不同药物对眼镜蛇神经毒素镇痛效应的影响

用电尾嘶叫法测量大鼠病阈。给大鼠侧脑室注射相当于1/10im有效量的眼镜蛇神经毒素(NT)可明显提高大鼠痛阈。利血平5mg/kg,ip并不影响NT的镇痛作用。纳洛酮3mg/kg,ip仅能轻度降低NT的镇痛作用。阿托品1mg/kg,im却能完全拮抗NT的镇痛效应。在对吗啡急性耐受的大鼠上,NT仍能产生明显的镇痛效应。结果提示,NT的镇痛部位可能位于中枢神经系统内。其镇痛机理可能涉及中枢的乙酰胆碱能系统。     

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。     

乳铁蛋白在大鼠坐骨神经慢性束缚损伤模型产生镇痛作用

目的:研究乳铁蛋白在大鼠坐骨神经慢性束缚损伤模型的镇痛作用。方法:30只成年SD大鼠被制作为坐骨神经慢性束缚损伤模型,用辐射热刺激法诱发鼠后腿回缩试验测定痛阈,实验动物分为5组,分别腹腔注射生理盐水及乳铁蛋白30mg/kg、100mg/kg、300mg/kg、1000mg/kg。药物效应以最大可能效应百分数(MPE%)表示。以t检验法分析乳铁蛋白各剂量组与对照组之间的差异。结果:腹腔注射乳铁蛋白剂量依赖性地延长大鼠后腿回缩潜伏期;乳铁蛋白的峰值作用时间在用药后60分钟;乳铁蛋白各剂量组的最大可能效应百分数与生理盐水组相比差异有显著性。结论:腹腔注射乳铁蛋白在大鼠坐骨神经慢性束缚损伤模型产生剂量依赖性镇痛作用。     

吲哚拉明和延胡索镇痛作用的比较医学实验研究

目的研究α受体颉颃剂吲哚拉明的镇痛作用。方法先建立小鼠神经痛模型,再用热板法测定小鼠缩爪反应潜伏期,观察注射吲哚拉明后小鼠痛阈值的变化。然后还观察了腹腔注射冰醋酸引起的内脏痛在注射了吲哚拉明后小鼠扭体次数的不同。结果在热板法和醋酸法分别注射了3mg/kg和3.5mg/kg吲哚拉明后,小鼠的缩爪反应潜伏期明显增加（P〈0.01）和扭体次数显著减少（P〈0.01）。结论α受体颉颃剂吲哚拉明对外创性神经痛病理模型或正常小鼠具有镇痛作用。     

美洛昔康贴片镇痛作用实验研究

目的观察美洛昔康贴剂(Mel T)镇痛作用。方法观察Mel T对醋酸引起的小鼠扭体数的增加和甲醛所致的小鼠足痛值的降低,以及对佐剂性关节炎大鼠的痛阈值的影响。结果Mel T局部粘贴小鼠20、105、mg/kg,明显抑制由醋酸引起的小鼠扭体数的增加并降低甲醛所致的小鼠足痛值。大鼠足部粘贴14、7、3.5mg/kg,明显降低佐剂性关节炎大鼠的痛阈值,提高炎性足的压痛值。结论Mel T有明显的镇痛作用。     

国产湿痛喜康的抗炎解热和镇痛作用

湿痛喜康对角叉菜胶诱发大鼠踝关节肿胀、二甲苯诱导小鼠耳水肿、大鼠佐剂性关节炎、酵母诱发大鼠发热、冰醋酸诱导小鼠扭体反应和“热板”致痛反应等实验模型,有明显的抗炎、解热和镇痛作用。对角叉菜胶性炎症模型和小鼠扭体反应的ED_(50)分别为5.26mg/kg和5.5mg/kg。     

地蜂子抗炎镇痛作用的实验研究

目的:探讨地蜂子的抗炎镇痛作用。方法:抗炎实验采用二甲苯致小鼠耳廓肿胀、角叉菜胶致大鼠足跖肿胀和大鼠棉球肉芽肿炎症模型;镇痛实验采用热板法和醋酸扭体法。结果:地蜂子水煎液灌胃100mL/(kg·d)能明显的抑制二甲苯致小鼠耳廓肿胀(P<0.05)。地蜂子醇提液腹腔注射2mL/kg在1h、2h、3h、4h时对角叉菜胶致大鼠足跖肿胀有非常明显的抑制作用(P<0.01)。水煎液腹腔注射2ml/kg对棉球埋藏引起的慢性肉芽肿有明显的抑制作用(P<0.01);在60min时对热板致小鼠痛阈有明显提高(P<0.01)。水煎液皮下注射2mL/kg、0.5mL/kg对醋酸致小鼠扭体反应有明显的抑制作用(P<0.01)。结论:地蜂子有明显的抗炎镇痛作用。     

不同剂量地西泮对小鼠吗啡镇痛效果的影响

目的观察不同剂量地西泮对吗啡镇痛效果的影响。方法30只小鼠随机均分为生理盐水组(NS组)、D1组(地西泮8 mg/kg)和D2组(地西泮16 mg/kg),连续注射14 d,第15日停止给药并正常饲喂1 d,第16日各组注射吗啡0.125 mg/kg,分别在地西泮注射及吗啡注射后以热甩尾法测定小鼠痛阈。结果不同剂量地西泮对吗啡镇痛效果的影响有显著性差异,D1组和D2组较NS组痛阈增加(P<0.01),而D1组与D2组间无显著性差异(P>0.05)。结论地西泮能显著增强吗啡的镇痛作用,且可能随剂量的增加增效的幅度有所降低。     

氢溴酸槐果碱的镇痛及抗炎作用

sc氢滇酸槐果碱(简称So,3、8～30mg/kg),都能显著减少乙酸引起的小鼠扭体反应次数。热板法实验表明,ig 30和60mg/kg So不明显延长热痛反应潜伏期。小鼠ig 60mg/kg So显著抑制乙酸引起的腹腔毛细血管通透性增高,大鼠ig 40mg/kgSo也能显著抑制组胺引起皮肤毛细血管通透性增加。SC 30mg/kg So明显抑制二甲苯引起小鼠耳壳水肿。ig 20和40mg/kg So显著抑制鲜蛋清引起大鼠足跖水肿,且抑制作用持续7h以上。实验表明So具有抑制急性渗出性炎症作用和弱镇痛作用。     

On the mechanisms of the development of tolerance to the muscular rigidity produced by morphine in rats

The development of tolerance to the muscular rigidity produced by morphine was studied in rats. Saline-pretreated controls given a test dose of morphine (20 mg/kg i.p.) showed a pronounced rigidity recorded as tonic activity in the electromyogram. Rats treated for 11 days with morphine and withdrawn for 36-40 h showed differences in the development of tolerance: about half of the animals showed a rigidity after the test dose of morphine that was not significantly less than in the controls and were akinetic (A group). The other rats showed a strong decrease in the rigidity and the occurrence of stereotyped (S) licking and/or gnawing in presence of akinetic or hyperkinetic (K) behaviour (AS/KS group), suggesting signs of dopaminergic activation. The rigidity was considerably decreased in both groups after 20 days' treatment. In a further series of experiments, haloperidol (0.2 mg/kg i.p.) was used in order to block the dopaminergic activation and to estimate the real degree of the tolerance to the rigidity without any dopaminergic interference. Haloperidol enhanced the rigidity in the A group. However, the level in the AS/KS group remained considerably lower than in the A group. The results suggest that rigidity, which is assumed to be due to an action of morphine in the striatum, can be antagonized by another process leading to dopaminergic activation in the striatum. Nevertheless, there occurs some real tolerance to this effect. The rapid alternations of rigidity and the signs of dopaminergic activation observed in the animals of the AS/KS group might be due to rapid shifts in the predominance of various DA-innervated structures.     

Reduction of morphine-withdrawal aggression by conditional social stimuli

Sixty male hooded rats were made physically dependent on morphine by steadily increasing doses of morphine sulphate. A maintenance dose of 400 mg/kg/day was reached in 10 days and was continued for 5 additional days. At the end of the 15-day period all rats were withdrawn for 72 h and aggressive responses (attacks, rearing, and vocalization) were recorded for a 60-min period. One treatment group, in which a social experience had been paired with each morphine injection, showed significantly less morphine-withdrawal aggression than rats in two other groups which either remained socially isolated throughout the addiction period, or were grouped both at the time of morphine injection and during between-injection intervals.     

The development of morphine antinociceptive tolerance in nitric oxide synthase-deficient mice

Elevations in nitric oxide (NO) have been implicated in the development of morphine antinociceptive tolerance. This study was conducted to establish the role of specific isoforms of NO synthase (NOS) in morphine tolerance development using genetically modified mice. METHODS: Three groups of mice (endothelial NOS [eNOS]-deficient, neuronal NOS [nNOS]-deficient, and NOS-competent) were used in this experiment. On Day 1, the analgesic response (radiant heat tail-flick) to a challenge dose of morphine (4 mg/kg) was determined over 3 hr. Tolerance was induced on Days 1-5 by administering morphine subcutaneously (10 mg/kg) or L-arginine, a NO precursor, intraperitoneally (200 mg/kg), twice daily. Analgesic response to the challenge dose was determined again on Day 6. RESULTS: Following sustained morphine administration, nNOS-deficient mice exhibited less tolerance development when compared to the control group, although measurable tolerance still occurred. Mice deficient in eNOS evidenced a degree of tolerance similar to that of control. Prolonged L-arginine administration produced significant functional tolerance to morphine in NOS-competent and eNOS-deficient mice. The loss of morphine responsivity after L-arginine administration was similar to that after morphine pretreatment. L-Arginine did not affect the antinociceptive response to morphine in mice deficient in nNOS, suggesting that the small degree of morphine-induced tolerance in this group occurs through an alternate pathway. CONCLUSIONS: These data demonstrate the pivotal role of the neuronal isoform of NOS in development of morphine antinociceptive tolerance. Furthermore, tolerance development appears to be predominantly a NO-mediated process, but likely is augmented by a secondary (non-NO) pathway.     

Drug withdrawal prior to hatch in the morphine tolerant chick embryo

Morphine tolerance and dependence were produced in chick embryos by injecting 20 mg/kg into the air space of the egg daily from incubation day 12. Starting on day 16, two groups of eggs were withdrawn from morphine by either substituting water or by treating with naloxone. Chick embryo activities were monitored on incubation day 18. Activities of the embryos withdrawn from morphine did not differ from control, but naloxone injection produced a substantial increase in activity. Neither regimen of morphine withdrawal affected the hatchability of the eggs. When these chicks were 1 day old, the effect of 1 mg morphine/kg on the rate of distress vocalization was measured. The withdrawn chicks vocalized at a rate that was intermediate between that of controls and that of nonwithdrawn chicks indicating that tolerance was still present one week after the last morphine injection.     

Additive effect of dextromethorphan on the inhibitory effect of anti-NT4 on morphine tolerance

It has been proposed that opioid tolerance is a model of neuronal plasticity similar to learning and memory. Recent evidence suggests that neurotrophins may be involved in synaptic development and plasticity. Observations indicate that neurotrophin 4 (NT4) is required for the synaptic plasticity mediating both tolerance and memory. Also there are lines of evidence to indicate that NMDA receptors are involved in the neural plasticity underlying the development of opiate tolerance. Neurotrophins affect central transmission postsynaptically by enhancing NMDA receptor responsiveness. So we used the clinically available NMDA receptor antagonist, dextromethorphan, and the neurotrophin 4 antibody, anti-NT4, concomitantly and alone to investigate their effects on morphine tolerance. Tolerance was induced by injecting morphine (7 and 10 mg/kg i.p.) once per day for 4 days. Anti-NT4 (1 microg/rat i.c.v.) was administered 15 min before morphine. Results showed that chronic concomitant treatment of anti-NT4 with morphine in both doses inhibited the development of morphine tolerance. Also acute treatment of anti-NT4 significantly reversed the tolerance that was induced by morphine 7 mg/kg but failed to reverse the tolerance of morphine 10 mg/kg. Dextromethorphan in both doses (10 or 30 mg/kg) has an additive effect on the inhibitory effect of anti-NT4 on the reversal of morphine tolerance (7 mg/kg). These findings provide additional support for the hypothesis that NMDA receptor and NT4 may be involved in neural plasticity underlying opiate tolerance.     

Facilitation of morphine-induced tolerance and physical dependence by prolyl-leucyl-glycinamide

The pretreatment of mice with 30 mg/kg morphine s.c. did not alter the analgesic effect of morphine in mice pretreated with saline but decreased the analgesic effect of morphine in mice pretreated with prolyl-leucyl-glycinamide (PLG). Tolerance was evaluated by the effect of PLG on morphine-induced enhancement of naloxone potency which is a measure of the capacity of naloxone to antagonize morphine-induced analgesia and is postulated to be an indicator of tolerance development. The naloxone potency of PLG-treated mice was 2-fold greater than that of control mice. PLG did not alter the whole brain levels of morphine, nor did it alter the naloxone potency in mice which were not pretreated with 30 mg/kg morphine. In mice treated with 100 mg/kg morphine or implanted with 50 mg morphine pellets for 24 or 72 h, the amount of naloxone required to induce jumping was not altered by PLG. However, PLG treatment did increase the hypothermia and body weight loss seen after naloxone-induced withdrawal. Administration of PLG to morphine-dependent mice 1 h prior to naloxone did not modify the resultant hypothermia or body weight loss. These results indicate that PLG facilitated the development of morphine tolerance and dependence.     

On the mechanism of tolerance to morphine-induced Straub tail reaction in mice

The effect of 5-HT and opioid receptor antagonists on morphine-induced Straub tail was studied in mice. Straub tail behavior was induced by subcutaneous administration of different doses (20, 30, and 40 mg/kg) of morphine hydrochloride to mice. The effect of morphine was dose-dependent. Maximum response was obtained with 40 mg/kg of the drug. The response induced by morphine (20 and 40 mg/kg) was decreased by different doses of intraperitoneal injection of naloxone (1 and 2 mg/kg) or methysergide, mianserin, and ritanserin (1 and 2 mg/kg). The effect of morphine (40 mg/kg) was also reduced by intracerebroventricular injection of naloxone (0.4-0.8 microg/animal) or mianserin (2 and 4 microg/animal). Different groups of mice received one daily dose (50 mg/kg sc) of morphine sulfate for 3 days to develop tolerance to morphine. The Straub tail reaction induced by morphine hydrochloride (40 mg/kg) was tested on the fourth day. Naloxone injection (1 and 2 mg/kg ip) on Day 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), decreased tolerance induced to morphine. Methysergide, mianserin, or ritanserin (intraperitoneal) on Days 2 and 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), also decreased tolerance induced to morphine. Intracerebroventricular injection of either naloxone or mianserin also reduced tolerance to morphine. It is concluded that 5-HT(2) and opioid receptor mechanisms are involved in morphine-induced Straub tail reaction and tolerance induced to morphine also may be mediated through these receptors.     

Effects of Pavlovian conditioning and MIF-I on the development of morphine tolerance in rats

Thirty male Sprague-Dawley-derived rats were given daily IP injections of morphine (5.0 mg/kg) in the presence of a specific set of environmental cues for eleven consecutive days. Twelve hours after each morphine session, a control injection was given in a different environment. On Day 12 through 14 the environmental cues associated with each session were reversed. On Day 15 environmental cues associated with each session were the same as on Days 1-11. Analgesia was assessed by the tail-flick method 30 minutes after each morphine and control injection. Four independent groups (n=6) received either a lower (0.1 mg/kg) or a higher (5.0 mg/kg) dose of MIF-I either 10 minutes before or immediately after each morphine and control session. A control group received an injection of a diluent vehicle both before and after each session. None of these peptide-treatments significantly affected either acute action of morphine or the development of tolerance across days. Tail-flick latencies from both morphine and control sessions significantly decreased across days. On Day 12, when morphine was administered in the presence of cues not previously associated with its administration, tail-flick latencies were significantly longer than on the previous day. Tail-flick latencies did not change from Day 11 to Day 15 during control sessions. Morphine-session latencies did not change from Day 14 to Day 15, although they did decrease from Day 12 to Day 14. The significant morphine-induced analgesia on Day 15 of the experiment increases a remarkable resistance to the development of tolerance to morphine. The results partially support the hypothesis proposed by Siegel [115-18] that principles of Pavlovian conditioning exert an important influence on the development of tolerance to morphine.     

Acamprosate decreases the induction of tolerance and physical dependence in morphine-treated mice

The effects of acamprosate, a drug thought to interact with N-methyl-D-aspartate (NMDA) receptors in the central nervous system (CNS), were examined on the antinociceptive action of morphine, induction of tolerance to and physical dependence on morphine, and expression of the abstinence syndrome to the opiate in mice. For the induction of tolerance and dependence, morphine (300 mg/kg) was administered by means of a slow-release preparation. Single doses of acamprosate (50, 100, 200, or 400 mg/kg) administered 30 min before a test dose of morphine did not change the antinociceptive effects of morphine in drug-naive mice. The drug was also administered in repeated doses (50, 100, 200, or 400 mg/kg, 30 min before and 12 and 24 h after the priming dose of morphine) in order to evaluate its effects on the induction of tolerance; all doses assayed, except the 400 mg/kg, did not affect the intensity of tolerance. The acute administration of acamprosate (50, 100, 200, or 400 mg/kg, injected 30 min before naloxone to morphine-pretreated mice) did not affect the intensity of the abstinence behavior. However, the repeated administration of 100 mg/kg of acamprosate (30 min before and 12 and 24 h after the priming dose of morphine) decreased the intensity of physical dependence. The results of these studies suggest that acamprosate may have modulatory effects on glutamatergic neurotransmission participating in the adaptive mechanisms induced by chronic morphine treatment.