INCREASED NALOXONE POTENCY INDUCED BY PRETREATMENT WITH MORPHINE AND NALBUPHINE IN MICE

1. Both morphine and nalbuphine were effective in suppressing the abdominal constriction response induced by intraperitoneal injection of acetic acid in mice. On a weight to weight basis, nalbuphine was more potent than morphine in this test. However, the effect of nalbuphine was more effectively blocked by naloxone. 2. Pretreatment with morphine 2.0 mg/kg subcutaneously did not alter the antinociceptive effect of either morphine or nalbuphine measured 3 h later. However, naloxone was about 1.4-fold more effective in antagonizing the antinociceptive effect of both drugs in morphine-pretreated mice than in saline-pretreated animals. 3. Pretreatment with nalbuphine (1.0–2.0 mg/kg s.c.) did not alter the antinociceptive effect of either morphine or nalbuphine measured 3 h later, while naloxone was more effective in antagonizing the antinociceptive actions of morphine and nalbuphine. 4. The increases in naloxone potency in antagonizing morphine after nalbuphine pretreatment were not dose-dependent on the amount of nalbuphine in the pretreatment and they were only marginally significant. In addition, these increases were much lower than that induced by morphine pretreatment. 5. On the other hand, the naloxone effectiveness against nalbuphine itself was enhanced to a greater extent than that induced by morphine pretreatment. Furthermore, these increases in naloxone potency showed a dose-dependent relationship to the amount of nalbuphine used in the pretreatment. 6. Based on these results, it was concluded that nalbuphine is an analgesic drug with properties in between those of the full agonist morphine and the partial agonist pentazocine.     

THE EFFECT OF CHLORPROMAZINE PRETREATMENT ON MORPHINE ANALGESIA AND NALOXONE POTENCY IN ADRENALECTOMIZED MICE

Morphine pretreatment (2.0 mg/kg s.c.) induced no overt tolerance to its antinociceptive effect in mice 3 h later, but enhanced the antagonistic potency of naloxone. 2 Pretreatment with chlorpromazine slightly potentiated the antinociceptive effect of morphine measured 3.5 h later. The antagonistic effect of naloxone was also enhanced. 3 The observed effect of chlorpromazine on naloxone potency was augmented when naloxone was administered in the pretreatment regime. 4 The enhanced naloxone potency induced by morphine pretreatment was inhibited by chlorpromazine administered 0.5 h before the morphine pretreatment. 5 Adrenalectomy sensitized the animals to the antinociceptive effect of morphine. However, the naloxone potency was similar to that of the sham-operated controls. 6 Adrenalectomy greatly attenuated the effect of chlorpromazine pretreatment on naloxone potency. However, the effect of combined pretreatment with either chlorpromazine plus naloxone or morphine remained unaffected. 7 These results indicate that the increased naloxone potency after chlorpromazine pretreatment may be partly mediated through an adrenal-linked process. However, it appears that this process is not essential for the development of increased naloxone potency induced by morphine pretreatment and for the interaction between chlorpromazine, naloxone and morphine.     

THE EFFECT OF QUATERNARY NALOXONE ON THE INCREASED NALOXONE POTENCY INDUCED BY MORPHINE

Using the abdominal constriction test in mice it was shown that the antinociceptive effect of morphine was inhibited by naloxone hydrochloride and its quaternary derivative naloxone methylbromide which presumably only acts peripherally. Pretreatment with a single dose of morphine 2.0 mg/kg s.c. did not alter the antinociceptive effect of a second dose of morphine given 3 h later. However, the antagonistic effect of naloxone against morphine was enhanced at this time. The development of increased naloxone potency was inhibited when naloxone hydrochloride was given together with morphine in the pretreatment. A similar inhibitory effect was observed when the quaternary derivative naloxone methylbromide was used instead of naloxone hydrochloride in the pretreatment regime. As there was no difference between the effects of naloxone hydrochloride and naloxone methylbromide in suppressing the development of increased naloxone potency induced by morphine pretreatment, it was concluded that this phenomenon may be mediated mainly through peripheral opiate receptors.     

THE EFFECT OF ADRENALECTOMY ON THE DEVELOPMENT OF MORPHINE TOLERANCE AND PHYSICAL DEPENDENCE IN MICE

A molecular sieve morphine pellet implanted for 24 h induced measurable tolerance and physical dependence in mice. 2 Adrenalectomy sensitized the animals to the antinociceptive effect of morphine. However, the degree of tolerance induced by morphine pellet implantation was not significantly affected. 3 Quantitative assessment of naloxone-precipitated withdrawal symptoms showed that adrenalectomy slightly enhanced the development of physical dependence. 4 These results indicate that adrenalectomy has no effect on the rate of development of morphine tolerance but may be involved in the development of physical dependence.     

甲氧氯普胺对小鼠吗啡身体依赖性的影响

目的·· :观察甲氧氯普胺对吗啡身体依赖性的影响。方法·· :皮下注射盐酸吗啡建立吗啡依赖小鼠模型,以纳洛酮催促戒断症状。分别在建立吗啡依赖模型前或后给予不同剂量的甲氧氯普胺,观察其预防性给药和急性给药产生的影响。结果·· :甲氧氯普胺急性给药(20 -80mg·kg-1,ip)吗啡依赖小鼠跳跃次数显著减少 ,体重下降加剧 ;预防性给药 (5-20mg·kg-1,ip)小鼠跳跃次数减少 ,但无统计学意义 ,体重下降有显著性改善。结论·· :甲氧氯普胺可缓解吗啡依赖小鼠的部分戒断症状,在一定程度上抑制吗啡身体依赖的形成。     

THE EFFECT OF CHLORPROMAZINE PRETREATMENT ON THE NARCOTIC ANTAGONISTIC POTENCY OF NALOXONE IN MICE

Morphine pretreatment (8.0 mg/kg s.c.) induced no overt tolerance to its antinociceptive effect in mice 4 h later, but enhanced the antagonistic potency of naloxone. Pretreatment with chlorpromazine hydrochloride (0.5–2.0 mg/kg s.c.) potentiated the antinociceptive effect of morphine measured 4.5 h later. The antagonistic effect of naloxone was also enhanced. The observed effect of chlorpromazine on naloxone potency was augmented when naloxone hydrochloride 0.2 mg/kg was administered in the pretreatment regime. The enhanced naloxone potency induced by morphine pretreatment was inhibited by chlorpromazine administered 0.5 h before the morphine pretreatment. These results indicate that pretreatment with either morphine or chlorpromazine increased the antagonistic potency of naloxone. However, it appears that these two drugs act by different mechanisms.     

河豚毒素与吗啡联合用药对吗啡依赖性与镇痛耐受作用的影响

目的:研究河豚毒素(tetrodotoxin,TTX)与吗啡联合使用对吗啡依赖性及镇痛耐受作用的影响。方法:采用吗啡依赖性小鼠模型及热板实验,评价单独使用吗啡(2.5 ml.kg-1)以及联合给药(吗啡2.5 mg.kg-1+TTX 0.5μg.kg-1、吗啡2.5 mg.kg-1+TTX 1.0μg.kg-1)对纳洛酮催促戒断症状及镇痛耐受性的影响。结果:联合用药可以抑制吗啡依赖性小鼠戒断后体重的丢失,明显抑制吗啡依赖小鼠纳洛酮催促后的跳跃反应,抑制小鼠热板实验的潜伏期时间的增加。结论:TTX与吗啡联合用药可以抑制吗啡的依赖性与镇痛耐受作用的产生。     

河豚毒素与吗啡联合用药对吗啡依赖性与镇痛耐受作用的影响

目的:研究河豚毒素(tetrodotoxin,TTX)与吗啡联合使用对吗啡依赖性及镇痛耐受作用的影响。方法:采用吗啡依赖性小鼠模型及热板实验,评价单独使用吗啡(2.5 ml.kg-1)以及联合给药(吗啡2.5 mg·kg-1+TTX 0.5μg·kg-1、吗啡2.5 mg·kg-1+TTX 1.0μg·kg-1)对纳洛酮催促戒断症状及镇痛耐受性的影响。结果:联合用药可以抑制吗啡依赖性小鼠戒断后体重的丢失,明显抑制吗啡依赖小鼠纳洛酮催促后的跳跃反应,抑制小鼠热板实验的潜伏期时间的增加。结论:TTX与吗啡联合用药可以抑制吗啡的依赖性与镇痛耐受作用的产生。     

褪黑素的镇痛作用和身体依赖性实验

本文在小鼠上观察褪黑素的镇痛作用和身体依赖性。热板法痛阈测试表明,腹腔注射（ｉｐ）褪黑素可产生显著的镇痛效应,并呈剂量依赖性。小鼠跳跃反应试验表明,在２ｄ内７次皮下注射（ｓｃ）褪黑素或吗啡后,再ｉｐ纳洛酮,吗啡组小鼠出现显著的跳跃反应,而褪黑素组则无;小鼠竖尾反应表明,ｉｐ不同剂量褪黑素,小鼠都未出现竖尾反应。上述结果提示,褪黑素对小鼠无身体依赖性作用,这为其开发研究提供了动物学实验依据     

三氟拉嗪对吗啡镇痛耐受性的翻转作用

目的··:研究三氟拉嗪对吗啡镇痛耐受性的影响。方法··:热板测痛法,测定三氟拉嗪对小鼠热板(55℃)痛阈值(s)的影响;慢性吗啡处理使小鼠对吗啡的镇痛作用产生耐受性 ,观察低剂量三氟拉嗪对吗啡耐受小鼠最大镇痛效率的影响。结果··:(1)三氟拉嗪(2-20mg·kg-1)呈剂量依赖性延长小鼠的热板(55℃)痛阈值(s) ;(2)慢性吗啡处理使6mg·kg-1 吗啡最大镇痛效率降低42.2%(P<0.05),9mg·kg-1 吗啡最大镇痛效率降低9.8%(P>0.05) ;(3)合用低剂量三氟拉嗪(2mg·kg-1)和吗啡(6mg.kg-1)可以使吗啡耐受小鼠的最大镇痛效率提高47.9 %(P<0.01),其最大镇痛效率与单独急性吗啡(6mg·kg-1)处理相同。结论··:三氟拉嗪对小鼠的吗啡镇痛耐受性存在翻转作用     

吗啡依赖对小鼠海马内一氧化氮合酶阳性神经元的影响

目的·· :探讨吗啡依赖对小鼠海马不同亚区一氧化氮合酶(NOS)活性的影响。方法·· :以剂量递增法皮下注射吗啡建立吗啡依赖小鼠模型 ,采用还原型辅酶Ⅱ -黄递酶(NADPH -d)组织化学法显示吗啡依赖组、纳洛酮催促戒断组和正常对照组小鼠海马CA1区、CA3区和齿状回NOS阳性神经元。结果·· :与对照组相比 ,吗啡依赖组和纳洛酮催促戒断组海马CA1区和齿状回NOS阳性神经元的数目均明显减少 (P<0.01) ,纳洛酮催促戒断组更为明显 ,而在CA3区无明显改变。结论·· :吗啡依赖和纳洛酮催促戒断小鼠海马CA1区和齿状回NOS活性降低 ,提示NO合成的能力下降 ,戒断期下降更明显。这些变化可能是吗啡依赖造成学习记忆功能下降的原因之一。     

纳美芬对小鼠吗啡身体依赖性的影响

本文研究盐酸纳美芬对小鼠吗啡身体依赖的拮抗作用。选用连续３ｄ给吗啡成瘾的小鼠用纳洛酮进行催瘾，记录催瘾后小鼠跳跃次数，结果表明，ｓｃ纳美芬０．０５—０．４ｍｇ·ｋｇ－１，能够完全拮抗小鼠对吗啡形成的身体依赖。     

甲氧氯普胺对吗啡依赖性的影响

目的:观察甲氧氯普胺对离体豚鼠回肠吗啡戒断收缩和吗啡精神依赖性的影响。方法:离休豚鼠回肠吗啡戒断收缩实验和吗啡诱导小鼠位置偏爱实验。结果:(1)离休豚鼠回肠吗啡依赖实验显示:250-500μmol·L~(-1)甲氧氯普胺可显著抑制离体豚鼠回肠吗啡依赖的形成和纳洛酮促发的戒断收缩,作用呈剂量依赖性;(2)甲氧氯普胺的剂量大于10(10-40)mg·kg~(-1)(ip),可有效抑制吗啡诱导的小鼠条件性位置偏爱的形成,而其本身并不造成位置厌恶。结论:甲氧氯普胺对吗啡身体依赖的形成、戒断症状以及精神依赖的形成均有一定的抑制作用。     

羟甲芬太尼镇痛效应和毒性的耐受性

羟甲芬太尼(OMF)和吗啡分别sc 1.5μg·kg~(-1)和1.0 mg·kg~(-1)后对小鼠的醋酸扭体反应有很好的抑制作用。以上述剂量间隔12 h重复给药,OMF和吗啡对扭体反应的抑制率随给药次数增加而下降;热板镇痛实验sc OMF 3μg·kg~(-1)吗啡15 mg·kg~(-1),其镇痛阳性率仍随给药次数增加而下降。OMF耐受组和吗啡耐受组交叉给药,各组耐受性仍然存在。这些结果表明OMF和吗啡的镇痛效应都有耐受性,且二者存在交叉耐受。小鼠毒性耐受实验显示OMF的毒性反应亦存在耐受性。     

左旋精氨酸及左旋精氨酸脱羧酶抗血清对吗啡镇痛及耐受的影响

目的:分析左旋精氨酸及左旋精氨酸脱羧酶(L-ADC)对吗啡镇痛及其所致耐受的影响。方法:用家兔制备L-ADC多克隆抗体;以小鼠热辐射甩尾法和小鼠55℃热板测痛模型分析此抗体及左旋精氨酸对吗啡镇痛和耐受的影响。结果:在热辐射甩尾和热板测痛模型中,0.5-50mg·kg~(-1)的左旋精氨酸(sc)不影响吗啡镇痛和耐受(P>0.05)。L-ADC抗血清(脑室注射,1:1000-1:10稀释)能对抗吗啡镇痛作用,在热辐射甩尾和热板测痛模型中,它能使吗啡可能最大镇痛百分率分别从94.3％和80.6％下降到57.7％和42.9％(P<0.01)。吗啡连续处理小鼠3d后形成耐受:在热辐射甩尾和热板测痛模型中,吗啡的可能最大镇痛百分率分别从90.3％和80.3％下降到47.2％和40.5％;L-ADC抗血清能进一步加重吗啡所致耐受,其可能最大镇痛百分率进一步下降至19.8％和27.7％(P<0.01)。结论:L-ADC可能参与调节了吗啡镇痛及耐受形成过程;而左旋精氨酸不影响吗啡镇痛和耐受。     

胍丁胺抗大鼠身体依赖作用与阿片受体的关系

目的··：观察胍丁胺抗大鼠身体依赖作用与阿片受体间的关系。方法··：本文实验采用大鼠身体依赖实验和放射配体结合实验两种方法进行。结果··：胍丁胺虽然能剂量依赖性地抑制纳洛酮催促所引起的吗啡依赖大鼠戒断反应,但对３Ｈ－纳洛酮与大鼠前脑阿片受体结合反应无抑制作用（无直接作用）,亦不能影响当身体依赖发生时阿片受体对配体的亲和力下降和受体数量下调等代偿性适应变化（无间接作用）。结论··：虽然胍丁胺能抑制阿片类药物身体依赖,但对阿片受体既无直接也无间接作用。     

吗啡依赖大鼠和小鼠戒断后应激行为和激素水平的观察

本文观察了吗啡依赖性大鼠和小鼠在纳络酮催促后的行为学表现及其血中三种激素水平的变化。结果显示 ,吗啡依赖性大鼠和小鼠的戒断症状与机体在应激状态下的表现极为相似 ,其应激能力明显强于对照组 ;戒断反应发生后其血清皮质酮、血管紧张素Ⅱ和胰高血糖素水平亦明显高于对照组。本文认为 ,戒断症状的产生可能与阿片类对中枢的长期作用使机体产生了一种反适应性的应激反应有关。     

DISSOCIATION OF INCREASED 5-HYDROXYINDOLEACETIC ACID LEVELS AND PHYSICAL DEPENDENCE: THE EFFECTS OF NALOXONE

1. A slow release emulsion of naloxone (naloxone SR) was administered subcutaneously to rats in an attempt to induce physical dependence of the morphine type. 2. Naltrexone (2.5 mg/kg), injected i.p., failed to elicit an abstinence syndrome in rats treated with 75, 100 or 150 mg/kg naloxone SR for 24, 48, or 72 h. 3. Naloxone SR had no effect on the whole brain levels of noradrenaline, dopamine, homovanillic acid or serotonin. 4. Naloxone SR caused an apparent dose-related increase in the brain levels of 5-hydroxyindoleacetic acid. 5. These results show that while naloxone does not induce physical dependence of the morphine type, it may, like morphine, increase the brain serotonin turnover rate. 6. It is proposed that the increase in brain serotonin turnover rate may not be causally related to physical dependence on morphine-like drugs but may be a property of drugs containing the basic opiate molecular structure.     

纳屈酮对吗啡和海洛因产生依赖的影响

本文观察了纳屈酮对吗啡和海洛因在大、小鼠产生依赖的影响。纳屈酮2.0-4.0mg·kg~(-1)或1.8-3.6mg·kg~(-1)po分别可对抗吗啡和海洛因在小鼠产生身体依赖;1.0-3.0mg·kg~(-1)sc可拮抗吗啡致小鼠条件性位置偏爱的形成。当吗啡诱发小鼠条件性位置偏爱形成后,纳屈酮可加速其消退。提示纳屈酮对小鼠吗啡精神依赖的产生和消退有一定影响。参考上述实验结果和人与动物间剂量折算,我们认为小剂量纳屈酮10-15mg·d~(-1)po防止阿片依赖病人戒毒后复吸是可行的。     

THE POSSIBLE INVOLVEMENT OF ADRENOCEPTORS IN THE INTESTINAL EFFECT OF MORPHINE IN MICE

The inhibitory effect of morphine on intestine was observed by following the intestinal transit of a charcoal meal. This inhibitory effect of morphine was antagonized by naloxone. In addition, the inhibitory effect of morphine was also suppressed by prior administration of yohimbine and phentolamine. However, prazosin, a selective alpha 1-adrenoceptor antagonist, had no effect on the inhibitory effect of morphine on intestinal transit. Furthermore, prior administration of propranolol did not alter this effect of morphine. These adrenoceptor antagonists by themselves, at the doses used, had no effect on the rate of intestinal transit of a charcoal meal in mice. These results suggest that alpha 2-adrenoceptors may be involved in the intestinal effect of morphine while alpha 1- and beta-adrenoceptors do not appear to play any significant role in this aspect of morphine action.