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.     

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.     

PRELIMINARY STUDIES ON INCREASED NALOXONE POTENCY AND ITS RELATIONSHIP TO MORPHINE TOLERANCE AND DEPENDENCE IN MICE

1. 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. 2. A molecular sieve morphine pellet implanted for 24 h induced measurable tolerance, but the relative potency of naloxone was not significantly different from that observed after single-dose morphine pretreatment. The development of tolerance and increased naloxone potency do not, therefore, run parallel. 3. Naloxone-precipitated withdrawal symptoms were observed after single-dose morphine and after pellet implantation. However, molecular sieve morphine pellet implantation induced a higher degree of dependence as compared with single dose morphine pretreatment. 4. These results indicate that the rate of development of increased naloxone potency and of morphine tolerance and dependence do not run parallel. This implies that caution must be exercised in regarding increased naloxone potency as a sensitive indicator of the initiation and development of tolerance and dependence to morphine.     

SHORT COMMUNICATION: EFFECT OF OESTRADIOL REPLACEMENT ON SWIM-INDUCED ANTINOCICEPTION IN OVARIECTOMIZED MICE

1. A 30 s swim in water at 30 degrees C reduced the number of abdominal constrictions produced in female mice by intraperitoneally administered acetic acid and this antinociceptive effect was antagonized by naloxone. 2. Oophorectomy abolished the development of antinociceptive activity in response to swim. 3. The development of antinociceptive activity and naloxone antagonism were restored in oophorectomized mice maintained on daily oestradiol injection. 4. The present study indicates that the increase in abdominal constriction response to acetic acid in oophorectomized mice was due to the removal of the source of female sex hormone.     

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.     

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.     

地高辛对吗啡戒断大鼠去甲肾上腺素能神经活动的影响

目的:探讨地高辛对吗啡戒断大鼠体内去甲肾上腺素能神经活动的影响。方法:按剂量递增法建立大鼠吗啡依赖模型,给予地高辛(0.05-0.2 mg.kg-1,ig)或等体积溶媒1 h后用纳洛酮催促戒断,参考文献方法对大鼠30 min内戒断症状进行评分。处死大鼠,分离左、右心室和下丘脑,采用酶联免疫吸附法检测去甲肾上腺素(NE)和间羟去甲肾上腺素(NMN)的含量并计算其比率(NMN/NE)。结果:地高辛剂量依赖地减弱纳洛酮催促的大鼠吗啡戒断症状(F=5.264,P<0.01),其中,0.2 mg.kg-1和0.1 mg.kg-1地高辛表现出明显的统计学差异(P<0.01,P<0.05);大剂量地高辛(0.2 mg.kg-1)能明显抑制NMN以及NMN/NE值的升高(P<0.05,P<0.05)。结论:地高辛能够缓解大鼠吗啡戒断症状,其机制可能与抑制去甲肾上腺素能神经活动有关。     

THE EFFECT OF CORTICOSTEROID PRETREATMENT IN VIVO ON THE CONTRACTION OF GUINEA-PIG ILEUM AND DUODENUM

The effects of corticosteroid pretreatment on the contraction caused by acetylcholine or electrical stimulation of guinea-pig ileum and duodenum were studied. The acetylcholine dose-response curves for steroid pretreated ileum but not duodenum were significantly shifted to the right; evidence that pretreated ileum required higher dose of acetylcholine than normal to cause 50% maximal contraction. Naloxone enhanced the contraction of normal ileum caused by acetylcholine given at the dose of ED50, but not that of normal duodenum. The dose of morphine required to abolish electrically induced contraction was higher in steroid pretreated ileum than in normal ileum. Hence, corticosteroid pretreatment may affect intestinal contractility via opioidergic mechanisms which are found in the ileum but not in the duodenum.     

扶正康冲剂对吗啡依赖大小鼠的治疗作用

目的:观察及评价中药制剂扶正康对吗啡依赖大小鼠戒断症状的治疗作用。方法··:以剂量递增法形成吗啡依赖大、小鼠模型 ,ip纳洛酮进行催促或自然戒断后 ,记录成瘾动物的戒断症状及体重变化 ,所得数据经统计学处理后进行评价。然后分6组给予不同的处理。结果··:扶正康中、高2个剂量组可明显降低成瘾大鼠纳洛酮催促戒断及自然戒断反应的总分值。扶正康3个剂量组均能减少成瘾小鼠的跳跃反应次数 ,对吗啡依赖大、小鼠的体重下降有不同程度的缓解作用。扶正康高剂量组的作用与阳性对照药可乐定相似 ,但可乐定对实验动物的体重下降无明显影响。结论··:扶正康对吗啡依赖大、小鼠的戒断症状具有明显的抑制作用 ,对成瘾动物的体重下降具有显著的缓解作用。     

THE EFFECT OF NALOXONE ON PRESSOR RESPONSES TO ANGIOTENSIN II IN ANAESTHETIZED GREYHOUNDS

In greyhounds anaesthetized with morphine and chloralose, vertebral artery infusions of angiotensin II resulted in a similar pressor response but smaller tachycardia than in greyhounds anaesthetized with chloralose alone. The pressor responses to intravenous infusions of angiotensin II were significantly larger in the morphine premedicated greyhounds. In greyhounds anaesthetized with morphine and chloralose, pressor responses to vertebral artery angiotensin II were potentiated following the administration of naloxone via either a vertebral artery or intravenously although the effect was more consistent with the former route. No such effect was seen in greyhounds anaesthetized with chloralose alone. Naloxone had no effect on the pressor responses to intravenous angiotensin II or carotid artery occlusion. The heart rate responses to vertebral artery angiotensin II in greyhounds anaesthetized with morphine and chloralose were potentiated by naloxone such that they were not significantly different from the responses obtained in greyhounds anaesthetized with chloralose alone before naloxone. As was observed with the pressor responses, the potentiation was more apparent with the vertebral artery route of administration of naloxone. There was no potentiation of the heart rate responses in the chloralose group of greyhounds. It is suggested that morphine premedication may repress the vagal withdrawal mechanism while potentiating the sympathetic vasomotor mechanism mediating the central cardiovascular actions of angiotensin II.     

SEX DIFFERENCES AND THE EFFECT OF GONADECTOMY ON MORPHINE-INDUCED ANTINOCICEPTION AND DEPENDENCE IN RATS AND MICE

1. Differences between sexes and the effect of bilateral surgical gonadectomy on the response to morphine analgesia and dependence were examined in rats and mice. 2. The analgesic response to morphine (5 mg/kg) was assessed by the hot plate and the abdominal constriction tests. Dependence was induced by injecting morphine at increasing doses (5–160 mg/kg) for 6 consecutive days and withdrawal signs elicited by injecting naloxone (2.5 mg/kg). 3. The base line reaction times in the intact control, shamoperated and gonadectomized animals of either sex were not significantly different from each other. 4. After treatment with morphine, the percentage increase in the reaction time in gonadectomized male and female rats and in gonadectomized male mice was significantly higher than in their respective controls. 5. The increase in the reaction time, after morphine treatment, was significantly higher in gonadectomized female rats than in gonadectomized male rats. 6. Naloxone-induced withdrawal signs in morphine-dependent gonadectomized rats and mice were not significantly different from those in sham-operated controls. However, female rats in both groups exhibited a significantly higher number of escape jumping responses than males.     

FURTHER STUDIES ON THE EFFECT OF ADENOSINE CYCLIC MONOPHOSPHATE DERIVATIVES ON CELL PROLIFERATION IN THE JEJUNAL CRYPTS OF RAT

1. Cell proliferation in the jejunal crypt epithelium of rat was measured using a stathmokinetic technique. 2. Sodium butyrate was found to promote jejunal crypt cell proliferation. 3. N6, O2'-Dibutyryl cyclic adenosine monophosphate (cAMP), N6-monobutyryl-cAMP and N6-monobutyryl-8-bromo-cAMP were found to inhibit cell proliferation when compared to sodium butyrate treated tissues. 4. 8-Chlorophenylthio-cAMP was found to inhibit cell division when compared to untreated animals. 5. O2'-Monobutyryl cAMP and 8-bromo-cAMP were not found to inhibit cell proliferation.     

THE EFFECT OF SODIUM INTAKE ON BLOOD PRESSURE RELATED TO THE AGE OF THE PATIENTS

Sodium intake was varied in 182 normotensive volunteers. 2. Systolic blood pressure rose by 3.3 (s.e.m. =0.9) mmHg supine, 2.8 (s.e.m. = 0.7) mmHg erect. 3. Diastolic blood pressure rose by 2.7 (s.e.m. =0.8) mmHg supine, 2.6 (s.e.m. = 0.8) mmHg erect. 4. In people over 50 y the rise was 12.4/8.1 mmHg (supine) and 9.1/7.1 mmHg (erect). 5. Blood pressure rose as sodium intake increased. Most of the rise was in the older patients but about 25% of younger patients were sensitive to sodium.     

NALOXONE DOES NOT REVERSE ETHANOL ANALGESIA IN MAN

The effects of intravenously administered ethanol and morphine on pain threshold, reaction time, motor skills and short-term memory were investigated, and the ability of naloxone to reverse any changes was studied. Morphine (loading dose 0.2 mg/kg with an infusion of 0.004 mg/kg per min) and ethanol (loading dose 0.75 ml/kg with an infusion of 0.0025 ml/kg per min) produced a similar increase in pain threshold of 6.3 (s.e.m. = 1.5, n = 8) pain units and 7.7 (s.e.m. = 1.9, n = 8) pain units, respectively. Naloxone 0.015 mg/kg produced a significant reduction in pain threshold in the morphine group, but not in the ethanol group, and there was a significant difference between the groups following naloxone (P less than 0.05, t-test, 7 d.f.). Ethanol produced a significantly greater deterioration in motor skills than did morphine (P less than 0.05, t-test, 7 d.f.) and performance in both groups was improved following naloxone (P less than 0.05, t-test, 7 d.f.). There was no significant change in the other modalities studied. It is concluded that the reversal of ethanol effects by naloxone is probably due to a non-specific analeptic action rather than blockade of opioid receptors.     

粉防己碱对小鼠吗啡戒断症状的影响

目的··：研究中药成分的钙拮抗剂粉防己碱（Ｔｅｔ）对小白鼠吗啡戒断症状的影响。方法··：以剂量递增法形成吗啡依赖模型,用纳洛酮催促戒断。结果··：ｓｃ给药,Ｔｅｔ１０ｍｇ·ｋｇ－１抑制“湿狗”样抖动、腹泻、前爪震颤症状;Ｔｅｔ３０ｍｇ·ｋｇ－１抑制打洞、上睑下垂、前爪震颤、体重下降等症状;Ｔｅｔ６０ｍｇ·ｋｇ－１抑制“湿狗”样抖动、打洞、腹泻、前爪震颤、体重下降等症状。３个剂量组的Ｔｅｔ都不影响小鼠的跳跃反应。结论··：Ｔｅｔ能抑制大部分吗啡戒断症状。     

EFFECTS OF MORPHINE ON BRAIN HISTAMINE, ANTINOCICEPTION AND ACTIVITY IN MICE

1. The effect of morphine on the histamine content of the mouse brain has been investigated. The changes in the brain histamine level have been related to morphine-induced analgesia and morphine-induced changes in locomotor activity. 2. With doses of morphine between 1 and 5 mg/kg there was a significant increase in histamine levels. The time required to produce a maximal rise in the brain histamine level with 5 mg/kg of morphine was 15 min. 3. There was a significant decrease in brain histamine levels with doses of morphine between 7.5 and 100 mg/kg. The time at which the greatest decrease was produced with 50 mg/kg was 30 min. 4. The time course of the alteration of brain histamine by morphine did not correlate with its antinociceptive activity. Both the 5 and 50 mg/kg doses of morphine produced analgesia in mice whereas brain histamine levels were increased and decreased, respectively. 5. Pretreating mice with compounds which modify histaminergic function did not modify the antinociceptive action of morphine. 6. Morphine produced a biphasic effect on locomotor activity when the dose was increased from 0.5 through to 100 mg/kg. Doses up to 2.5 mg/kg caused a reduction of activity and doses above this produced significant increases. 7. There appears to be an inverse relationship between the morphine-induced changes of brain histamine and the morphine-induced changes in locomotor activity.     

川芎嗪对吗啡依赖大鼠戒断综合征的抑制作用

目的··:观察川芎嗪对吗啡依赖大鼠戒断综合征的影响。方法··:采用剂量递增方式皮下注射吗啡5d的大鼠,经过川芎嗪处理30min后,用纳洛酮催促,在停用吗啡后不同时间里观察评定戒断症状分值。结果··:川芎嗪明显减轻戒断症状和体重下降。结论··:川芎嗪能明显抑制吗啡依赖大鼠的戒断反应,其作用机制可能与阻断细胞钙内流有关。     

新合成的生长抑素SOMa对吗啡依赖大鼠的影响

目的 :研究自行设计、合成的生长抑素类似物 (SOMa)对吗啡依赖大鼠的影响。方法 :建立大鼠吗啡依赖模型和SOMa模型 ;观察SOMa对大鼠吗啡依赖和吗啡依赖大鼠纳洛酮催促戒断症状的影响及SOMa自身的躯体依赖性。结果 :SOMa能明显降低吗啡依赖大鼠纳洛酮催促戒断症状 ,减轻甚至阻断大鼠吗啡依赖形成 ;大鼠连续使用SOMa 2 1d后纳洛酮催促戒断 ,无明显戒断症状发生。结论 :SOMa具有明显的抑制纳洛酮催促的吗啡依赖戒断反应 ,可降低大鼠对吗啡的依赖性 ;SOMa不产生躯体依赖性。SOMa可作为生物源性的有效脱毒药物进一步研究。     

BUPRENORPHINE AND GASTROINTESTINAL TRANSIT IN RATS: EFFECT OF NALOXONE ON THE BIPHASIC DOSE-RESPONSE CURVE

1. Buprenorphine (0.01-10 mg/kg, subcutaneous [s.c.]) slowed the passage of a charcoal meal along the gastrointestinal tract in rats. The dose-response relationship was U-shaped. 2. When rats were pretreated with naloxone (0.30 mg/kg, s.c.), both the descending and ascending components of the buprenorphine dose-response curve were displaced to the right. 3. Buprenorphine-induced delay of transit was maximal at a dose of 0.10 mg/kg. In rats pretreated with naloxone, a 30-fold higher dose of buprenorphine was required for a comparable peak effect. 4. Moderate-high doses of buprenorphine may be acting on a functionally related binding site which non-competitively inhibits the usual buprenorphine-mu opioid receptor interaction.