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BIPHASIC ACTION of PENTAZOCINE in MORPHINE DEPENDENT RATS Eijiro TAGASHIRA, Tomoko URANO, Tameo HIRAMORI and Saizo YANAU RA Depa

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BIPHASIC ACTION of PENTAZOCINE in MORPHINE DEPENDENT RATS Eijiro TAGASHIRA, Tomoko URANO, Tameo HIRAMORI and Saizo YANAU RA Depa BIPHASIC ACTION OF PENTAZOCINE IN MORPHINE DEPENDENT RATS Eijiro TAGASHIRA, Tomoko URANO, Tameo HIRAMORI and Saizo YANAURA Departmentof Pharmacology.Hoshi Collegeof Pharmacy,2-4-41 Ebara, Shinagawa-ku,Tokyo 142, Japan Accepted February15, 1982 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. " A large number of clinical reports on exposure to drug" where the drug was dependence liability to pentazocine appeared always existing in the body using an inter from 1968 through 1969 (1-6). The clinical mittent i.v. infusion method which applied use of pentazocine also became popular in the drug automatically 24 times a day, and Japan, and pentazocine-dependent cases Laska and Fennessy (12) likewise studied tended to increase among general patients the dependence on the same drug by a slow and medical service people since 1971 release emulsion method. Yanagita et al. (counting 55 cases in these 5 years), calling (13) applied a gradually increased dose of one's attention to the problem of pentazocine pentazocine to monkeys by s.c. injection, 4 dependency. to 6 mg/kg, 4 times a day, for 60 consecutive Pentazocine is a drug rapidly metabolized days. A Drug-Admixed Food (DAF) method in animals (7, 8) as well as in man (9, 10), developed by the authors (14) was used in and its analgesic effect lasts only for a short the present study. This method is easy to time such as 90 to 120 min. Koga (11) follow and not time-consuming, and as studied the dependence liability to pen described in a previous paper of a study on tazocine under a condition of continuous the physical dependence on pethidine (15), this method has been proven to be applicable group given the drug from a low to an inter to a dependence formation study on drugs mediate dose (group B), the third group rapidly metabolized or those which become administered a low dose of pentazocine quickly toxic as in the case of barbiturates constantly for a long period (group C), and when continuously applied (16). the last group was the untreated control Only few systematic studies on the (group D). Each animal was allowed to dependence liability of laboratory animals to eat freely from either of 2 food containers, pentazocine have been published (1, 13, 17), one containing twice as much pentazocine and those results do not necessarily agree admixed as the other. As the drug depen with one another. In their studies on cross dence was developed, animals would tend physical dependence between morphine and to eat preferably the food with a heavier drug pentazocine, Koga (11) and Yanagita et al. content. Group A and B were fed initially (13) showed that the suppressive action on with a pair of food-admixtures with pentazocine against the sings of morphine pentazocine contents of 0.5 and 1 mg per g withdrawal varied with the degree of of food and these were gradually increased morphine dependence (or the dose for up to 4 and 6 mg/g food, and moreover, maintaining morphine dependence); and in 6 mg/g food (group A) was administer after mildly morphine-dependent animals, pen 77 days. During this period, the drug was tazocine suppressed the sings of morphine withdrawn for 24 hr before increasing the withdrawal, but hardly suppressed or even dosage as well as about midway during one tended to aggravate the signs of morphine dose level feeding. Group B was fed withdrawal in severely morphine-dependent initially with pentazocine at 0.5 and 1 mg/g animals. From various aspects in their food for 7 days, then at 1 and 2 mg/g food studies on the dependence liability to for 18 days, further at 2 mg/g food for 7 cyclazocine, benzomorphan derivatives days, and finally the drug was naturally analogus to pentazocine, Martin et al. (18), withdrawn. Animals were exposed to the Jasinski et al. (2, 3), and Gilbert and Martin drug totally for 32 days. Group C was fed (19) indicated that the dependence on the with pentazocine at 0.5 and 1 mg/g food for benzomorphan derivatives was qualitatively 32 days with no increase in the dosage before different from that on morphine in subjective withdrawal. Group D was fed only with symptoms, withdrawal signs, and mode of normal food througout the experiment (naive antagonism against naloxone. In the present control). study, the physical dependence on pen 2. Manifestation of withdrawal signs with tazocine (oral route) and the cross-physical levallorphan: During the continuous admin dependence liability to morphine were istration with pentazocine to the 3 groups of studied in comparison with those of codeine. rats described under 1, each group received Some new findings will be presented. 2 mg/kg of levallorphan s.c. at different times: group A at 7 and 15 days when the MATERIALSAND METHODS dose of pentazocine reached 4 and 6 mg/g 1. Dependence formation to pentazocine: food, respectively, group B at 12 days with Sprague-Dawley rats (6 weeks of age) were pentazocine at 1 and 2 mg/g food, and divided into 4 groups, each consisting of 6 group C at 19 days with the unchanged initial animals. Animals of the first group were dosage of 0.5 and 1 mg/g food. These administered pentazocine in a range from a animals were investigated for general low to a high dose (group A), the second behaviors and measured for body weight and food consumption at intervals during the withdrawal, the animals were put back on 24 hr after the challenge with levallorphan. the same foods as before. Morphine-dependent groups prepared with b-1) Three groups of morphine-dependent 1 /4 and 1 /2 mg/g food (M-L,) and 1 /8 and rats, M-H, M-I, and M-L2 were prepared. 1 /4 mg/g food (M-L2 group) for not less All 3 groups received pentazocine 20 mg/kg than 3 weeks were challenged with 2 mg/kg s.c. every 3 to 5 hr for the period from 17 hr of levallorphan. The body weights of rats until 48 hr after morphine withdrawal. After used in this experiment were 230-250 g. the cross-administration, animals were 3. Cross-physical dependence liability to completely off any drug, and they were pentazocine in morphine-dependent rats: For examined for general behaviors and measured the purpose of investigating the cross for body weight until they recovered in body physical dependence between morphine and weight up to the level before the cross pentazocine, 3 groups of rats (N=6) were administration. The control group again was prepared differently in the degree of physical fed only with normal food. dependence on morphine or in the main b-2) Seven groups (N=6) of rats (body tenance doses of morphine dependence. weight: 230-250 g) which had developed Highly dependent rats (M-H group) were physical dependence on morphine (M-I prepared by feeding them with food con groups of rats) received pentazocine at 0, 5, taining morphine at both 1 and 2 mg/g food, 10, 20, 40, 80, and 150 mg/kg for in intermediately dependent ones (M-I group) vestigating the dose-response relationship in were fed with 0.5 and 1 mg/g food, and the suppressive action of pentazocine on the lightly dependent ones (M-L2 group) were morphine-withdrawal signs. The cross fed with morphine at 1 /8 and 1 /4 mg/g food. administration was performed every 3 hr All groups were fed as described above for from 17 hr until 48 hr after morphine with 3 weeks. The control animals were fed only drawal. Rats were kept off morphine com with normal food (naive control). pletely for 5 to 6 days after the cross The cross-administration of pentazocine administration for the purpose of investigating was started at a) 0 hr (when the animals whether morphine dependence was main were non-withdrawn dependent state) or tained or cross-dependence had been b) 17-18 hr after withdrawal of morphine induced. During the cross-administration when the moderate withdrawal signs became period that ensued, the animals were manifest. examined for general behaviors and measured a) M-H and M-I groups of morphine for body weight. dependent rats (body weight: 350-380 g) b-3) For the purpose of comparing the received pentazocine at 20 mg/kg s.c. The cross-physical dependence liability to control rats were fed only with normal food pentazocine with that to codeine, the sup during the same period.
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