No psychological dependence after oral administration of morphine to rats (original) (raw)
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British Journal of Pharmacology, 1982
1 Rats are capable of consuming solutions of morphine sulphate in drinking water ad libitum in the absence of taste-masking chemicals and without the need for scheduled provision or prior parenteral administration of the drug. 2 The success of this method depends on the initial provision of a 0.1 mg/ml solution of morphine sulphate. 3 When the drug concentration is increased to 0.4 mg/ml, the rats achieve an average daily intake of 50 mg/kg body wt. each. 4 Daily intake of morphine may be increased by at least about three fold by increasing the drug concentration to 1.2 mg/ml. 5 Oral morphine administration causes only a moderate loss in body weight. 6 Rats whose daily intake of the drug is 50 mg/kg exhibit tolerance to the analgesic action of morphine and show a drastic loss in body weight at 24 h after withdrawal and most of the behavioural symptoms of the naloxone-precipitated withdrawal syndrome. 7 It is suggested that this simple method of morphine administration is suitable for further biochemical and behavioural studies of the actions of the drug.
The Japanese Journal of Pharmacology, 1996
The severity of naloxone-precipitated withdrawal in rats infused intravenously with mor phine at the rates of 2.5, 5 and 10 mg/kg/hr over various time periods was investigated. Plasma morphine concentration reached a constant and rate-dependent level at 1 hr after the start of morphine infusion, and this level was maintained until the termination of infusion. Naloxone (2.0 mg/kg, s.c.) was challenged 18 hr after infusion was stopped, and the withdrawal was evaluated by plasma corticosterone (PCS) increase, diarrhea and body weight loss. The incidence of naloxone-precipitated withdrawal signs was related to both the infusion rate and duration of morphine infusion. The duration of morphine infusion (ET50) needed to elicit naloxone-precipitated PCS increase and diarrhea in 50% of the rats was inversely related to the mor phine infusion rates, but the total amount of infused morphine (EA50) that elicited naloxone-precipitated withdrawals in 50% of rats was the same at all infusion rates. These results suggest that the total amount of morphine infused may play an important role in the development of acute physical dependence on mor phine rendered by continuous intravenous morphine infusion for 1-8 hr.
Voluntary morphine ingestion, morphine dependence, and recovery from withdrawal signs?
Pharmacology Biochemistry and Behavior, 1975
We are reporting on conditions (without forced drinking or premedications) where rats voluntarily drink high quantities of sucrose-morphine solutions in preference to water. The volume ingested is inversely related to the morphine concentration in the liquid. The morphine antagonist, nalorphine, produced a clear set of opiate withdrawal signs in these (voluntarily) morphine-drinking rats. The severity of withdrawal signs was a function of the amount of ingested morphine. The present finding is the first report to show that rats ingest high quantities of sucrose-morphine without premedication or forced hydration procedures. Morphine Nalorphine Voluntary ingestion Withdrawal signs Rats
Chronic morphine administration: Plasma levels and withdrawal syndrome in rats
Pharmacology Biochemistry and Behavior, 1976
Sprague-Dawley rats over a period of 65 hr either by the simultaneous implantation of two 75 mg pellets, or by a series of twice daily 20 or 30 mg/kg injections, produced dependence as indicated by the precipitation of the abstinence syndrome with the antagonist, naloxone. Plasma morphine levels, analyzed fluorometrically at various times during the treatment procedures, revealed peak concentrations that were 3 or 4 fold higher for injected animals than the maximum steady-state level established in the pellet-implanted animals. The calculated plasma concentration of the drug over time was not statistically different for the groups. It is noted that although the 2 methods of morphine administration produce a qualitatively identical dependent state, the pellet implantation technique causes greater weight loss and a higher incidence of jumping and wet-dog shakes during withdrawal.
The concentration of morphine in serum of rats made dependent using a drug-admixed food method
Pharmacology, Biochemistry and Behavior, 1988
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. ARer long-term administration of I g/kg morphine in food a steady-state level of about 0.5 mg/I 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. l mg/l within 24 hours and to below the detection limit within 48 hours. During the withdrawal period sharp drops were noted in body weight (20%) and food intake (50%) after one day.
A Novel Morphine Drinking Model of Opioid Dependence in Rats
International Journal of Molecular Sciences, 2022
An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants’ presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine wa...
The role of self-administration in morphine withdrawal in rats
1997
Rats assigned to a self-administration-of-morphine group (SA-M) could press a lever in an operant chamber to deliver an intravenous infusion of morphine to themselves and to a yoked morphine (Y-M) rat, and an infusion of Ringer's solution to another yoked rat. Although rats assigned to SA-M and Y-M groups received the same drug doses at the same time, withdrawal symptoms were more pronounced in SA-M rats, Possible mechanisms for the differences in drug withdrawal between animals that selfadminister morphine and animals that passively receive the drug are discussed, There is increasing evidence that the effects of a variety of drugs are different if they are self-administered rather than passively received, For example, Moolten and Kornetsky (1990) evaluated the ability of ethanol to reduce the threshold of rewarding electrical brain stimulation (a putative measure of drug-induced euphoria), They found that ethanol reduced the stimulation threshold in rats that self-administered ethanol (by drinking a sucrose ethanol solution), but not in rats that had ethanol intragastric ally infused at the same rate as that at which selfadministrators consumed the drug, 1 Ator and Griffiths (1993) evaluated the effect of a series of intravenous midazolam infusions on the discriminative stimulus effects ofthe tranquilizer. They found that when 2 baboons selfadministered midazolam, their sensitivity to the stimulus effects of the drug increased, In contrast, when they received the drug in a response-independent manner (in a pattern that mimicked their self-administration protocol), their sensitivity to the stimulus effects of midazolam decreased, Reports that self-administered drugs are less toxic than passively received drugs provide especially dramatic evidence for the importance of the self-administration contingency, Johanson and Schuster (1981) discuss findings suggesting that experimenter-programmed administration of phencyclidine in monkeys frequently is lethal "at dose levels at or below those self-administered, which animals survived" (p, 280), They suggested that the role of selfadministration in drug lethality should be assessed in species more readily available than primates, such as rats, Just that has been done by S, L Dworkin and colleagues (S, L
The Japanese Journal of Pharmacology, 1995
Plasma morphine concentration and naloxone-precipitated withdrawal body weight loss and plasma corticosterone (PCS) increase were determined at 12, 18 and 24 hr after i.v. infusion of morphine at a constant rate of 10 mg/kg/hr for 4 hr in Sprague-Dawley rats. Plasma morphine concentration declined 98.0% within 12 hr and further declined 58.8% during 12-24 hr after morphine infusion. There was a significant difference between plasma morphine concentrations at 12 and 24 hr after the morphine infusion. Naloxone (0.5 and 2.0 mg/kg)-precipitated withdrawal, but not spontaneous withdrawal, was elicited at 12-24 hr after the morphine infusion, and the severity of withdrawal precipitated by 2.0 mg/kg naloxone was the same at 12-24 hr after the morphine infusion. Furthermore, there was no significant correlation between plasma morphine concentration and body weight loss or PCS increase. The results suggest that a constant degree of morphine dependence is sustained during 12-24 hr after the morphine infusion and the severity of naloxone-precipitated withdrawal is not related to the plasma morphine concentration at the time of naloxone injection, that is, the rate of morphine removal from its receptor sites.
Drug and Alcohol Dependence, 2008
To induce morphine dependence, different programs have been used and a wide range of behaviors evaluated. A quantitative method based on mice withdrawal jumping behavior has been suggested and later described by Marshall and Grahame-Smith. The purpose of this work was to evaluate different aspects of this method using variations in doses and duration of the protocol. All experiments were done in three parallel methods according to the Marshall protocol: (i) except the dose of morphine (n = 20) where we divided all morphine doses by two in first 3 days, (ii) 2-day (M100%-2D, n = 14) and (iii) 1-day morphine application (M100%-1D; n = 13). The results showed that only 50% doses of morphine that are used according to Marshall method is sufficient to induce morphine dependence whereas they are not able to induce tolerance. On the other hand, M100%-2D protocol could induce morphine tolerance but not dependence whereas M100%-1D group could induce neither morphine tolerance nor dependence in mice. Therefore, these simple modifications in dose and period of morphine application in Marshall method resulted in distinct protocols for induction of morphine tolerance and dependence along with saving of drug and time.