Physical Dependence on Morphine, Phenobarbital and Diazepam in Rats by Drug-Admixed Food Ingestion

Yanaura, Saiζo; Tagashira, Eijiro; Suzuki, Tsutomu

doi:10.1254/jjp.25.453

Cited by 80 publications

(21 citation statements)

References 16 publications

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“…Other studies extended this finding to demonstrate that physical dependence on barbiturates can be demonstrated in rodents (9,(11)(12)(13)(14). Until recently, severe physical dependence on pentobarbital as manifested by withdrawal convulsions had not been shown in rodents.…”

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Genetic differences in the development of physical dependence on pentobarbital in four inbred strains of rats.

et al. 1987

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Abstract-Fischer 344 (F344), Lewis (LEW), spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats were chronically fed food containing pentobarbital on an escalating drug dosage schedule over a period of 47 days. During treatment, the growth curve in LEW, SHR and WKY rats was suppressed as compared with the respective controls. Motor incoordination was evaluated by a rotarod per formance test. The ranking of the motor incoordination was as follows: WKY>>j LEW>SHR>F344.After substitution of normal food for the pentobarbital admixed food, various signs of pentobarbital withdrawal occurred. The withdrawal signs from pentobarbital in F344, LEW and SHR rats were mild as compared with those in WKY rats. The order of the severity of withdrawal signs in four inbred strains was parallel to that for motor incoordination. These results suggest that the differences between strains in withdrawal can be attributed to differences in the degree of chronic CNS depression produced by pentobarbital. Genetic differences in tolerance and physical dependence to several drugs have been reported. Among the more commonly used inbred strains of mice, the C57BL/6 strain seems to develop a greater degree of physical dependence on morphine (sensitivity to naloxone-induced jumping) than the DBA/2 strains (1). There have been several genetic studies of tolerance to and physical de pendence on ethanol in inbred mice. Grieve et al. (2) reported that the C57BL strain developed tolerance much faster than does the DBA strain, and the C57BL strain showed brief and mild withdrawal signs in comparison with the DBA strain. Goldstein and her collaborator (3, 4) showed a differential resistance to withdrawal seizures in the C57BL strain. These experiments suggest that genotype is an important determinant of the degree of tolerance to and physical dependence on ethanol and morphine.Acute effects of barbiturates have also been examined in genetic studies. C57BL mice are known to be more sensitive than DBA and BALB mice to pentobarbital (5-7). Recently, Khanna et al. (8) reported that pentobarbital and barbital sleep times for spontaneously hypertensive (SHR) rats were significantly less than for Wistar Kyoto (WKY) rats, and barbiturate blood levels at awakening were significantly higher in SHR than in WKY rats. Very few studies of physical dependence on barbiturates have examined genetic

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“…For preparing the drug admixed food, sodium pentobarbital (Tokyo kasei Kogyo, Tokyo, Japan) was mixed with a normal powdered food (CA-1, Japan Clea, Tokyo, Japan) in a mortar (13,14). Each rat was allowed to eat the pentobarbital admixed food and to drink tap water ad libitum.…”

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Genetic differences in the development of physical dependence on pentobarbital in four inbred strains of rats.

et al. 1987

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“…Furthermore, the rats on repeated adminis tration of pentazocine-admixed food were challenged with levallorphan, but no distinct withdrawal signs were precipitated in these animals compared with those on morphine, codeine, or pethidine treatment (14,15). Keats and Telford (22) reported that neither levallorphan nor nalorphine exerted any antagonistic action on the respiratory de pression with pentazocine.…”

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“…A Drug-Admixed Food (DAF) method developed by the authors (14) was used in the present study. This method is easy to follow and not time-consuming, and as described in a previous paper of a study on the physical dependence on pethidine (15), this method has been proven to be applicable to a dependence formation study on drugs rapidly metabolized or those which become quickly toxic as in the case of barbiturates when continuously applied (16).…”

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Biphasic action of pentazocine in morphine-dependent rats.

et al. 1982

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Abstract-The characteristic actions of pentazocine in morphine-dependent rats were investigated by a drug-admixed food (DAF) method. Pentazocine did not cause evident withdrawal signs when stopped after a continuous administration for 2 months at 3 different dose levels. A state of physical dependency on morphine was produced in rats by feeding them for 3 weeks with food that contained different levels of morphine. Animals exhibiting a moderate degree of morphine-withdrawal signs (17-18 hr after with drawal) received a s.c. cross-administration with pentazocine at 0, 5, 10, 20, 40, 80, and 150 mg/kg. This drug at 20 mg/kg proved most supressive of morphine-withdrawal signs, being about 1 /4 as potent as codeine. In a dose range from 20 to 40 mg/kg, the action of pentazocine on the with drawal signs was reversed, that is, doses not less than 40 mg/kg exerted a dose-related antagonistic action in all the 3 levels of morphine dependent rats. The challenge with levallorphan (2 mg/kg, s.c.) during the chronic application of pentazocine revealed slight withdrawal signs. These findings show that pentazocine has biphasic action on morphine dependence and suggests that this type of drug must have different properties from morphine type drugs.

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“…The drug admixed food (DAF) method developed by Yanaura et al (10,11) is an easy way to produce physical dependence on opioids in rodents without the stress of surgery or injection. It is well-known that the degree and severity of physical dependence are influenced by dose, frequency (dosing inter val) and duration of drug administration and that the frequency is the most important factor (12).…”

Section: Physical Dependence 1 Opioidmentioning

confidence: 99%

Pharmacological studies on drug dependence in rodents: Dependence on opioids and CNS depressants.

Suzuki

1990

Jpn.J.Pharmacol

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Abstract-Physicaland psychic dependence on opioids and CNS depressants in rodents were examined using the drug-admixed food (DAF) method.A comparison of several methods for developing physical dependence on opioids was made. The DAF method has the advantage of rapidly inducing a high degree of physical dependence without causing morbidity or mortality. When morphine-dependent rats were pretreated with several opioids, naloxone-precipitated weight loss was suppressed in a dose-dependent manner.A procedure for the development of severe physical dependence on CNS depressants was also established. Drug con centrations were rapidly increased until animals showed moderate to severe CNS depression, and then this condition was maintained for at least 10 days. With this procedure, animals became severely dependent on CNS depressants. Another technique, intermittent infusion, was developed that has been used to quantify short acting CNS depressant dependence potential.The sedative effects of pentobarbital were used as an index in the determination of the injection intervals.These results suggest that the DAF method and the new approaches are useful tools for assessing the physical dependence potential of new drugs. Moreover, oral self-administration and weight pulling procedures were utilized along with the DAF method. Pro cedures for the oral self-administration of opioids and CNS depressants were estab lished. Opioid-dependent rats pulled the weight to obtain the DAF even though they had free access to normal food. This weight-pulling procedure may be useful for assessing the degree of reinforcing effects for drugs in rats. I. Physical dependence 1. OpioidOn the basis of many years of study with the opioids, well defined methods have been developed for the assessment of physical de pendence.Physical dependence on opioids can quickly be induced in rodents by a variety of techniques, including implantation of mor phine pellets (1-3), infusion of opioids (4-6), treatment with slow release emulsion (SRE) of opioids (7,8) and implantation of a re servoir of morphine solution (9). The drug admixed food (DAF) method developed by Yanaura et al. (10,11) is an easy way to produce physical dependence on opioids in rodents without the stress of surgery or injection. It is well-known that the degree and severity of physical dependence are influenced by dose, frequency (dosing inter val) and duration of drug administration and that the frequency is the most important factor (12). From these points of view, we examined physical dependence on opioids using the DAF method. a) Effects of dose: Rats were chronically administered 5 doses of morphine (0.0625, 0.125, 0.25, 0.5 and 1.0 mg/g of food) for 7 days by the DAF method. physical dependence on morphine was car ried out using withdrawal signs precipitated by naloxone (3.0 mg/kg, s.c.) challenge. The average daily morphine intake for 7 days was 5. 29, 10.58, 21.49, 38.19 and 76.94 mg/kg/ day in animals treated with morphine at doses of 0.0625, 0.125, 0.25, 0.5 and 1.0 mg/g of food, resp...

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Physical Dependence on Morphine, Phenobarbital and Diazepam in Rats by Drug-Admixed Food Ingestion

Cited by 80 publications

References 16 publications

Genetic differences in the development of physical dependence on pentobarbital in four inbred strains of rats.

Genetic differences in the development of physical dependence on pentobarbital in four inbred strains of rats.

Biphasic action of pentazocine in morphine-dependent rats.

Pharmacological studies on drug dependence in rodents: Dependence on opioids and CNS depressants.

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