Buprenorphrine: demonstration of physical dependence liability

This study was designed to assess the dependence-producing capacity of the opiate partial agonist, buprenorphine. Rats chronically treated with buprenorphine for 4 days showed only very weak signs of withdrawal upon cessation of buprenorphine treatment or upon challenge with naloxone, although complete tolerance had developed to the drug at this time. However, more intense withdrawal could be induced when buprenorphine treatment was followed by substitution treatment with morphine. Even one injection of morphine given 12 h after the last buprenorphine treatment enabled the precipitation of withdrawal with naloxone. Naloxone could not precipitate signs of withdrawal in naive rats treated with this dose of morphine. Thus, contrary to some claims in the literature, buprenorphine, like other opiate agonists and partial agonists, induces dependence. The fact that only few signs of withdrawal are seen in direct dependence tests, probably reflects the slow dissociation of the drug from the receptor - which probably limits the intensity of withdrawal by preventing the rapid uncovery of the receptor upon discontinuance of treatment with the drug or upon injection of an antagonist. In addition, the maximum degree of dependence induced by buprenorphine - in comparison to pure agonists is limited, like that of other partial agonists.     

Chronopharmacological study of physical dependence on morphine in rats

Relationship between withdrawal time or naloxone injection time and withdrawal signs were examined in morphine-treated rats. Sixty-five rats were treated chronically with morphine-admixed food (1 mg/g food) for 7 days and were divided into 13 groups. The rats of 4 groups were abruptly withdrawn from morphine, and the rats of another 4 groups were given naloxone (3 mg/kg, s.c.) at 20:00 on the 8 th day and 2:00, 8:00 and 14:00 on the 9 th day after the morphine administration, respectively. Withdrawal signs were observed at intervals of 2 hr. After each naloxone injection, abnormal behaviors were observed for 60 min, and body weight was measured for 3 hr at intervals of 15 or 30 min. In the withdrawal test, weight loss at 24 hr after withdrawal in each group was approximately 10%, and there was no difference between each group. However, the body weight of non-treated rats and morphine-treated rats increased during the night period (20:00-8:00) and decreased during the daytime (8:00-20:00). Therefore, body weight reached the minimum at 20:00, and then this time is appropriated for withdrawal. In the naloxone test, withdrawal signs in the night period were more potent than that in the daytime. The withdrawal signs induced by naloxone at 8:00 showed the maximum magnitude. Plasma morphine levels in rats treated with morphine-admixed food were high in the night period and low in the daytime. These results suggest that the magnitude of naloxone-precipitated withdrawal signs depends on the amount of morphine in the plasma.     

延胡索甲素与左旋延胡索乙素抗吗啡躯体依赖和精神依赖的作用研究

目的 观察并比较延胡索甲素(corydaline,Cor)与左旋延胡索乙素(l-tetrahydropalmatine,l-THP)抗吗啡躯体依赖和精神依赖的作用。方法 SD大鼠随机分为对照组、模型组、Cor组、l-THP组。连续递增sc吗啡9 d后,纳洛酮促瘾,制备吗啡依赖大鼠催促戒断模型,促瘾前30 min ip Cor(40、80 mg/kg)或l-THP(5.0、10.0 mg/kg),观察大鼠戒断症状和体质量的降低;应用旷场实验,观察Cor(5、10 mg/kg)和l-THP(2.5、5.0 mg/kg)对吗啡诱导的大鼠自发活动的影响、对吗啡连续递增给药致大鼠行为敏化效应的影响,以及Cor(10、20、40 mg/kg)和l-THP(2.5、5.0、10.0 mg/kg)对大鼠自发活动的影响。结果 Cor(40、80 mg/kg)、l-THP(5.0 mg/kg)对吗啡催促戒断症状无显著改善作用,10 mg/kg l-THP显著改善大鼠戒断症状(P<0.05);Cor和l-THP对吗啡降低大鼠体质量效应有改善趋势,但差异不显著;Cor 40 mg/kg以下剂量、l-THP 10 mg/kg以下剂量对大鼠自发活动无显著影响;Cor(5、10 mg/kg)和l-THP(2.5、5.0 mg/kg)均可显著降低吗啡诱发的大鼠高活动性行为、行为敏化的形成(P<0.05、0.01)。结论 Cor和l-THP对吗啡所致的大鼠躯体依赖和精神依赖均有不同程度的调节作用,l-THP的起效剂量明显低于Cor。     

Effects of tizanidine on morphine physical dependence: attenuation and intensification.

It has previously been shown that subchronic and acute administration of L-asparaginase and glutaminase inhibitors D-Aspartic acid (D-ASP) and prolyl-leucyl-glycinamide (PLG) intensifies and attenuates morphine (M) physical dependence, respectively, by the inhibition of ASP and glutamic acid (GLU) production, and subsequently their normal releases. Tizanidine (TIZ) has long been known to be an alpha 2-adrenoceptor agonist and inhibitor of ASP and GLU release. Therefore, in this study TIZ has been administered subchronically during the development of M physical dependence to rats in which M-containing pellets had been implanted or acutely 30 min before naloxone (NL)-induced abstinence syndrome. The subchronic administration of TIZ intensified NL-precipitated abstinence syndrome whereas its acute administration attenuated it, as did D-ASP and PLG. On the other hand, TIZ added into the medium prevented the in vitro M-dependent-made guinea pig ileum from contracting following NL application. Furthermore, TIZ stopped the already started contraction by NL of the M-dependent ileum, which completely relaxed later. These effects of TIZ on M-dependent ileum were antagonized by the alpha 2-adrenoceptor antagonist yohimbine. The intensification by subchronic TIZ administration of abstinence syndrome was attributed to the lesser release of ASP and GLU, which resulted in the larger blockade of M of ASPergic/GLUergic receptors due to the lesser release of their endogenous agonist ASP and GLU and consequently the higher upregulation of the receptors. The attenuation by acute TIZ administration of NL-precipitated abstinence syndrome was explained with lesser release of ASP and GLU and concomitantly the lesser stimulation of the receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on the physical dependence liability to guanabenz

The physical dependence liability of guanabenz, a hypotensive agent with central noradrenergic alpha 2-agonistic activity, was investigated. 1) Guanabenz showed a potent analgesic effect nearly equipotent to morphine by the modified Haffner's method, and repeated p.o. treatment resulted in the development of tolerance to the effect. 2) In the combined treatment of guanabenz with morphine or hexobarbital, it potentiated morphine analgesia and prolonged hexobarbital hypnosis in a dose dependent manner. 3) The natural withdrawal signs appearing in morphine or barbital dependent mice was suppressed by guanabenz; however, the effect was accompanied by a marked loss of body weight and weakness of the animals, and especially the dose required for the suppression of barbital withdrawal signs was extremely high and was even lethal in some cases. A substitution test in barbital dependent mice showed that guanabenz could not substitute for barbital. In the primary dependence test after 30 days oral treatment with guanabenz, no appreciable withdrawal signs were observed after discontinuation of the administration. Thus, from the results obtained in the present experiments, it is revealed that guanabenz possesses no physical dependence liability of the morphine or barbital type.     

The physical dependence liabilities of oxybutynin and morphine in rats

The anticholinergic/antispasmodic agent oxybutynin does not induce physical dependence in rats when administered by oral gavage twice daily for 40 days; nor did challenge with naloxone precipitate withdrawal signs in these (oxybutynin-treated) animals. In contrast, morphine treatment resulted in a high degree of physical dependence as evidenced by the withdrawal signs noted after treatment was halted. Challenge with naloxone also induced severe withdrawal signs in morphine-treated rats. Withdrawal signs characterised by squealing, teeth chattering and "wet-dog" shakes were seen in one from five morphine-treated rats challenged with oxybutynin.     

Antidiuretic effect of morphine in the rat: tolerance and physical dependence.

1 Injection of rats with morphine or methadone, before they received a water load equivalent to 5% of their body weight, produced a dose-dependent antidiuretic effect. Following the antidiuresis, urine was eliminated with kinetics similar to control untreated rats. 2 The antidiuretic effect of morphine or methadone was blocked by naloxone administered before the opiate, or reversed when given after the opiate. 3 Rats implanted with morphine pellets developed a marked degree of tolerance to the antidiuretic effect of morphine. Tolerance was also obtained on injection of three daily doses of morphine or methadone over two days. 4 Withdrawal symptoms were precipitated by naloxone in rats implanted with pellets of morphine; under these conditions the animals showed a marked reduction in urine production as compared to naive rats.     

Effects of MK 801 on morphine physical dependence: attenuation and intensification.

It has previously been reported that the noncompetitive NMDA receptor antagonists ketamine and dextromethorphan suppressed the naloxone-induced morphine abstinence syndrome. In addition, the previous blockade by ketamine and dextromethorphan of NMDA receptors has been shown to intensify the naloxone-elicited morphine abstinence syndrome. On the basis of this information, another noncompetitive NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-a,d-cyclohepten-5,10-imine maleate (MK 801), was administered to rats in which two morphine-containing (75 x 2 morphine base) pellets had been implanted. The naloxone-precipitated abstinence syndrome in rats injected with 0.3 mg/kg MK 801 36 h after pellet implantation was found significantly more intense than controls whereas the abstinence syndrome in rats that received 0.1 mg/kg MK 801 before naloxone injection was less intense. The intensification by MK 801 given 36 h following pellet implantation was attributed to the further increase in upregulation and supersensitivity of NMDA receptors caused by morphine. The attenuation was explained by the blockade by MK 801 of NMDA receptors as occurred in the case of ketamine and dextromethorphan.     

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.     

Comparative study of the physical dependence on proline analog of dermorphin and morphine

On the model of acute physical dependence, naloxone treatment of animals dependent on D-Pro6 peptide ([D-Pro6]DM) (a demorphin analog) led to tremor, shaking, convulsions, and rare jumps typical of morphine-dependent animals. The variety and intensity of reactions depended on the naloxone dose and the interval between naloxone and peptide injections. In the state of reject syndrome upon peptide and morphine subchronic treatments according to identical schedules, the symptoms in [D-Pro6]DM dependent animals were much less pronounced than in morphine-dependent ones.     

Intravenous self-administration of morphine and cocaine: a comparative study

The aim of the present study was to estimate differences between patterns of morphine and cocaine use in Sprague-Dawley rats. This was done by first developing a set of conditions under which both drugs would be consistently self-administered over time. Subsequently rats were studied in groups of three, with only one rat actively self-administering morphine or cocaine while others two receiving yoked injections of either the drug or saline. With the exception of the 0.056, 0.1, 0.3 and 1.0 mg/kg/inj. training-dose regimens, intravenous (i..v.)self-administration of morphine was acquired at the dose of 0.56 mg/kg/inj. and subsequently maintained by rats. In contrast to morphine self-administration, rats rapidly acquired cocaine self-administration behavior at either the 0.3 or 0.56 injection dose and showed typical inverted U-shaped dose-response curves with maximal responding occurring at the injection dose of 0.3 mg/kg. With the "yoked" pairs of subjects, the rate of responding of the animal actually self-administering the drug was significantly higher than that of a paired animal which passively received injection whenever the first animal self-administered the drug. Thus, both morphine and cocaine served as a positive reinforcer of self-administration behavior under the fixed ratio 5 schedule of reinforcement. However, the 0.56 mg/kg injection dose of morphine resulted in an acquisition curve that was markedly, temporally delayed relative to the injection dose of cocaine. Finally, cocaine maintained higher rates of responding for its delivery than morphine. These differences between self-administration patterns of morphine and cocaine may provide significant information about the nature of drug reinforcement and dependence.     

Effects of beta-funaltrexamine on butorphanol dependence.

The present experiments were performed to investigate the effects of the selective mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on the physical dependence liability of butorphanol (a mixed agonist/antagonist opioid analgesic). Butorphanol (26 nmol/microliter/h) was continuously infused via osmotic minipumps into the lateral cerebral ventricle of male Sprague-Dawley rats for 72 h. beta-FNA (12, 24, and 48 nmol/5 microliter/rat) was administered ICV 3 h prior to and 48 h after initiation of the butorphanol infusion. Treatment with beta-FNA significantly diminished naloxone-induced escape behavior, hypothermia, and loss of body weight in a dose-dependent manner, while naloxone-induced teeth-chattering, forepaw tremors, and urination were also reduced, but in a dose-independent manner. These results suggest that the mu opioid receptor is partially involved in the development of physical dependence upon butorphanol.     

布托啡诺与舒芬太尼在肺叶切除术后镇痛效果的比较

目的比较布托啡诺和舒芬太尼在电视辅助胸腔镜(VATS)下小切口肺叶切除术后患者静脉自控镇痛(PCIA)的效果。方法择期全麻下行VATS肺叶切除术患者75例(22～57岁),ASAⅡ级,随机分成布托啡诺Ⅰ组(BⅠ组)、布托啡诺Ⅱ组(BⅡ组)、舒芬太尼组(S组),每组25例。在手术结束前30min,BⅠ、BⅡ组给予布托啡诺负荷量30μg/kg,S组给予舒芬太尼负荷量0.1μg/kg,术毕BⅠ、BⅡ组分别予布托啡诺3μg·kg-1·h-1,4μg·kg-1·h-1维持PCIA,S组予舒芬太尼0.05μg·kg-1·h-1维持PCIA。观察并记录术后1h、6h、12h、18h、24h、36h、48h的平均动脉压、心率、呼吸频率、脉搏氧饱和度、患者平静时的视觉模拟(VAS)疼痛评分及Ramsay镇静评分,术后12h、24h、36h、48h的恶心评级和呕吐评级。并记录患者术后36h和48h咳嗽时的VAS疼痛评分。结果术后48h内三组患者各观察时点的呼吸循环指标、Ramsay镇静评分、恶心、呕吐评级比较无显著性差异。在术后6～24h各时点,BⅡ组与S组间VAS评分差异无显著性,但BⅡ组和S组VAS评分均低于BⅠ组(P<0.05)。术后36h、48h患者咳嗽时VAS评分,BⅡ组和S组均低于BⅠ组(P<0.05),但BⅡ组与S组间无显著差异。结论VATS手术结束前30min缓慢静注布托啡诺负荷量30μg/kg,术后给予4μg·kg-1·h-1的维持量,与舒芬太尼PCIA同样安全有效。     

The effects of naltrexone on the development of physical dependence on morphine

A single i.p. injection of naltrexone (20 mg/kg) partially inhibited the development of physical dependence upon morphine in mice rendered dependent on morphine by implantation of a pellet containing 75 mg of morphine free base for three days. This was evidenced by an increase in the dose of naloxone (ED50) required to precipitate withdrawal jumping response. The increase in naloxone ED50 was much more pronounced when naltrexone was given prior to and during the course of pellet implantation. Inhibition was also observed when naltrexone was administered one day after the morphine pellet implantation, i.e., after some dependence had already developed. Naltrexone administration prior to and during the development of dependence also inhibited, but only partially, the loss of body weight and hypothermic response observed during abrupt withdrawal of morphine in morphine-dependent mice. The inhibitory effect of naltrexone on morphine dependence development was not associated with changes in brain morphine concentration.     

奥丹西隆对小鼠吗啡身体依赖性的影响

目的　观察 5 HT3受体特异性拮抗剂奥丹西隆 (on dansetron ,Ond)对吗啡身体依赖性的影响。方法　采用小鼠吗啡依赖模型及离体豚鼠回肠吗啡依赖模型。结果　奥丹西隆 12d预防性给药可有效抑制小鼠吗啡戒断反应 ,使其体重降低减小 (Ond 2～ 10 0 μg·kg-1·d-1组 ) ,或体重降低 ,跳跃反应均明显减弱 (Ond 10 0 μg·kg-1·d-1组 )。另外 ,奥丹西隆 (1～ 2 0 μmol·L-1)亦可抑制纳洛酮促发的离体豚鼠回肠收缩。作用均呈剂量依赖性。结论　奥丹西隆预防性的慢性给药可在一定程度上抑制吗啡身体依赖的形成     

Predicting the emetic liability of novel chemical entities: a comparative study

BACKGROUND AND PURPOSE

Emesis is a multi-system reflex, which is usually investigated using in vivo models. The aim of the study is to compare the response induced by emetic compounds across species and investigate whether dogs, ferrets and rats are all similarly predictive of humans.

EXPERIMENTAL APPROACH

A systematic review was carried out and relevant publications were identified from PubMed. The search was restricted to four species (human, dog, ferret, rat) and ten compounds representative of various mechanisms of emesis induction (apomorphine, cisplatin, cholecystokinin octapeptide, copper sulphate, cyclophosphamide, ipecacuanha, lithium chloride, morphine, nicotine, rolipram).

KEY RESULTS

1046 publications were reviewed, and 311 were included, the main reason for exclusion was the lack of quantitative data. Emetic or pica data were extracted as incidence, intensity or latency. All three animal species identified emetic liability but interspecies differences for dose sensitivity were detected.

CONCLUSIONS AND IMPLICATION

These results suggest that emetic liability can be reliably identified in a common laboratory species such as the rat. However, to evaluate the characteristics of the emetic response, no animal species is a universal predictor of emetic liability and the choice of species should be an informed decision based on the type of compound investigated. Limitations relating to the conduct and reporting of emesis studies were identified, the main ones being the lack of comparable outcome measures between human and animal data, and the limited availability of human data in the public domain.