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At least 19 recordsLinked to original sources
PubMed1984

Morphine preference in rats previously morphine dependent.

Morphine preference and tendency to relapse to morphine tolerance and dependence were studied in rats which were previously made morphine dependent. Tolerance to, and physical dependence on, morphine were initially produced by administration of increasing concentrations of morphine sulphate in 5% sucrose solution for 3 weeks. A test for drinking preference was performed 4 days after the rats had been successfully detoxified and showed no significant signs of morphine dependence. It was found that, while control animals drank only negligible amounts of morphine solution, previously morphine-dependent rats consumed significantly larger volumes of morphine solution and had recurrence of morphine tolerance and dependence. The present findings show that chronic administration of morphine in drinking fluid produces tolerance and physical dependence as well as addiction in rats; the latter definition is exemplified by these animals having a high tendency to relapse after successful drug withdrawal.

Animals↗
PubMed1995

[Opioid receptors altered binding nature in guinea-pig brain following the development of morphine dependence].

Morphine is well known to produce tolerance and dependence. The mechanisms for these phenomena are not clearly understood and there are a number of conflicting reports that chronic morphine administration decreases, increases, or leaves unchanged the number of opioid binding sites. We examined the potency of MScontin (oral controlled-release preparation of morphine) to induce morphine dependence and also determined the change of mu, delta and kappa opioid receptor types in brain homogenates obtained from morphine-dependent guinea-pigs. 1. Guinea-pigs were implanted subcutaneously with MScontin (300 mg.kg-1) and naloxone was employed to precipitate jumping behavior of withdrawal symptoms at various times. The highest degree of physical dependence was observed on the 2nd day after implantation. Therefore, this period was chosen to investigate opioid receptor binding assay. 2. Two days after implantation, the binding of 3H-DAGO (mu agonist), 3H-DPDPE (delta agonist) and 3H-U69593 (kappa agonist) to brain membranes prepared from morphine dependent and control guinea-pigs was determined. Scatchard plot of the saturation binding data revealed an increase in Bmax values (maximum specific binding) and no change in the Kd values (equilibrium dissociation constants) of 3H-opioid ligand bindings obtained from morphine-dependent animals as compared to controls. These results indicate that brain mu, delta and kappa opioid receptors are up-regulated in morphine dependent guinea-pigs.

Animals↗
PubMedDate not supplied

The effect of aspartic acid on the intensity of physical dependence in morphine dependent mice.

The mice (Balb/C strain) given 2% aspartic acid in 5% saccharose solution or only saccharose solution (p. os) starting 12 hr before the sc morphine pellet implantation until the removal of pellet were rendered physically morphine dependent. During the development of morphine dependence and after the removal of pellets (on 3-d day) spontaneous motor activity and analgesic threshold were measured as reliable abrupt withdrawal signs. Aspartic acid prevented to some extent the appearance of symptoms of physical morphine dependence.

Analgesia↗
PubMed1984

Disposition of ethanol and its effect on rectal temperature in morphine-dependent, morphine-abstinent and morphine-naive rats.

Rats were treated chronically with twice daily injections of morphine hydrochloride in gradually increasing doses from 20 to 200 mg/kg for 22 consecutive days. Rats in a control group were injected with 0.9% NaCl. At 1 hour after the last injection of morphine (dependent state) and at 3 and 16 days after abrupt withdrawal (abstinent state) the animals were injected intraperitoneally with 2.0 g/kg ethanol. Blood ethanol concentrations (tail blood) and rectal temperatures were determined at 30-60 min. intervals for up to 7 hours. The absorption of ethanol was slower in rats treated with morphine and the time taken to reach the end of the blood concentration curve was increased. This implies a slower turnover of ethanol in morphine-dependent and abstinent rats. At 16 days after withdrawal, the blood ethanol profiles were the same as in control rats not exposed to morphine. Injection of morphine (200 mg/kg) intolerant animals caused a pronounced hyperthermia which lasted for about 4 hours. Ethanol treatment rapidly counteracted the rise in body temperature. Morphine abstinent rats showed a hypothermic response to ethanol. The altered disposition of ethanol in acute withdrawal may result from physiological disturbances such as impaired fluid balance, dehydration, altered peripheral blood flow and poor nutritional status. There was no evidence for a faster rate of ethanol metabolism in the hypermetabolic state associated with morphine tolerance and dependence.

Animals↗
PubMed1986

Sensitivity to the narcotic cue in non-dependent, morphine-dependent and post-dependent rats.

Using a food-reinforced two-lever operant procedure, 12 rats were trained to discriminate 10 mg/kg (i.p.) of morphine from saline. Five animals were given daily non-contingent exposure to morphine (20 mg/kg on saline, or no-test days, and 10 mg/kg on drug days) from the beginning of the experiment; the others received injections of saline. In the morphine generalization tests, the dependent rats showed an increased sensitivity to the narcotic cue as compared with non-dependent animals (ratio of the ED50 values: 2.30). This increased sensitivity was still present 3 months after discontinuing the non-contingent treatment with morphine (ratio of the ED50 values: 1.98). The results of the present study, together with other results reported in the literature, suggest that the experimental procedure plays a role in determining whether tolerance, no tolerance or enhanced sensitivity to the discriminative stimulus properties of narcotics, is observed.

Animals↗
PubMed1977

The effects of ethanol and pentobarbital on the naloxone precipitated escape response in morphine dependent mice.

Morphine dependence in mice is produced in a two day test. The effects of (1) ethanol, (2) pyrazole, (3) ethanol with pyrazole, and (4) pentobarbital are observed and recorded on the naloxone precipitated escape response in morphine dependent mice. Ethanol suppresses the escape response in doses of 2.0 and 3.0 g/kg which produce mean blood ethanol concentrations of 1.88 and 3.28 mg/ml, respectively. When a pyrazole regimen is employed with morphine dependent mice, ethanol reduces or abolishes the naloxone precipitated escape response at doses of 1.0, 2.0 and 3.0 mg/kg. The corresponding mean blood ethanol concentrations are 1.14, 2,82 and 3.74 mg/ml, respectively. When pentobarbital (20 and 30 mg/kg) is given to morphine dependent mice, jumping bevarior is prevented following naloxone injection. Since narcotic antagonists such as naloxone may be employed in studying the phenomenon of physical dependence on ethanol based on the hypothesis of a relationship between endogenous opiates and ethanol dependence, it is essential to verify that blood ethanol concentrations are low enough so that ethanol will not interfere with the effects of naloxone in ethanol dependent animals.

Animals↗
PubMed1975

Urinary excretion of morphine and its metabolites in morphine-dependent subjects.

Morphine, morphine glucuronide, morphine ethereal sulfate, normorphine and total normorphine in three consecutive 24-hour urines of four morphine-dependent subjects receiving morphine sulfate 60 mg s.c. q.i.d. have been determined with thin-layer chromatography and gas-liquid chromatography. With thin-layer chromatography the mean daily excretion of free morphine was 10% of the administered dose; morphine glucuronide, 65%; total (free and acid hydrolyzable conjugate) morphine 85%; and total normorphine, 3.5%. With gas-liquid chromatography, the percentage excretion for free morphine was 10%; total morphine, 74%; free normorphine, 1%; and total normorphine, 4%. The excretion of total drug was linearly related to the volume of the daily urine output.

Adult↗
PubMed1986

Morphine dependence and diabetes. I. The development of morphine dependence in streptozotocin-diabetic rats and spontaneously diabetic C57BL/KsJ mice.

Spontaneously diabetic (db/db) and nondiabetic (db/m+, m+/m+) C57BL/KsJ mice were made dependent by a 9-day exposure to increasing doses of morphine-admixed food. Radioimmunoassay for morphine demonstrated that diabetic mice had significantly greater brain accumulations of morphine than nondiabetic littermates after morphine-admixed food. Despite their greater brain levels of morphine, diabetic mice showed significantly fewer behavioral signs of withdrawal after naloxone, and lost significantly less weight at 60 min after naloxone than their nondiabetic littermates. Streptozotocin-diabetic and nondiabetic rats rendered dependent by a 6-day i.p. infusion of morphine had equal brain levels of morphine, but the diabetic rats showed significantly fewer behavioral signs of withdrawal than nondiabetic rats at 24 and 48 hr after the end of the infusion. These results indicate that spontaneously diabetic mice and streptozotocin-diabetic rats were both significantly less physically dependent upon morphine than their respective nondiabetic controls and support our conclusion that the development of physical dependence upon morphine is reduced in experimental models of diabetes.

Animals↗
PubMed2000

Ketanserin reverses dizocilpine-suppression of morphine dependence but not tolerance in mice.

The present study investigated the effect of co-administration of ketanserin, a 5-HT(2A) receptor antagonist and dizocilpine, a non-competitive NMDA receptor antagonist on the development of tolerance and dependence to morphine in mice. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg, twice daily) on day 3 and the degree of tolerance was further enhanced on day 9 and 10. Dizocilpine (0.2 mg/kg, twice daily for 9 days) prevented the development of tolerance to the antinociceptive effect of morphine. Dizocilpine (0.2 mg/kg) or combination of dizocilpine (0.2 mg/kg) and ketanserin (0.5, 1 and 2 mg/kg) acutely on day 10 did not affect morphine tolerance. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days) pre-treatment failed to reverse the effect of dizocilpine on morphine tolerance. Dizocilpine (0.2 mg/kg, twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal jumps and diarrhea on day 10 of testing. Similarly, dizocilpine (0.2 mg/kg) acutely on day 10 suppressed the development of morphine dependence. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days and acutely on day 10) pre-treatment reversed the effect of dizocilpine on morphine dependence. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days) did not affect development of morphine tolerance and dependence. The present study demonstrated that ketanserin, a 5-HT(2A) receptor antagonist reversed the effect of dizocilpine on morphine dependence. This study gives behavioral evidence to the hypothesis that 5-HT(2A) receptor antagonists facilitate NMDA neurotransmission.

Animals↗
PubMed2001

Attenuation of morphine dependence and withdrawal by glycine B site antagonists in rats.

Numerous data indicate that noncompetitive and competitive N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the development of physical dependence on opioids when these substances are administered together, and NMDA receptor antagonists are used at lower range of doses. Higher doses of these antagonists can enhance some opioid-induced effects. The present study extends these findings to the effects of NMDA/glycine (glycine(B)) site antagonists. Wistar rats were rendered dependent on morphine by implantation of morphine pellets. Both of the glycine(B) site antagonists used, 7-chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2(H)-quinolone (L-701,324; 2.5 and 5.0 mg/kg) and 5,7-dichlorokynurenic acid (5,7-DCKA; 25, 50, and 100 mg/kg), suppressed the expression of morphine withdrawal syndrome estimated as wet dog shakes. Furthermore, L-701,324 (2.5 and 5 mg/kg), given twice a day during the development of morphine dependence, attenuated the development of morphine dependence, and the results were comparable to those obtained after administration of noncompetitive NMDA receptor antagonist - MK801 (0.1 mg/kg). Our data suggest that glycine(B) site antagonists may attenuate wet dog shakes (withdrawal) and the development of dependence, both being induced by chronic morphine administration in rats.

Animals↗
PubMed2005

Proteomic analysis of phosphotyrosyl proteins in morphine-dependent rat brains.

Morphine has been used as a potent analgesic, having a high propensity to induce tolerance and physical dependence following their repeated administration. Although the mechanisms that underlie the development of dependence on morphine remain unclear, previous studies suggested that phosphorylations of diverse types of cellular proteins are crucial determinants of the neuroadaptive mechanisms associated with morphine dependence. Thus, understanding global phosphorylation events induced by chronic morphine administration is essential for understanding the complex signaling mechanisms of morphine dependence. This study characterized the alteration of tyrosine phosphorylation of frontal cortical proteins in morphine-dependent rat brains using a proteomic approach. Dependence was produced by continuous intracerebroventricular (i.c.v.) infusion of morphine (26 nmol/microl/h) for 72 h via osmotic minipumps in rats. Phosphotyrosyl (p-Tyr) protein spots in brain frontal cortical regions were detected by two-dimensional electrophoresis (2-DE) and immunoblotting with anti-p-Tyr-specific antibodies. The protein spots showing significant changes in tyrosine phosphorylation were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). Similar patterns of protein expression were detected by 2-DE gels in morphine-dependent and saline-treated control rat brains. However, phosphotyrosine 2-DE images of the frontal cortical proteins from saline-treated control and morphine-dependent rat brains were apparently different. The densities of most matched p-Tyr protein spots were increased in morphine-dependent rat brains compared with that of control samples. Additional p-Tyr protein spots were detected in 2-DE image of morphine-dependent rat brains. Fifty of p-Tyr protein spots, corresponding to 40 different proteins, were identified from 2-DE gels of morphine-dependent rat brains. The identified proteins include enzymes, cytoskeletal proteins, cell signaling molecules, and other proteins. In conclusion, the first available phosphotyrosine proteomic resources of morphine dependence were established using an animal model. The findings illustrate the potential of proteomics as an effective technique for studying phosphorylation events of morphine dependence in brains.

Analgesics, Opioid↗
PubMed1979

Mode of antagonistic action of levallorphan in morphine-dependent rats and assessment of physical dependence liability.

The antagonistic mode of levallorphan in rats dependent on morphine or codeine was studied from the viewpoints of the doses of morphine and the lengths of administration and also from the standpoint of timing of the challenge. In morphine-dependent rats on morphine-admixed food (60--100 mg/kg/day) for 1, 3 and 6 weeks, the rate of maximum weight loss on application of levallorphan (2 mg/kg, s.c.) did not correlate with the length of morphine treatment. The rate of weight loss on single application of levallorphan 0, 6, 12 or 24 hours after withdrawal or morphine was lower with the passage of time after the withdrawal. Rats which were given levallorphan 3 times in succession, i.e., at 0, 5 and 10 hours after morphine withdrawal showed such a pattern of weight loss that the first application of levallorphan resulted in 7% loss, while with the second and third applications there was little weight loss. Despite the continued withdrawal, the animals began to gain body weight as early as 14 hour, and body weight was totally recovered before the withdrawal in 24 hour. In conclusion, it is advisable to challenge with levallorphan at 0 hour of withdrawal to obtain qualitative and reproducible results. In addition, the application of levallorphan to morphine-dependent rats at adequate intervals provides for the early recovery of abstinence signs.

Animals↗
PubMed1994

Comparative effects of NG-monomethyl-L-arginine and MK-801 on the abstinence syndrome in morphine-dependent mice.

The effects of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthase and MK-801, an NMDA receptor antagonist on abrupt and naltrexone-precipitated abstinence symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by subcutaneous implantation of a pellet containing 75 mg of morphine base for 3 days. Mice which served as controls were implanted with placebo pellets. Six hours after pellet removal, mice were injected intraperitoneally with either the vehicle or MK-801 (0.03, 0.1 and 0.3 mg/kg). Thirty minutes later the animals were injected with naltrexone subcutaneously (50 micrograms/kg) and the intensity of abstinence symptoms were determined. Of the three doses of MK-801 used, only 0.1 mg/kg dose inhibited the jumping behavior precipitated by naltrexone in morphine-dependent mice. Whereas the lower dose (0.03 mg/kg) of MK-801 increased, the higher doses of MK-801 (0.1 and 0.3 mg/kg) displayed a decrease in the formation of fecal boli. Administration of MK-801 did not affect the body weight loss observed during abrupt withdrawal (induced by removal of the pellets) in morphine-dependent mice. MK-801 at 0.1 mg/kg dose further decreased the body temperature during abrupt withdrawal in morphine-dependent mice. Other two doses of MK-801 (0.03 and 0.3 mg/kg) did not modify the hypothermia observed during abrupt morphine withdrawal. On the other hand, L-NMMA (0.02 to 4.0 mg/kg) injected intraperitoneally 15 min prior to the naltrexone administration blocked the stereotyped jumping response in a dose-dependent manner. Higher doses of L-NMMA 2.0 and 4.0 mg/kg also decreased the number of fecal boli formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1985

Characterization of opioid dependence of isolated ileum of morphine dependent and of chronically stressed Wistar-Kyoto (WKY)-rats.

The opioid antagonist naloxone induced tonic contraction ("gut dependence") of isolated ilia of both morphine dependent WKY-rats and WKY-rats chronically stressed by immobilization. Morphine and met-enkephalin but neither dynorphine nor leu-enkephalin antagonized the naloxone induced "gut dependence" of isolated ilia obtained from morphine dependent WKY-rats. Met-enkephalin as well as dynorphine inhibited the "gut dependence" of chronically stressed rats; morphine and leu-enkephalin had no inhibitory effect. These differences between influences of different opioid peptides on "gut dependence" of morphine dependent rats versus "gut dependence" of rats chronically stressed by immobilization suggest that chronic stress induced or facilitated production of a different population of receptors.

Animals↗
PubMed1998

Dopamine-dependent responses to morphine depend on glucocorticoid receptors.

Previous work has shown that glucocorticoid hormones facilitate the behavioral and dopaminergic effects of morphine. In this study we examined the possible role in these effects of the two central corticosteroid receptor types: mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). To accomplish this, specific antagonists of these receptors were infused intracerebroventricularly and 2 hr later we measured: (i) locomotor activity induced by a systemic injection of morphine (2 mg/kg); (ii) locomotor activity induced by an infusion of morphine (1 microg per side) into the ventral tegmental area, which is a dopamine-dependent behavioral response to morphine; (iii) morphine-induced dopamine release in the nucleus accumbens, a dopaminergic projection site mediating the locomotor and reinforcing effects of drugs of abuse. Blockade of MRs by spironolactone had no significant effects on locomotion induced by systemic morphine. In contrast, blockade of GRs by either RU38486 or RU39305, which is devoid of antiprogesterone effects, reduced the locomotor response to morphine, and this effect was dose dependent. GR antagonists also reduced the locomotor response to intraventral tegmental area morphine as well as the basal and morphine-induced increase in accumbens dopamine, as measured by microdialysis in freely moving rats. In contrast, spironolactone did not modify dopamine release. In conclusion, glucocorticoids, via GRs, facilitate the dopamine-dependent behavioral effects of morphine, probably by facilitating dopamine release. The possibility of decreasing the behavioral and dopaminergic effects of opioids by an acute administration of GR antagonists may open new therapeutic strategies for treatment of drug addiction.

Animals↗