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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of noscapine and chlorpheniramine on physical dependence liability and antitussive activity of dihydrocodeine, a narcotic antitussive, were studied. For developing physical dependence, male Sprague-Dawley rats were treated with dihydrocodeine (DC), noscapine (N), and chlorpheniramine (CP) singly or simultaneously admixed with food (drug-admixed food method (DAF): DC: 0.125, N: 0.25, CP: 0.05 mg/g of food, for 7 days) or were intermittently medicated for 3 days at one-hour intervals through an implanted intravenous cannula (infusion method: DC: 0.5-2, N: 1-4, CP: 0.2-0.8 mg/kg x 24 times/day). Subsequently, rats were treated with naloxone (0.5 mg/kg, sc) and checked for withdrawal signs during 3 hours. Naloxone-precipitated body weight loss of DC was suppressed by simultaneous administration of N or CP. In combined group of DC, N, and CP, withdrawal signs, such as body weight loss, body shakes, and diarrhea, were more remarkably suppressed. Papaverine, the same kind of spasmolytic as N, was tested by the same schedule of DAF. Papaverine did not suppress the naloxone-precipitated withdrawal signs of DC. These results suggest that suppressive effect of N is not due to its spasmolytic action. On the other hand, the cough reflex was induced by electric stimulation in guinea pigs and the fifty percent of antitussive dose (AtD50) was estimated in order to evaluate the influence of N and CP on antitussive effect of DC. N and CP did not change the antitussive effect of DC. These results may suggest that N and CP suppress the development of physical dependence of DC without diminishing the pharmacological effects of DC.
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PMID:[The effects of noscapine and chlorpheniramine on physical dependence and antitussive activity of dihydrocodeine]. 321 81

This study assessed the effects of i.m. naloxone (10 mg) 6 hr after acute i.m. injections of morphine (0, 1, 3, 5.6, 10 and 17 mg). Naloxone reversed residual morphine-produced respiratory depression, miosis and subjective reports of drug "high." In addition, naloxone precipitated signs and symptoms characteristic of opioid withdrawal. Subjective report measures of "bad" drug effects and specific opioid withdrawal symptoms increased as a function of morphine pretreatment dose, as did observer-rated signs of withdrawal. Yawning was the most prominent observed sign, whereas yawning and irritability were the most consistently reported subjective symptoms. Peak withdrawal effects were seen within 15 min post-naloxone. The results of this study confirm previous reports of acute physical dependence in man and extend those findings by demonstrating a morphine dose-response function.
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PMID:Acute physical dependence in man: effects of naloxone after brief morphine exposure. 333 95

The effect of D-Phenylalanine (D-Phe), putative carboxypeptidase A inhibitor and its four derivatives (T1-T4) on analgesia, development of tolerance and physical dependence to morphine, and on degradation of both exogenous and endogenous enkephalins was investigated. Systemic administration of either D-Phe or its derivatives produced naloxone-reversible analgesia in the hot-plate test in mice. Naloxone-precipitated morphine withdrawal syndrome was attenuated in mice after systemic subacute administration (7 days, 1.2 mmol/kg, sc) of D-phe derivatives, the development of tolerance to morphine being unchanged. In the presence of either D-Phe or its derivatives in incubation mixture (up to 10(-3) mol/l) the hydrolysis of exogenous 3H-Met5-and 3H-Leu5-enkephalin in striatal homogenates was slightly inhibited. Moreover, the addition of D-Phe or its derivatives seemed to increase the per cent of recovered endogenous Met5-enkephalin released from veratridine-depolarized striatal particles. In contrast, bestatin, an amino-peptidase inhibitor, and a mixture of dipeptides (Tyr-Tyr, Leu-Leu, Leu-Gly) markedly inhibited degradation of both endogenous and exogenous enkephalins in vitro. The results obtained in this study suggest that that pharmacological activity of D-Phe is not directly related to the endogenous opiate system.
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PMID:The effects of D-phenylalanine and its derivatives on enkephalin degradation in vitro: relation to analgesia and attenuation of the morphine withdrawal syndrome. 376 85

The possible role of succinic dehydrogenase (SD) in producing physical dependence to morphine by affecting tissue respiration was investigated in Swiss albino mice during the development of morphine tolerance through a period of addiction and naloxone withdrawal therapy. Tolerance and physical dependence were induced by injecting the mice with morphine sulfate subcutaneously at 8-hour intervals, increasing the dose from 10 mg/kg BW every 24 h for 15 days. The animals were considered to be addicted when they were able to tolerate an otherwise lethal dose of 150 mg/kg 3 times a day. Results indicated that succinic dehydrogenase was inhibited throughout the 15-day period of morphine administration and that this effect was greatest in tolerant animals. Increasing the dose and duration of treatment did not cause further decreases in enzyme activity; instead, after 15 days levels of enzyme activity increased in addicted animals compared with tolerant mice. Furthermore, morphine abstinence for 2 days, markedly increased the levels of SD activity, while 6 days of abstinence had little effect. Naloxone withdrawal at each stage was associated with increased SD activity, but the increase was significant only in tolerant mice.
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PMID:Changes in succinic dehydrogenase activity in the central nervous system of mice during morphine dependence development, withdrawal and naloxone treatment. 404 Apr 49

U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide) displays analgesic actions in a variety (thermal, pressure and irritant) of assays in mice and rats. Naloxone and MR-2266 block this analgesic effect; thus it is mediated by opioid receptors. However, when compared to morphine analgesia, the naloxone and MR-2266 pA2 values for U-50,488 analgesia were much lower and higher, respectively. Likewise, although tolerance occurs to both morphine and U-50,488 analgesia, there was no cross-tolerance between these drugs, and U-50,488 does not cause morphine-type physical dependence. These observations suggest that different opioid receptors mediate the analgesic effects of morphine and U-50,488. The effects of U-50,488 appear to be mediated by the so-called kappa opioid receptor. In contrast to U-50,488, other reputed kappa opioid agonists displayed varying degrees of mu agonist (ketazocine and ethylketocyclazocine) and narcotic antagonist (bremazocine) activities. Thus U-50,488 is a more selective kappa agonist. This conclusion is further supported by binding studies; of all compounds tested, U-59,488 displacement of [3H]ethylketocyclazocine binding was uniquely not blocked by high concentrations of dihydromorphine. In addition to analgesia, this selective kappa agonist also causes opioid receptor-mediated sedation, diuresis and corticosteroid elevations. U-50,488 is a useful tool for studying contrasting kappa and mu opioid receptor-mediated effects.
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PMID:U-50,488: a selective and structurally novel non-Mu (kappa) opioid agonist. 612 21

1 Morphine and related synthetic surrogates as well as beta-endorphin and methionine enkephalin caused a contractile response of the longitudinal musculature of the terminal colon of Long Evans rats.2 The muscular contraction caused by the narcotic analgesics exhibited stereospecificity, with levorphanol being about 50 times more potent than dextrorphan and (-)-methadone 4 times more potent than (+)-methadone. In addition, the rank order in potency of a homologous series of N-alkyl substituted norketobemidones demonstrated that the activity of these compounds in eliciting contractile responses corresponded to that for analgesic efficacy in the rat and also correlated to the ability of these derivatives to inhibit the muscular twitch evoked by electrical stimulation of the guinea-pig ileum.3 Naloxone blocked the contractile response of the opiates following competitive kinetics; the naloxone pA(2) values for morphine, etorphine, levorphanol and methadone were very close, in spite of the marked differences in potency of these agents.4 The contractile effect of morphine on the rat colon was abolished by incubation of the tissues with tetrodotoxin 2.0 x 10(-7) M or by decreasing the external Ca(2+) level 100 fold. Increasing the external Ca(2+) concentration caused an apparent non-competitive antagonism of the response to morphine.5 Pretreatment of the tissues with hexamethonium 8.3 x 10(-5) M caused a modest antagonism of the morphine effect while atropine 5.8 x 10(-7) M did not significantly modify the morphine contractile effect. In contrast, methysergide 10(-5) M caused a 10 fold increase in the morphine EC(50).6 Colons from rats rendered tolerant-dependent on morphine were markedly less sensitive to the contractile effects of morphine than those from placebo-treated controls. Tolerance to morphine was also accompanied by an increased sensitivity to the contractile effects of 5-hydroxytryptamine (5-HT).7 A marked increase in the spontaneous muscular activity of segments of the terminal colon of rats chronically treated with morphine was found to occur upon removal of the residual morphine in the tissues by repetitive washings. The spontaneous activity was arrested by applications of morphine, suggesting that physical dependence can be demonstrated in vitro in this particular preparation.8 It is concluded that the opiate-induced contractile response is mediated via stereospecific, naloxone-sensitive, opiate receptors and that the muscular response involves the activation of a 5-HT neurone in the nerve terminals of the colon.
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PMID:Contractile effect of morphine and related opioid alkaloids, beta-endorphin and methionine enkephalin on the isolated colon from Long Evans rats. 617 Mar 77

In order to examine the development of tolerance to opioids, eight cynomolgus and two rhesus monkeys were trained to press a lever for food reinforcement and then were catheterized so that drugs could be infused. Three doses of hydromorphone and six different interdose intervals were studied. Hydromorphone infusions initially suppressed lever pressing for food in both species. The rhesus monkeys acquired tolerance to these sedative effects after 14 exposures to the opioid. However, the cynomolgus monkeys failed to acquire tolerance after more than 100 exposures. Naloxone challenge elicited withdrawal symptoms from the rhesus monkeys but not from the cynomolgus monkeys. This differential response to sustained opioid administration in these closely related species suggests that a genetic mechanism may underlie tolerance to and physical dependence on opioids.
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PMID:Cynomolgus monkeys do not develop tolerance to opioids. 618

A comparison of several methods for developing physical dependence to morphine was made. Male Sprague-Dawley rats were treated with morphine-admixed food (drug-admixed food, DAF; 0.5 and 1 mg/g food), morphine slow release emulsion (SRE; 75, 100 and 150 mg/kg) and morphine (75 mg) pellets. In the SRE and pellet methods, the typical signs of morphine toxicity, such as catatonia, exophthalmos and shallow respiratory movements, were observed 15-20 min after the treatment and these signs were maintained for 14-18 hr. In rats treated with SRE and pellets, plasma morphine levels reached a maximum 1 day after the morphine treatment, and subsequently decreased, while plasma morphine levels in rats treated with DAF increased treatment period-dependently. Withdrawal signs precipitated by naloxone (3 mg/kg, sc) in rats treated with DAF, SRE and pellets were characterized by loss of body weight, shaking, vocalization, diarrhea, ptosis, tooth-chattering, nose bleed, salivation and lacrimation. Naloxone-precipitated withdrawal signs reached a maximum 1-2 days after treatment with SRE and pellets, and were correlated with the duration of DAF treatment. Rats treated with DAF, SRE (150 and 225 mg/kg) and pellets for 3 days, manifested loss of body weight, diarrhea etc. after the morphine withdrawal. Maximum body weight loss in each group was 7-10% at 1-2 days after the morphine withdrawal. It was thus, concluded that physical dependence on morphine can be induced rapidly by these three methods. However, the SRE and pellet methods induced morphine toxicity and it was difficult to maintain physical dependence on morphine in these rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Comparison of three methods of inducing physical dependence to morphine in rats using short-term medication]. 654 77

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.
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PMID:Acute physical dependence induced by continuous intravenous infusion of morphine or meperidine in the rat. 678 39

The effects of morphine, naloxone, and combinations of these drugs were examined in squirrel monkeys under shock-postponement schedules. In the absence of a lever press, shocks could be presented every 4s. and each response postponed shock for 20s. Acutely, morphine (0.10-3.00 mg/kg) produced not only overall response-rate decreases, but also increases in the number of shocks, whereas naloxone (0.10-30.00 mg/kg) had little effect on responding. When given in combination with morphine, several doses of naloxone antagonized the rate-reducing and shock-increasing effects of morphine. Daily administration of morphine resulted in a substantial decrease in the number of shocks received and a moderate attenuation of the rate-decreasing effects of morphine (tolerance). Lower doses substituted for the fixed daily dose resulted in a smaller effect on behavior than under acute administration. Naloxone given in combination with the daily morphine dose or substitute for the daily morphine dose or substituted for the daily administration or morphine, produced effects similar to those seen prior to chronic drugging. Thus, behavioural effects of naloxone were not altered even though tolerance to morphine was observed. Larger doses of naloxone continued to antagonize the effects of morphine for at least 24 h. No signs of physical dependence were noted when naloxone was administered or when administration of morphine ended.
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PMID:Behavioral effects of morphine and naloxone following chronic morphine administration. 681 91


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