therapeutic agents with greater separation between analgesia and side-effects or physical dependence. Furthermore, the methodology described herein provides model systems for the in vivo screening of such agents.
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PMID:Opioid mu receptor subtypes (possibly mu 1 and mu 2) revealed by morphine-induced antinociception vs endothelin-1 in recombinant inbred CXBK mice. 828 81

The difference between the development of physical dependence on morphine administered via Alzet miniosmotic pumps as well as syringe injection (twice a day) at fixed times was examined in conscious dogs. Physical dependence was quantified by polygraphically measuring naloxone-precipitated withdrawal signs on the day 8 after the subcutaneous implantation of miniosmotic pumps which supplied morphine at 1-5 mg/kg/day. Morphine plasma levels were maintained at 19-25 and 41-47 ng/mL during infusions of morphine at doses of 2.5 and 5 mg/kg/day, respectively. Morphine withdrawal was characterized by hyperactivity, biting, digging, tremors, nausea, hyperthermia, and increased wakefulness, and by electroencephalographic (EEG) activation in the amygdala and hippocampus, followed by dissociation of the EEG in the cortex (fast wave) from that in the limbic (slow wave) system, increased heart rates, and raised blood pressure. These morphine withdrawal signs seemed to be more severe than those exhibited in animals that had received syringe injections of morphine at the same doses. These results suggest that the use of miniosmotic pumps in dogs may be a very convenient and useful method for both evaluating drug dependence and studying its mechanisms.
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PMID:Physical dependence on morphine induced in dogs via the use of miniosmotic pumps. 829 85


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