维生素K_3中枢镇痛效应的探讨

经由大鼠、小鼠甩尾及兔甩头法测痛,证实k_3具有剂量依赖的镇痛作用。兔侧脑室微量注射k_3亦有显著镇痛效应。k_3的镇痛作用可被阿片拮抗剂纳络酮所拮抗。实验观察到k_3与吗啡的镇痛效应间存在交叉耐受现象。一定浓度的k_3可抑制电场刺激所致豚鼠回肠纵肌标本的收缩,这一效应亦可被纳络酮部分逆转。小鼠经k_3预处理后对k_3的镇痛产生耐受;连续k_3大剂量预处理后纳络酮激发不产生跳跃。     

维生素K3粉末降解动力学

在温度为50～90℃,相对湿度为50～93%范围内,维生素K₃的变色速率方程为—dR/dt=k_RR,降解速率方程为d(C_o—c)/dt=k_C(c_o—c)^1/2,光解速率方程为—dR/dt=k_P(R_o—R)^-1。k_R和_C与热力学温度T和相对湿度RH的关系通式为k=k′exp(—E_A/RT)exp(m′RH)。在实验温度和湿度范围内,变色和降解的表观活化能平均值分别为105.51和130.72 kJ/mol。     

用流式细胞光度术(FCM)研究争光霉素对肿瘤及正常细胞周期的影响

用流式细胞光度术发现七种争光霉素组分(A₂+B₂混合品,A₂,A₂,A₅,A₆,A₅₀₃₃和B₂)都使中国仓鼠卵巢细胞(CHO)阻断在G₂期,而对G₁→S→G₂的进行无影响。这种G₂期阻断呈剂量依赖性。不同组分的G₂阻断效应不同,在40 μg/ml时,以A₄和A₅最强,其次为A₆,A₂,A₂+B₂混合物和B₂,而A₅₀₃₃无影响。用等毒性剂量,所有组分都使小鼠艾氏腹水癌产生多倍化细胞。由于争光霉素的G₂期阻断效应与抑瘤存在着平行关系,我们认为争光霉素的抑瘤作用与癌细胞被阻断在G₂期有关。     

3-甲基芬太尼衍生物QSAR研究

Hansch途径研究了一系列3-甲基芬太尼衍生物理化性质与镇痛活性间的关系。初步结果表明,镇痛活性与化合物的油/水分配系数之间无规律性变化;与R₂取代基的立体效应(如L,B₁～B₄及MR_R2)和疏水常数(π_R2)间有一定的匹配关系,与R₃取代基的Hammen常数(σ)呈抛物线型。引入1-β羟基亦颇为有利。从作用机理推测,该类衍生物的R₂和可能是与受体相结合的基团,R₁可能仅起药物转运的载体作用,1-β羟基也可能通过氢键参与与受体的互补部位缔合。     

丁基苯酞对原代培养的大鼠皮层神经细胞外液6-keto-PGF1α和TXB2及其比值的影响

目的旨在观察丁基苯酞(NBP)对神经细胞培养液中6-酮-PGF_1α和TXB₂含量及其比值的影响。用放射免疫方法,结果发现神经细胞在低糖低氧5h或低糖低氧5h/恢复糖氧3h条件下,d-,l-和dl-NBP(0.1～100μmol·L^-1)能够剂量依赖性升高细胞外液中的6-酮-PGF_1α含量,降低TXB₂水平,从而使6-酮-PGF_1α与TXB₂比值升高。而阿司匹林仅在小剂量(0.1,1μmol·L^-1)时能升高6-酮 PGF^1α与TXB^{2比值,大剂量(10,100μmol·L-1)时无影响。提示:NBP对6-酮-PGF_1α/TXB₂比值的升高可能与其增加局部脑血流和改善缺血性脑损伤有关。}     

基于JAK-2/STAT3信号通路观察维生素D3对炎症相关性结直肠癌的影响

目的 基于Janus蛋白酪氨酸激酶2（JAK2）/信号转导及转录激活因子3（STAT3）信号通路观察维生素D₃（VitD₃）对炎症相关性结直肠癌（CAC）的影响。方法 取30只雄性昆明小鼠给予葡聚糖硫酸钠（DSS）造模,并随机分为模型组、VitD₃低剂量组、VitD₃高剂量组,另取10只正常小鼠作为对照组。VitD₃低、高剂量组造模过程中分别给予10 IU·g^-1、20 IU·g^-1的VitD₃灌胃,灌胃体积2 mL,连续给药28 d;对照组和模型组均给予等体积花生油。造模第7、14、21、28 d称取小鼠重量;造模结束后,取出结直肠组织,计算成瘤数量;HE染色、ELISA、免疫组化检测小鼠结直肠组织形态、组织匀浆液上清中炎症因子含量及上皮钙黏素（E-cadherin） 和波形蛋白（vimentin） 的表达;RT-qPCR检测H19、let-7a、c-Myc mRNA、HMGA2 mRNA表达;Western blotting检测JAK2/STAT3通路蛋白表达。结果 与对照组相比,模型组小鼠各时间点体重均明显减轻,且有肿瘤生成,结直肠组织中H19、c-Myc mRNA、HMGA2 mRNA表达水平,vimentin蛋白评分及p-JAK2、p-STAT3蛋白表达水平明显上升,let-7a表达水平及E-cadherin蛋白评分明显下降,血清TNF-α、IL-1β、IL-6表达水平明显升高,IL-10表达水平明显下降（P<0.05）;与模型组相比,VitD₃低、高剂量组小鼠各时间点体重均明显升高,肿瘤数量明显减少,结直肠组织中H19、c-Myc mRNA、HMGA2 mRNA表达水平,vimentin蛋白评分及p-JAK2、p-STAT3蛋白表达水平明显下降,let-7a表达水平及E-cadherin蛋白评分明显升高,血清TNF-α、IL-1β、IL-6表达水平明显下降,IL-10表达水平明显升高（P<0.05）,且VitD₃高剂量组变化更为明显。结论 VitD₃可能通过调控JAK2/STAT3信号通路减轻炎症反应,并影响上皮间质转化（EMT）,对CAC小鼠发挥保护作用。     

雷公藤红素对IL-1和IL-2活性及PGE2释放的抑制作用

雷公藤红素0.1～1.0μg/ml在试管内能降低LPS诱导的小鼠腹腔巨噬细胞外和细胞内白细胞介素-1(IL-1)的活性,也能抑制ConA诱导的小鼠脾细胞产生白细胞介素-2(IL-2).动态观察表明,雷公藤红素经预处理8h和3h后已能分别抑制IL-1和IL-2的产生。此外,雷公藤红素能降低A23187刺激家兔滑膜细胞释放前列腺素E₂(PGE₂)。     

多抗甲素抗肿瘤转移作用及其机理

多抗甲素(PAA)在100mg·kg^-1·d^-1剂量下,给药18d,显著抑制B₁₆-F₁₀黑色素瘤人工肺转移,肺转移结节数由137个下降到95个。同位素参入法测定PAA对正常及荷瘤小鼠脾细胞有促增殖作用,并使小鼠脾细胞对PHA刺激的反应性不因荷瘤而降低;PAA且能增强正常及荷瘤小鼠脾脏NK细胞活性,拮抗环磷酰胺对NK细胞活性的抑制作用;PAA体外能不同程度地抑制B₁₆-F₁₀黑色素瘤细胞DNA,RNA和蛋白质合成。放射免疫测定法表明PAA对小鼠血浆TXA₂/PGI₂比值影响较小。PAA抗肿瘤转移作用主要与促进荷瘤机体抗肿瘤免疫反应和直接抑制肿瘤细胞有关。     

三种国产阿片受体拮抗剂催促活性的比较研究

用大鼠和小鼠对三种国产阿片受体拮抗剂-纳络酮、环丙羟丙吗啡、烯丙吗啡的催促作用强度进行了比较，研究结果表明：1．使用剂量逐步递增方式给药，可在短期内使大鼠和小鼠对吗啡、芬太尼、噻芬太尼和强痛定产生快速耐受和身体依赖性；2．三种国产阿片受体拮抗剂的催促作用强度从强到弱依次为：环丙羟丙吗啡，纳络酮，烯丙吗啡，与国外从拮抗镇痛强度方面所报道结果相一致；3．国产环丙羟丙吗啡与纳络酮的催促活性基本相近。     

非普拉宗对环氧酶活性的影响

目的　研究非普拉宗(feprazone, Fep)对环氧酶-1和环氧酶-2活性的影响。 方法　用放免法测定PGE2含量反映环氧酶-2活性,测定6-酮-前列腺素F_1α含量反映环氧酶-1活性。 结果　Fep在0.1,1.0,10.0 μmol.L^-1能剂量依赖性抑制小鼠腹腔巨噬细胞PGE₂生成,在相同浓度下对小牛主动脉内皮细胞6-keto-PGF_1α生成抑制作用较弱。结论　Fep显著抑制PGE₂生成,对PGI₂生成影响较小,提示其对环氧酶-2有较强的抑制作用。     

滇西嘟拉碱甲的镇痛和身体依赖性研究

用扭体法、热板法、光热-甩尾法和甲醛致痛法证实Bul有明显镇痛作用。连续给药9 d,镇痛作用无耐受现象。小鼠跳跃反应试验阴性;Bul对吗啡依赖大鼠或猴的戒断症状,均无替代作用。Bul的镇痛作用不能被纳络酮翻转;利血平可取消Bul的镇痛作用,补充5-HT或5-HTP能翻转利血平取消Bul的镇痛作用。     

利血平与优降宁对动物痛阈和吗啡镇痛作用影响因素探讨

采用三种测痛方法,观察了利血平、优降宁对小鼠、大鼠正常痛阈和吗啡镇痛作用的影响,结果表明:ip利血平2 mg/kg,优降宁100 mg/kg均能明显抑制小鼠扭体反应;ip利血平1 mg/kg能明显提高小鼠热板反应时间,但ip优降宁75 mg/kg无明显影响;ip利血平6 mg/kg,优降宁75 mg/kg对大鼠甩尾反应时间均无明显影响;利血平(小鼠0.5～1.0 mg/kg,大鼠2 mg/kg ip)能明显对抗吗啡镇痛作用;优降宁(小鼠35 mg/kg,大鼠50 mg/kg ip)能明显增强吗啡镇痛作用,并能“逆转”利血平对抗吗啡镇痛作用。其“逆转”作用的强弱取决于利血平、优降宁给药的先后次序。     

利血平与优降宁对动物痛阈和吗啡镇痛作用影响因素探讨

采用三种测痛方法,观察了利血平、优降宁对小鼠、大鼠正常痛阈和吗啡镇痛作用的影响,结果表明:ip利血平2 mg/kg,优降宁100 mg/kg均能明显抑制小鼠扭体反应;ip利血平1 mg/kg能明显提高小鼠热板反应时间,但ip优降宁75 mg/kg无明显影响;ip利血平6 mg/kg,优降宁75 mg/kg对大鼠甩尾反应时间均无明显影响;利血平(小鼠0.5～1.0 mg/kg,大鼠2 mg/kg ip)能明显对抗吗啡镇痛作用;优降宁(小鼠35 mg/kg,大鼠50 mg/kg ip)能明显增强吗啡镇痛作用,并能“逆转”利血平对抗吗啡镇痛作用。其“逆转”作用的强弱取决于利血平、优降宁给药的先后次序。     

Morphine induced changes in ethanol-and water-intake are attenuated by the 5-HT3/4 antagonist tropisetron (ICS 205-930)

The opiate agonist morphine has been shown to increase ethanol intake and mesolimbic dopamine (DA) levels. Conversely, the 5-HT_3/4 antagonist tropisetron has been shown to decrease ethanol intake and morphine-induced increases in mesolimbic DA levels. This study was designed to test the effects of acutely administered tropisetron on morphine-induced changes in ethanol (6% v/v) and water intake in a two-bottle test procedure. Ten water restricted male rats were injected with combinations of morphine (0.0, 0.56, 1.0, 1.5, 10.0, and 17.0 mg/kg, SC) and tropisetron (0.0, 1.0, 10.0, and 17.0 mg/kg, SC) prior to test sessions. Morphine (1.0 and 1.5 mg/kg) significantly increased absolute (g/kg) and relative ethanol intake (ethanol/total fluid). Tropisetron alone did not affect ethanol or water intake. When tropisetron (10.0 and 17.0 mg/kg) was administered in combination with morphine (1.5 mg/kg), the increase in ethanol intake induced by morphine was attenuated. Tropisetron (1.0 mg/kg) reversed a decrease in ethanol intake induced by morphine (17.0 mg/kg). The two highest doses of tropisetron partially attenuated a significant decrease in water intake produced by morphine (17.0 mg/kg). These data suggest that opiate and 5-HT₃ mechanisms could interact in the regulation of ethanol intake. However, the doses of tropisetron tested were high and, therefore, the potential involvement of 5-HT₄ receptors or other neurotransmitter systems in regulating ethanol intake is discussed.     

Reversal of morphine-induced memory impairment in mice by withdrawal in Morris water maze: possible involvement of cholinergic system

The effects of morphine and morphine withdrawal on memory performance were examined in mice by using Morris water maze task. Morphine-induced memory impairment at the doses of 5 and 10 mg/kg recovered after repeated administration. Oxotremorine, a muscarinic receptor agonist, at the dose of 0.1 mg/kg ip, and physostigmine, a cholinesterase inhibitor, at the dose of 0.1 mg/kg ip, significantly antagonized morphine (10 mg/kg sc)-induced memory impairment in mice. Furthermore, repeated naloxone (0.5 mg/kg ip) attenuated scopolamine (0.2 mg/kg ip)-induced memory impairment. By using escalating doses of morphine for 13 days, morphine-induced memory impairment was continuously maintained. When withdrawal was precipitated by naloxone (5 mg/kg ip), or administration of oxotremorine (0.1 and 0.2 mg/kg ip) or physostigmine (0.05 and 0.1 mg/kg ip), the impairment was completely reversed. These results suggest that morphine-induced memory impairment could be partially due to the inhibition of the central cholinergic activity.     

Antagonism of gut,but not central effects of morphine with quaternary narcotic antagonists

Naltrexone methylbromide and naloxone methylbromide, quaternary derivatives of naltrexone and naloxone respectively, are assumed to act peripherally. Both compounds reversed the intestinal stimulating effect of morphine in the dog. Naltrexone methylbromide 5 mg/kg s.c. blocked morphine-induced intestinal spike potentials for 50 min while intravenous doses caused antagonism for only 25 min. The antagonism by the s.c. route approximated that produced by naltrexone 0.2 mg/kg s.c. In morphine-dependent dogs, naltrexone methylbromide did not appear to antagonize morphine centrally in doses ranging from 0.25 to 50 mg/kg s.c. since it did not induce behavioral signs of narcotic withdrawal. Similarly, i.v. naloxone methylbromide was also able to reverse morphine-induced intestinal spike potential in dogs but the protection lasted only 25 min. In rats, naltrexone methylbromide 10 and 30 mg/kg i.p. neither reversed morphine block of PGF_2α-induced diarrhea nor antinociception. This suggests a lack of CNS narcotic antagonism in both tests. In mice, naltrexone methylbromide, 60–720 mg/kg orally and 3–140 mg/kg i.p. failed to block morphine inhibition of prostaglandin F_2α-induced diarrhea. Paradoxically, in this species, 30 mg/kg s.c. of naltrexone methylbromide appeared to cross the blood-brain barrier since this dose reversed morphine-induced antinociception. In conclusion, naltrexone methylbromide effectively antagonizes the acute gut stimulating effect, but not the chronic behavioral effect of morphine administration in dogs. Based upon the antinociception test, naltrexone methylbromide does not cross the blood-brain barrier in rats but may in mice. Morphine inhibits prostaglandin F_2α-induced diarrhea by a central mechanism in rodents.     

Morphine-ethanol interaction on body temperature.

1. The interaction between ethanol and morphine on core temperature was investigated in Swiss Webster mice. 2. Morphine (2.5-30 mg/kg) and ethanol (0.5-3.0 mg/g) administered individually resulted in a dose dependent decrease in body temperature. 3. When both drugs were injected simultaneously, body temperature decreased less than it would be expected to if the effects were additive. 4. Naloxone antagonized the hypothermic effect of morphine, but the hypothermic effect of ethanol and that of the combination of morphine plus ethanol was only reversed with high doses of naloxone (10 mg/kg). 5. Individual morphine and ethanol plasma levels were not significantly altered by their concomitant administration. 6. Binding of tritiated naloxone to opiate receptors in mouse brain membrane preparations was unchanged by pretreatment with ethanol (0.5 and 2 mg/g). 7. The interaction between morphine and ethanol was found to be less than additive and not related to pharmacokinetic changes of either drug.     

Quercetin,a bioflavonoid,reverses development of tolerance and dependence to morphine

Quercetin, a bioflavonoid (25 and 50 mg/kg), when chronically administered for 9 days, failed to produce any significant change in tail flick latency as compared to control mice. However, repeated administration of quercetin (25 and 50 mg/kg) for 9 days attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg). Quercetin (25 and 50 mg/kg) also suppressed naloxone (2 mg/kg)‐precipitated withdrawal jumps on day 10 in morphine‐tolerant mice. Pretreatment of mice with quercetin (10–50, ip) significantly reversed the morphine (5 mg/kg)‐induced delay in gastric transit, whereas a higher dose of quercetin (100 mg/kg) did not have any significant effect on morphine‐induced delay in gastric transit. Quercetin per se had no effect on gastric transit. In conclusion, the results of the present study suggest potential use of quercetin in alleviating the adverse effects of opioid treatment. Drug Dev. Res. 57:167–172, 2002. © 2003 Wiley‐Liss, Inc.     

Studies on the antiinflammatory,immunoregulatory, and analgesic actions of melatonin

In order to develop melatonin (MT) as a potential new drug for the treatment of diseases with inflammation, pain, and abnormal immune responses, the effects and mechanisms of MT on inflammation, immunoregulation, and nociception were studied systematically. MT (40–160 mg/kg, ip) had significant analgesic effects in the hot-plate, writhing, and tail-flick models, with a marked dose- and time-dependence. The onset of its analgesia about 30–60 min after ip, was slower than that of pethidine, but the duration was longer (about 1.5–2 h). The analgesia was also induced by icv MT (0.25 mg/kg) injection. A lower dose of MT (10 mg/kg) could enhance the analgesic effect of pethidine, which was blocked by naloxone (10 mg/kg). MT (100 mg/kg, ip) decreased the content of beta-endorphin in the hypothalamus and pituitary. The analgesia of MT could be attenuated by pretreatment with reserpine (30 mg/kg, ip) or phentolamine (10 mg/kg, ip). CaCl₂ (230 mg/kg) could antagonize the analgesia of MT. EGTA and verapamil had opposite effects to CaCl₂. No tolerance and dependence to MT was found in mice. Further studies showed that MT could enhance the functions of T and B lymphocytes and macrophages in vitro and in adjuvant arthritis, and inhibit the disturbance of immune cells. MT could inhibit the swelling of hindpaw induced by carrageenin and complete Freund's adjuvant. These factors suggest that MT possesses marked antiinflammatory, immunoregulatory, and analgesic effects which may be related to the system of opiate, monoamine, and Ca²⁺ modulation. Drug Dev. Res. 39:167–173. © 1997 Wiley-Liss, Inc.     

Neuropeptide trefoil factor 3 attenuates naloxone-precipitated withdrawal in morphine-dependent mice

Rationale

The persistence of physical dependence and craving in addicts is considered to contribute to relapse. Increasing evidence indicates that neuropeptide systems are associated with several phases of drug addiction, but little is known about whether the neuropeptide trefoil factor affects withdrawal symptoms.

Objectives

This study aims to investigate the potential effects of the neuropeptide trefoil factor 3 (TFF3) on naloxone-precipitated withdrawal symptoms in morphine-dependent mice.

Results

Mice received increasing doses of morphine over 3 days. On day 4, the mice were injected with TFF3 (1.0 mg/kg, i.p.) 30 min after the last dose of morphine. Thirty minutes after TFF3 treatment, naloxone (1 mg/kg, i.p.) was injected, and body weight, jumping behavior, wet-dog shakes, and locomotor activity were assessed 30 min later. Naloxone caused significant weight loss and increased jumping behavior and wet-dog shakes in morphine-dependent mice. TFF3 (1.0 mg/kg) reversed these behavioral symptoms caused by morphine withdrawal, suggesting that TFF3 might ameliorate physical dependence associated with opiate addiction. Furthermore, TFF3 pretreatment significantly reduced morphine withdrawal-induced increases in plasma corticosterone and adrenocorticotropic hormone levels. The glucocorticoid receptor agonist RU486 blocked the behavioral effects of TFF3 on morphine withdrawal symptoms. Finally, Fos expression in the medial prefrontal cortex which was decreased during morphine withdrawal was increased by TFF3 pretreatment.

Conclusion

These findings indicate that TFF3 might be a potential therapeutic candidate for opiate addiction by regulating glucocorticoid secretion and neuronal activation in the prefrontal cortex.