Physical Dependence In Rats Research Articles

“Paradoxical” analgesia and aggravated morphine dependence induced by opioid antagonists

Chronic treatment with naloxone (Nx) or naltrexone (Ntx) induces paradoxical analgesia. In the present study, the effects of chronic treatment with opioid receptor antagonists, such as nor-binaltorphimine (nor-BNI) for kappa and naltrindole (NTI) for delta receptors, on analgesic response using the hot plate test and on morphine physical dependence in rats were examined. The hot plate latency was significantly increased by pretreatment with Nx (5 mg/kg, s.c.), nor-BNI (20 mg/kg, i.p.) or NTI (20 mg/kg, i.p.) for 5 days. After chronic pretreatment with these antagonists, the rats were treated with morphine-admixed food (0.5 mg/g of food) for 3 days. Chronic pretreatment with Nx and NTI significantly increased Nx precipitated body weight loss in morphine dependent rats, while chronic pretreatment with nor-BNI produced small increase. These results indicate that chronic treatment with nor-BNI or NTI as well as with Nx induces obviously paradoxical analgesia, and that chronic blockade of mu or delta may enhance the development of physical dependence on morphine.

Induction of physical dependence on pentobarbital by new infusion method in the rat

1. A new intermittent intravenous infusion method was developed for the induction of tolerance to and physical dependence on pentobarbital in rats. 2. Female and male rats were injected with pentobarbital (20 mg/kg/injection) through an implanted intravenous cannula. 3. The rats were allowed to receive an injection after the completion of a fixed amount of behavioral activity counted from the preceding injection, and therefore, the sedative and hypnotic effects of pentobarbital were used as an index in the determination of the injection intervals. 4. During pentobarbital treatment, the number of pentobarbital injections per day rapidly increased and stabilized (approximately 40: male, approximately 30: female) on the third to fifth day. 5. Upon withdrawal, the female and male rats who were maintained on pentobarbital administration of more than 30 and 40 injections/day for approximately 10 days manifested withdrawal signs which included spontaneous convulsion. 6. These results suggest that a new infusion method exists to produce a high degree of physical dependence in rats on a short-acting barbiturates, pentobarbital.

The concentration of morphine in serum of rats made dependent using a drug-admixed food method

The present study reports on the induction of physical dependence in rats using morphine-admixed food and addresses the question of the resulting concentration of morphine in serum. The stability of morphine in food is good, since no decrease in concentration could be observed. The concentration of morphine in serum during the experiment was measured using a radioimmunoassay technique. A correlation was found between the food intake during a 7-hour period and the concentration of morphine in the serum at the end of that period, both for a 1 g/kg and a 2 g/kg batch of morphine-admixed food. The concentration of morphine in serum was also found to be dose-related during a period of 6–23 days when the rats were fed for a prolonged period. After long-term administration of 1 g/kg morphine in food a steady-state level of about 0.5 mg/l serum was obtained. Similarly with 2 g/kg morphine in food a steady-state level of 0.8–1.1 mg/l serum was reached. After withdrawal of morphine the serum concentration of morphine dropped to 0.1 mg/l within 24 hours and to below the detection limit within 48 hours. During the witdrawal period sharp drops were noted in body weight (20%) and food intake (50%) after one day.

Chronic ethanol administration increases the binding of the benzodiazepine inverse agonist and alcohol antagonist [ 3H]RO15-4513 in rat brain

Chronic ethanol treatment which produced intoxication and physical dependence in rats, produced an increase in the specific binding of ethanol antagonist [ 3H]RO15-4513 in rat brain cerebral cortex and cerebellum, but not in hippocampus and striatum. The increase in both the regions was due to an increase in the number (B max) of receptor sites. These results suggest that the RO15-4513 binding sites on the oligomeric GABA receptor complex are altered following chronic ethanol administration, and support the notion of a unique role of RO15-4513 as an ethanol antagonist.

Production of physical dependence in rats by drinking a morphine solution

The plasma concentrations of morphine and glucose, the body weight, and the severity of the naloxone-precipitated withdrawal syndrome were studied in female rats in which morphine dependence was induced by administration of the opiate, with or without sucrose, in their drinking water. It was found that sucrose encouraged the animals to consume more morphine and that the initial plasma concentrations of the opiate, as well as the rate of development of physical dependence, were higher than the group not given sucrose. Plasma glucose concentrations, maximum plasma morphine levels and the maximum severity of the naloxone-precipitated withdrawal syndrome were, however, not significantly different between the two groups. The findings suggest that both regimens of administering the opiate in drinking fluid are effective in inducing morphine dependence in rats; the addition of sucrose tends to speed up the development of physical dependence, probably by increasing intake of the opiate through consuming more sucrose solution.

Effects of β-funaltrexamine (β-FNA) on morphine dependence in rats and monkeys

The opioid μ receptor antagonist β-funaltrexamine (β-FNA) blocked the development of physical dependence in rats when infused simultaneously with morphine for 6 days. In addition, β-FNA given s.c. 24 h prior to the initiation and on day 3 of a 6 day period of morphine infusion in rats reduced the development of physical dependence in a dose-dependent manner. In morphine-dependent rhesus monkeys, β-FNA precipitated a prompt and long-lasting withdrawal, which was not reversed within by 30 h by subsequent injections of morphine. In contrast, naloxone-induced withdrawal lasted approximately 90 min. These results provide further evidence that β-FNA is a long-acting antagonist of the opioid μ receptor, and that this receptor has a major role in the development of morphine-induced physical dependence.

Acute physical dependence induced by continuous intravenous infusion of morphine or meperidine in the rat.

An intravenous infusion method is described for rapidly producing physical dependence in rats. Rats were infused with morphine or meperidine for 24 or 48 h at constant rates and the development of physical dependence was assessed by body weight loss after naloxone challenge. Naloxone challenge induced body losses that were dependent upon magnitude, rate and duration of infusion. The steady-state concentrations of morphine (4 mg/kg/h) in serum and meperidine (6 mg/kg/h) in plasma were 4 and 2.5 microgram/ml, respectively. Morphine concentration in the brain in the steady-state (40 mg/kg/h) was 0.7 micrograms 1 g and in the serum was proportional to the infusion rate. Maximum body weight loss was significantly correlated with total amount of infused morphine, but not with the steady-state concentration of the drug in the serum. These results suggest that total doses of infused morphine, not steady-state concentrations, are critical in producing body weight loss.

Development of dependence on levorphanol in rats by oral intake of the drug — The influence of taste on drinking behaviour in rats physically dependent on levorphanol

Oral administration of levorphanol solution induces physical dependence in rats within a few days, as demonstrated by abstinence symptoms such as loss of body weight, sensitivity to touch and inversion of locomotor activity after withdrawal from the drug. In order to examine whether the physically dependent rats show an active drug-seeking behaviour they were given successively free choice between sweetened levorphanol solution (LSa) and two alternative drinking liquids -- sweetened tap water (WSa) and unadulterated water (W). In the case of LSa and W the rats chose LSa, but they preferred WSa to LSa. Another group of rats made dependent on unsweetened levorphanol solution (L) had the choice between L and W. They rejected L immediately.

Pentylenetetrazol seizure threshold: A quantitative measure of ethanol dependence in rats

The chronic administration of ethanol in large amounts to rats gives rise to an increasing degree of withdrawal hyperexcitability as demonstrated by reduction in the seizure threshold to the convulsant drug pentylenetetrazol. The latter response is reasonably specific and is a more sensitive measure of physical dependence in rats than the changes in behavior or susceptibility to audiogenic seizures. The results in total indicate that the induction of physical dependence of ethanol in rats can be objectively and quantitatively followed by assessing the intensity of withdrawal hyperexcitability with pentylenetetrazol.

280 - Studies on drug dependence (Rept.50): Induction of physical dependence in rats by short treatment of morphine-admixed food.

280 - Studies on drug dependence (Rept.50): Induction of physical dependence in rats by short treatment of morphine-admixed food.

The influence of morphine dependence on some specific effects mediated by monoaminergic and GABAergic systems

Physical dependence in rats was attained by increasing doses of morphine twice daily for 14 days. The effects of drugs modifying neurotransmitter functions were then monitored during withdrawal from the morphine treatment in comparison with controls withdrawn from saline at 40, 64, 112, and 184 h after the last injection. The stereotypy due to dopaminergic stimulation by apomorphine (1.5 and 2 mg/kg SC) was significantly potentiated in the rats withdrawn from morphine. Characteristic wet-dog shake behavior induced by elevating brain levels of serotonin (5-HT) with 5-hydroxy-DL-tryptophan (150 mg/kg SC) preceded by the decarboxylase inhibitor benserazide (50 mg/kg IP) was similar in animals withdrawn from either morphine or saline. The hypothermia and the general behavior following elevation of brain GABA levels with the GABA transaminase inhibitors D,L-4-amino-hex-5-ynoic acid (RMI 71645) (γ-acetylenic GABA) (100 mg/kg IP) or D,L-4-amino-hex-5-enoic acid (RMI 71754) (γ-vinyl GABA) (800 mg/kg IP) did not differ significantly between morphine-withdrawn and saline-treated rats. The central cholinergically mediated hypothermia and tremor induced by tremorine (15 mg/kg IP) was similar in both groups, but the peripheral chromodacryorrhea was blocked during morphine withdrawal. It is thus concluded that during morphine withdrawal in the rat under these conditions, the behavior mediated by dopaminergic system shows enhancement, but effects dependent upon central 5-HT, GABA, and cholinergic systems are not affected.

Development of morphine tolerance and physical dependence in rats depleted of brain catecholamines by 6-hydroxydopamine

The present study was undertaken to evaluate the roles of brain norepinephrine (NE) and/or dopamine (DA) in the development of morphine tolerance and physical dependence in rats. Rats were permanently depleted of brain catecholamines (CA, i.e. NE + DA) or DA by 6-hydroxydopamine (6-OHDA) treatment alone or desmethylimipramine plus 6-OHDA treatment at two weeks of age. Five weeks after either treatment, twice daily morphine injections were begun and continued for 32 consecutive days. The antinociceptive activity of morphine in the tail-flick test and the naloxone-precipitated abstinence syndrome were periodically observed throughout the course of chronic morphine treatment. A decreased antinociceptive response to morphine occurred in DA-depleted rats in both the non-tolerant and tolerant states, but the development of tolerance was not affected. The antinociceptive effect of morphine was not modified in either non-tolerant or tolerant CA (NE + DA)-depleted rats, nor was the development of tolerance affected. The spontaneous withdrawal syndrome after abrupt cessation of morphine after 32 days of treatment was markedly enhanced in CA-depleted rats. The results suggest that DA may be involved in mediating the antinociceptive effect of morphine, but not in the development of tolerance to that effect.

Induction of physical dependence in rats by ethanol inhalation without the use of pyrazole

Rats were exposed to increasing air ethanol concentrations (14 to 28 mg/liter) over a 10-day period without the use of pyrazole. There was a positive correlation between the rising air ethanol concentrations in the chamber and the concentrations of ethanol in the blood. On Day 10 the animals were removed from the chamber with a mean blood ethanol concentration of 3.13 mg/ml and observed for signs of withdrawal over a 24-hr period. During this time all animals manifested spontaneous signs of withdrawal and convulsions on handling. There was a positive correlation between the spontaneous signs and convulsions on handling. The disappearance of ethanol from the blood followed zero-order kinetics over the first 7 hr. In the withdrawal phase of the experiments a definite negative correlation existed between the decreasing blood ethanol concentrations and the rise in the scores for convulsions on handling. This inhalation procedure is a simple, reproducible approach for causing physical dependence on ethanol in rats without the use of pyrazole and with the maintenance of original body weight.

Sites of action of morphine involved in the development of physical dependence in rats

Morphine withdrawal was precipitated by injection of 3H-naloxone into restricted parts of the ventricular system of rats made tolerant to and dependent on morphine by repeated pellet implantation. The spread of the drug was evaluated by autoradiography and compared with the withdrawal signs precipitated in the same experiment. When the antagonist could spread into the tissue surrounding the 4th ventricle and the caudal parts of the aqueduct (penetration depth about 1.5 mm), a strong withdrawal syndrome was displayed. In contrast, only weak or no withdrawal signs were observed when the spread of naloxone was restricted to the surroundings of the lateral ventricles, the 3rd ventricle, and the rostromedial parts of the aqueduct. The same was true when the spread of the antagonist was limited to the ventral surface of the brain stem. It is concluded that structures located in the anterior part of the fossa Rhomboidea, and possibly also in the caudal part of the periaqueductal grey matter, are sites for the development of physical dependence on morphine giving rise to the withdrawal signs studied in these experiments.

Sites of action of morphine involved in the development of physical dependence in rats. II. Morphine withdrawal precipitated by application of morphine antagonists into restricted parts of the ventricular system and by microinjection into various brain areas.

Morphine withdrawal was precipitated by injection of various morphine antagonists into restricted parts of the ventricular system or by microinjection of levallorphan into specific brain areas of rats made dependent on morphine by repeated pellet implantation. When the antagonists could spread only within the lateral ventricles and the 3rd ventricle, a weak withdrawal syndrome was induced; by antagonist administration into the restricted 4th ventricle, however, strong withdrawal signs like jumping were elicited even at small dosages. In microinjection experiments, structures in the midbrain and the lower brain stem proved to be the most sensitive to antagonist action. Although microinjections into thalamic nuclei also had some effect, it could not be excluded that the effects were due to uncontrolled spreading of the drug. This became especially clear from experiments with tritium-labeled levallorphan. It is concluded that brain structures located in the anterior parts of the floor of the 4th ventricle and/or caudal parts of the periaqueductal gray matter are important sites of action for the development of physical dependence on morphine.

Induction of physical dependence in rats by short interval medication.

Rats were intermittently medicated at one hour intervals through an implanted intravenous cannula. Physical dependence on morphine and codeine was developed rapidly and it was detectable with the maintenance dose as low as 9.6 mg/kg/day. Physical dependence on pentazocine was also developed with the maintenance dose of 96 mg/kg/day, but was not with 9.6 mg/kg/day. In the pentazocine-treated rates, body weight loss was observed after the abrupt withdrawal, and abstinence signs were precipitated by naloxone 1 mg/kg. Cross physical dependence between morphine and pentazocine was demonstrated. Pentazocine suppressed the abstinence signs of rats weakly dependent on morphine, and morphine suppressed those of pentazocine-dependent rats. ID-1229, a new benzomorphan analgesic, did not produce dependence in this test and did not suppress the abstinence signs of morphine- and pentazocine-dependent rats.

Simple method for producing an alcohol withdrawal syndrome in rats

Rats received intragastric intubations of ethanol at 8 hr intervals for 1, 7, 15 or 30 days. The dosage for each animal was one which produced observable signs of intoxication 1 hr after the intubation. All of the rats in the experimental groups developed a tolerance to ethanol as indicated by the increasing dose required to induce intoxication, but the degree of tolerance was related to the duration of the ethanol administration. During the withdrawal period the incidence of hyperreactivity, convulsive symptoms, and the susceptibility to audiogenic seizures was determined for all 4 groups. Although every experimental animal displayed withdrawal symptoms, the incidence of these symptoms was found to be an increasing, negatively accelerated function of the duration of ethanol exposure. For situations where voluntary consumption of alcohol is not necessary this method is a simple, controlled, reliable, way of inducing ethanol tolerance and physical dependence in rats.

166) - Acute morphine tolerance and physical dependence in rats. 6th report: Tolerance to increasing effect of morphine on plasma corticosterone in rats

166) - Acute morphine tolerance and physical dependence in rats. 6th report: Tolerance to increasing effect of morphine on plasma corticosterone in rats

Morphine-like physical dependence: A pharmacologic method for drug assessment using the rat

Rats maintained on various dosage regimens of morphine showed dose related taste aversions to a saccharin solution offered to them upon withdrawal from the drug. Maximal saccharin aversions occurred between 72 and 96 hr after termination of morphine injections, and gradually returned to baseline preference levels after 14 days of morphine abstinence. The results were interpreted as suggesting that the morphine treated animals associated the aversive components of the morphine withdrawal syndrome with saccharin consumption, and manifested conditioned aversions to the saccharin solution which extinguished as the withdrawal syndrome subsided. The findings were further discussed with regard to the potential use of conditioned taste aversions in determining whether test compounds are capable of causing physical dependence in rats.

Physical dependence in rats after low morphine doses

The minimum level of morphine administration necessary to produce physical dependence in rats was investigated. Rats received low doses of morphine (10 mg/kg) intraperitoneally once daily for 1, 3, or 5 days. Naloxone given intraperitoneally 1 hr. after the last morphine injection produced significant withdrawal signs after only three days.