Opiate-like action of methionine-enkephalin in inhibiting morphine abstinence syndrome

Intracerebroventricular administration of methionine-enkephalin or morphine sulfate immediately prior to naloxone administration inhibited the precipitated withdrawal jumping response in mice rendered dependent on morphine by the pellet implantation method. Both methionine-enkephalin and morphine sulfate failed to inhibit withdrawal defecation and rearing behavior. Morphine sulfate was found to be four times as potent as methionine-enkephalin, on molar basis, in inhibiting the abstinence syndrome. These data provide new in vivo pharmacologic evidence for the opiate-like action of methionine-enkephalin.     

二氢埃托啡对吗啡依赖大鼠和猴的实验治疗

二氢埃托啡(DHE)能明显缓解吗啡依赖大鼠和猴用纳洛酮(Nal)催促或停用吗啡后出现的戒断症状,DHE对吗啡依赖猴替代治疗的疗效与美沙酮(Met)相当,经9d替代治疗,Met替代组动物Nal催促后仍出现一定的戒断症状,而DHE替代组动物未见戒断症状.     

Comparative effects of synthetic enkephalinamides and morphine on abstinence responses in morphine-dependent mice

The effects of intracerebroventricular (ICV) administration of two synthetic enkephalinamides, D-Ala²-Met⁵-enkephalinamide and D-Met²-Pro⁵-enkephalinamide, were compared with those of morphine on abstinence responses in morphine dependent mice. Mice were rendered dependent by morphine pellet implantation for three days. When administered six hours after pellet removal, both enkephalinamides and morphine reversed the naloxone-induced abstinence jumping response. On a molar basis, D-Met²-Pro⁵-enkephalinamide was the most potent compound and morphine was the least potent. Thus, substitution of D-Methionine in the two-position and prolineamide in five-position of the naturally occurring enkephalins, methionine- and leucine-enkephalin resulted in potent compound. The enkephalinamides and morphine also prevented hypothermia when injected immediately after or six hours after morphine withdrawal (pellet removal).     

Inhibition of enkephalinase activity attenuates naloxone-precipitated withdrawal symptoms

In this study we examined the effects of the enkephalinase inhibitor, thiorphan, on the naloxone-precipitated withdrawal syndrome in chronic morphine dependent rats. Intracerebroventricular administration of thiorphan (40 micrograms/2 microliter) in morphine dependent rats, inhibited the severity of the naloxone-precipitated abstinential syndrome. Administration of thiorphan (20 micrograms/0.5 microliter) in the periaqueductal grey matter of morphine dependent rats, in addition to explosive motor behaviour and ipsilateral rotation, also significantly suppressed most of the naloxone-precipitated withdrawal symptoms. It is suggested that a decreased biotransformation of endogenous opioid peptides might replace the relative shortage of morphine during withdrawal in opiate addicted subjects and attenuate the abstinence symptoms.     

Matricaria chamomilla extract inhibits both development of morphine dependence and expression of abstinence syndrome in rats

The effect of Matricaria chamomilla (M. chamomilla) on the development of morphine dependence and expression of abstinence was investigated in rats. The frequencies of withdrawal behavioral signs (paw tremor, rearing, teeth chattering, body shakes, ptosis, diarrhea, and urination) and weight loss induced by naloxone challenge were demonstrated in morphine-dependent rats receiving M. chamomilla extract or saline. The withdrawal behavioral manifestations and weight loss were inhibited significantly by chronic co-administration of M. chamomilla extract with morphine. Administration of a single dose of M. chamomilla before the naloxone challenge in morphine-dependent animals abolished the withdrawal behavioral manifestations. The dramatic increase of plasma cAMP induced by naloxone-precipitated abstinence was prevented by chronic co-administration of M. chamomilla extract with morphine. These results suggest that M. chamomilla extract inhibits the development of morphine dependence and expression of abstinence syndrome.     

吗啡依赖、戒断及丁丙诺啡的替代治疗对大鼠垂体POMC基因表达的影响

目的··:结合戒断体征的观察从分子水平研究吗啡依赖和戒断机理及丁丙诺啡对吗啡戒断的影响。方法··:观察吗啡戒断及经丁丙诺啡治疗大鼠的戒断体征 ;利用核酸分子杂交技术研究其垂体阿黑皮源(POMC)基因表达的变化。结果··:丁丙诺啡能有效减轻或消除戒断体征,吗啡依赖及戒断时大鼠垂体POMC -mRNA含量下降,丁丙诺啡对其影响不大。结论··:吗啡依赖和戒断抑制大鼠垂体POMC基因表达,丁丙诺啡能纠正吗啡躯体依赖,但从基因水平看丁丙诺啡可能也具有依赖潜能     

Assessment of precipitated abstinence in morphine- dependent rats

An experimental model is described for quantifying the precipitated abstinence syndrome in morphine-dependent rats. Male rats were made dependent on morphine by subcutaneous implantation of a morphine pellet and the abstinence syndrome precipitated by intraperitoneal injection of naloxone hydrochloride. A ranking system, based on the median effective dose of naloxone for abstinence signs, quantitatively related the incidence of certain precipitated signs to the dose of naloxone. The time course for the development of dependence was shown to be maximal 70–74 h after pellet implantation. Food or water deprivation for 48 h dissociated the body weight loss during abstinence from the behavioral signs of precipitated withdrawal. Ganglionic blockade did not significantly modify abstinence behavior. An evaluative procedure which ranks abstinence signs is proposed for quantifying physical dependence on morphine.     

Influence of Plasma-protein Binding on Analgesic Effect of Methadone in Rats with Spontaneous Withdrawal

The effect of spontaneous withdrawal on α₁-acid glycoprotein (AAG) levels and methadone protein binding has been studied in the rat. Animals were made physically dependent on morphine by providing morphine HCl in drinking water for three weeks. The natural opiate withdrawal was induced in rats by substituting the morphine solution with drinking water. The severity of the abstinence syndrome was assessed at various time intervals. After 12 h of withdrawal, the animals showing abstinence signs and low morphine levels were injected with intravenous methadone (0.35 mg kg^?1) and the analgesic effect was measured by the tail-flick method and compared with animals receiving water. The oral administration of morphine produced an increase in AAG levels from 0.64 ± 005 g L^?1 in control animals to 1.47 ± 0.92 g L^?1 in experimental animals at the point of withdrawal and 1.21 ± 009 g L^?1 24 h after withdrawal. The percentage of methadone unbound was significantly lower in morphine-treated than in control animals. A significant correlation between AAG levels and percentage of methadone bound was observed. A parallel analgesic effect after intravenous methadone, as measured by AUC in the tail-flick test, was less in abstinence animals than in control (287.6 ± 24.8 compared with 401.0 ± 37.06 s min). We suggest that in the withdrawal syndrome an adjustment of methadone dose may be necessary because of changes in protein binding.     

Effect of selective monoamine oxidase inhibitor drugs on morphine tolerance and physical dependence in mice

Clorgyline and Lilly 51641, given at dose levels that inhibited selectively brain type A monoamine oxidase (MAO), significantly lowered the incidence of stereotyped jumping produced by naloxone in mice rendered dependent on morphine by subcutaneous implantation of a pellet of the drug. In contrast, selective inhibition of brain type B MAO by deprenyl or pargyline, or nonspecific inhibition of both type A and type B MAO by high doses of Lilly 51641 or pargyline did not modify the abstinence syndrome. Tolerance to the analgesic effect of morphine was unchanged regardless of the enzyme form blocked. The attenuation of withdrawal jumping by low doses of clorgyline or Lilly 51641 does not seem related to changes in brain dopamine. which was found to be deaminated by both enzyme types. The results suggest the possible implication of different and interrelated neurochemical systems in the development of morphine dependence in mice.     

Morphine-like physical dependence: a pharmacologic method for drug assessment using the rat

Rats maintained on various dosage regimens of morphine showed dose related taste aversions to a saccharin solution offered to them upon withdrawal from the drug. Maximal saccharin aversions occurred between 72 and 96 hr after termination of morphine injections, and gradually returned to baseline preference levels after 14 days of morphine abstinence. The results were interpreted as suggesting that the morphine treated animals associated the aversive components of the morphine withdrawal syndrome with saccharin consumption, and manifested conditioned aversions to the saccharin solution which extinguished as the withdrawal syndrome subsided. The findings were further discussed with regard to the potential use of conditioned taste aversions in determining whether test compounds are capable of causing physical dependence in rats.     

Comparison of peripheral and central administration of naloxone in precipitating abstinence in morphine-dependent rats

Although it has been known that a morphine abstinence syndrome can be induced by naloxone administered centrally or peripherally, data on a detailed qualitative and quantitative comparison are not available. In the present study morphine pellets were implanted into rats and naloxone was administered intracerebroventricularly (i.c.v.) or subcutaneously (s.c.) 72 h later. A full array of abstinence signs with similar latency, duration, and intensity was seen in morphine-dependent rats following naloxone by either route. There were no major differences in the spectrum of withdrawal signs or in the proportion of rats showing the individual signs. In terms of body weight and temperature, the highest doses tested by each route produced similar quantitative effects. Our results demonstrate that naloxone given i.c.v. can precipitate the full morphine abstinence syndrome in rats at about 1/3 the dose needed for comparable effects when the antagonist is administered s.c.     

Action of 5-hydroxytryptamine on electrical activity of Auerbach's plexus in the ileum of the morphine dependent guinea pig

Guine pigs were made dependent to morphine by a daily s.c. injection of morphine hydrochloride. Half of them were given morphine hydrochloride (50 mg/kg) s.c. 30 min befor sacrifice; these animals were termed ‘morphine-treated’ guinea pigs. The animals in the abstinence syndrome were sacrificed 30 to 40 hr after the last morphine dose. Effective concentrations of 5-hydroxytryptmine on Auerbach's plexus of the guinea pig in the abstinence syndrome was significantly smaller than those on Auerbach's plexus of normal and morphine-treated animals, while the responses to nicotine and caerulein were unchanged. The results suggest that withdrawal of morphine excites the M-receptors in Auerbach's plexus.     

盐酸二氢埃托啡依赖性潜力的进一步探讨

盐酸二氢埃托啡(DHE)是一种新的强效麻醉性镇痛药,本文着重对DHE在啮齿类动物Do及舌下给药条件下的自然戒断,替代吗啡,催促戒断等方面的致依赖性潜力进行了研究,结果表明,DHE的致身体依赖性潜力确实较低;以DHE替代吗啡抑制阿片类戒断症状时舌下给药剂量低于po给药剂量;在一定剂量条件下DHE舌下给药可使实验动物对其产生身体依赖性。     

氯胺酮对大鼠吗啡戒断症状的影响及其作用机理

目的　研究氯胺酮对大鼠吗啡戒断症状的影响及其可能的机理。方法　建立大鼠吗啡依赖模型 ,在用纳洛酮催瘾前 2min给予不同剂量的氯胺酮 ,观察其戒断症状的改变 ;用分光光度法测定戒断时大鼠一氧化氮 (NO)含量、一氧化氮合酶 (NOS)活性 ,用放射免疫法测定环鸟苷酸 (cGMP)含量。结果　 3个剂量的氯胺酮 (5、10和 2 0mg·kg- 1)均可缓解吗啡戒断时探究、扭体、湿狗样抖动、跳跃等运动反应 ,减少活动次数 ,抑制植物神经系统症状。10、2 0mg·kg- 1氯胺酮可显著减轻吗啡戒断所致的体重下降 ,小剂量氯胺酮 (5mg·kg- 1)可抑制吗啡依赖大鼠前额叶皮质、小脑的NOS活性和NO、cGMP含量的增高。结论　氯胺酮可缓解大鼠吗啡戒断症状 ,其作用机理可能与减弱大鼠吗啡戒断时NMDA NO cGMP通路效应有关。     

Radioimmunoassay of enkephalins

Summary Using highly sensitive and highly specific antisera methionine- and leucine-enkephalin levels were determined in various areas of the rat brain. The highest content of both enkephalins was found in the striatum and the hypothalamus, whereas in the hippocampus, the cerebellum and the cortex only a low content was present. The ratio methionine-enkephalin/leucine-enkephalin was about three. Neither acute or chronic morphine treatment nor precipitated morphine withdrawal induced significant changes in enkephalin levels in any brain region. Also hypophysectomy did not affect the enkephalin content of the various brain regions.     

The effects of thyrotropin-releasing hormone on the central nervous system responses to chronic morphine administration

The effects of thyrotropin-releasing hormone (TRH) on abrupt and naloxone-precipitated abstinece symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by SC implantation of morphine pellets. Intracerebral (IC) administration of TRH inhibited the hypothermic response observed during abrupt (removal of morphine pellets) and naloxone (0.1 mg/kg SC) precipitated withdrawal. IC injection of TRH also inhibited the naloxoneprecipitated withdrawal jumping response as evidenced by increases in the dose of naloxone required to elicit the response. The effects of TRH on the development of morphine dependence were also investigated. A single SC injection of TRH (4–16 mg/kg) did not modify development of morphine dependence. Administration of TRH prior to and during morphine pellet implantation inhibited the development of dependence as evidenced by inhibition in the development of abrupt and naloxone-induced withdrawal hypothermia. Even though the hypothermic response was blocked, multiple SC administration of TRH failed to modify naloxone-induced stereotyped jumping response. These studies indicate that TRH administration can modify central nervous system responses to chronic morphine treatment and that separate sites may initiate withdrawal jumping behavior and affect temperature regulation during abrupt and antagonist-induced abstinence.This work was presented in part at the International Narcotic Research Conference, North Falmouth, Massachusetts, June 10–15, 1979     

Comparison of simultaneous administration of lithium with L-NAME or L-arginine on morphine withdrawal syndrome in mice

Due to the claim that chronic administration of lithium or L-N(G)-nitroarginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor reduces morphine withdrawal syndrome, the effects of chronic administration of lithium, L-NAME, or L-arginine (L-Arg), a precursor of NO, alone or co-administration of lithium with L-Arg or L-NAME, on naloxone-precipitated withdrawal syndrome and physical dependence development to morphine in mice chronically treated with morphine, were evaluated. Morphine dependency was induced by the intraperitoneal injection (i.p.) of morphine (10 mg/kg), once daily for 7 days. Physical dependence to morphine was observed by precipitating an abstinence syndrome with naloxone (2 mg/kg, i.p.). Chronic administration of L-NAME (10 mg/kg, i.p., once daily, for 7 days after 10 days of receiving only tap water and food prior to naloxone), decreased all withdrawal signs significantly, while L-Arg (200 mg/kg, as above) increased only some withdrawal signs significantly in morphine-dependent mice. Chronic administration of lithium (600 mg/kg, in drinking water) alone or co-administration of lithium (as above) with L-NAME (10 mg/kg) or L-Arg (200 mg/kg, i.p., once daily) for 7 days after 10 days of receiving only lithium (as above) and food, decreased all withdrawal signs and physical dependence significantly in morphine-dependent mice. The results obtained indicate that co-administration of L-NAME with lithium increases the effect of lithium or L-NAME alone, on withdrawal signs, but this increase is not significantly different as compared to chronic lithium or L-NAME administration alone; while co-administration of L-Arg with lithium decreases the effects of lithium on withdrawal signs and this decrease is not significant as compared to chronic lithium administration alone. These findings indicate that nitric oxide may be involved in modulation of naloxone-induced withdrawal syndrome, and treatment with lithium could have some effect on this system. Copyright 2000 John Wiley & Sons, Ltd.     

Time course of the effects of naturally occurring cannabinoids on morphine abstinence syndrome

The effects of a single intraperitoneal injection (10 mg/kg) of delta9-tetrahydrocannabinol, delta8-tetrahydrocannabinol and 11-hydroxy-delta8-tetrahydrocannabinol on abstinence syndrome were investigated in mice rendered dependent on morphine by pellet implantation. In morphine dependent mice from which the pellets had been removed, delta9-tetrahydrocannabinol inhibited the naloxone-precipitated jumping response as evidenced by an increase in the ED50 of naloxone. This inhibition was evident for 24 hr, the most pronounced effect being produced between two to four hr after delta9-tetrahydrocannabinol administration. Withdrawal defecation was also inhibited for two hours. Similarly, in mice from which pellets were not removed, delta9-tetrahydrocannabinol suppressed the jumping response; however, the intensity of effect was less than when the pellets were removed. delta8-tetrahydrocannabinol and 11-hydroxy-delta8-tetrahydrocannabinol were not effective in suppressing morphine abstinence syndrome two hr following their administration. The suppression of jumping response was specific, since, the vertical jumping behavior induced by coadministration of amphetamine and l-dopa was not affected by cannabinoids. These results demonstrate that single injection of delta9-tetrahydrocannabinol is effective in controlling morphine abstinence syndrome for 24 hr, and that the drugs related to cannabinoids may show promise in narcotic detoxification.     

Modulation of src-kinase attenuates naloxone-precipitated opioid withdrawal syndrome in mice

This study was designed to investigate the effect of 2,3-dihydro-N, N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide (SU-6656), a selective inhibitor of src family kinase, on the development of naloxone-induced opioid withdrawal syndrome in mice. Subacute morphine administration followed by a single injection of naloxone (8 mg/kg, intraperitoneally) was used to precipitate the opioid withdrawal syndrome in mice. Behavioral observations were made immediately after naloxone treatment. The withdrawal syndrome was quantitatively assessed in terms of withdrawal severity score and frequency of jumping, rearing, forepaw licking, and circling. Daily single administration of SU-6656 was continued during the morphine treatment procedure. Injection of naloxone precipitated severe withdrawal in morphine-dependent mice. However, once-daily administration of SU-6656 (1.5, 3, and 6 mg/kg, intraperitoneally) markedly and dose-dependently attenuated the naloxone-induced morphine withdrawal syndrome. Therefore, it seems that an src family-kinase-linked mechanism is involved in the development of physiological opioid dependence; thus, src family kinase may serve as a potential target to address the pathological condition of physiological dependence and abstinence associated with continuous opioid usage.     

Three different types of alpha-interferons alter naloxone-induced abstinence in morphine-addicted rats

The opiate abstinence syndrome represents a fundamental feature of the addictive process, with the degree of addiction being directly correlated to the intensity of withdrawal. Therefore, the discovery of substances capable of attenuating withdrawal signs may provide insights into the dynamics of opiate addiction. The present study demonstrates that three different types of alpha-interferons modify the behavioral signs associated with naloxone-induced abstinence in rats addicted to morphine. These observations suggest that opiate addiction may, in part, be due to an immune response in that immunomodulators (interferon) are capable of altering the naloxone-induced abstinence syndrome in morphine-dependent rats.