Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats

To study the antinociceptive synergy resulting from the combination of opioid receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists on neuropathic pain, an isobolographic analysis of equianalgesic combinations of ketamine with methadone or morphine was performed in rats with mononeuropathy produced by placing four constrictive ligatures around the common sciatic nerve. Two weeks later, the antinociceptive effect of subcutaneous administration of the drugs alone or combined was evaluated by using the paw pressure test. Drugs and their combinations produced dose-dependent antinociception. Combinations produced synergy of a supra-additive nature in the neuropathic paw, but only additive antinociception in the normal paw. The ketamine/methadone combination was more effective to produce antinociception in the neuropathic paw than was the ketamine/morphine association, as revealed by the lower ED25. The results indicate supra-additive synergy between NMDA receptor antagonists and opioids, especially methadone, to produce antinociception in experimental neuropathy.     

氯诺昔康、右美沙芬与吗啡协同镇痛作用的临床观察

目的:观察小剂量氯诺昔康、右美沙芬复合小剂量吗啡用于上腹部手术后镇痛的效果.方法:择期上腹部手术患者45例,术后使用100mL一次性镇痛泵.所用药物为分别为吗啡50mg(吗啡组,n=14)、吗啡30mg 右美沙芬15mg(右美沙芬组,n=14)、吗啡30mg 氯诺昔康16mg(氯诺昔康组,n=14)和吗啡30mg(对照组,n=6).记录术后3,6,24,48h疼痛视觉模拟评分(VAS)、Ramsay镇静评分、活动后VAS评分和48h内使用吗啡总量并记录可能出现的不良反应.结果:术后6和24h吗啡组、氯诺昔康组VAS明显低于对照组,右美沙芬组6h明显低于对照组.术后6和24h吗啡与氯诺昔康组活动后VAS明显低于对照组,而右美沙芬组与对照组差异无显著性,且在6h显著高于吗啡组.各组术后镇静评分无差异.术后48h吗啡总量吗啡组明显高于其他3组,氯诺昔康与右美沙芬组低于对照组.术后恶心呕吐病例吗啡组明显高于其他3组.右美沙芬组1例眩晕,吗啡组1例皮肤瘙痒,未发现其他不良反应.结论:小剂量非阿片类药物氯诺昔康与右美沙芬与吗啡联合应用可增加吗啡的镇痛效果.     

The effect of reserpine and alpha-methyldopa on the analgesic action of morphine in the mouse

In the tail clip test, reserpine inhibited the analgesic action of morphine, and this action of reserpine was prevented by pretreatment with α-methyldopa. In the hot plate test reserpine potentiated the action of morphine, and α-methyldopa pre- treatment had no inhibitory action on reserpine. α-Methyldopa alone, and in combination with reserpine, showed an analgesic action in the hot plate test.     

On the role of a central adrenergic mechanism in morphine analgesic action

The influence of drugs interfering with brain monoamine metabolism on morphine analgesia of rats was estimated by the tail pressure method. Central adrenergic stimulation produced by apomorphine, cocaine, pyrogallol or amphetamine led to stereotyped behaviour and elevation of the pain threshold. Lower doses of these drugs potentiated morphine analgesic action. Reserpine, iproniazid and disulfiram weakened morphine analgesic action. α-Methyldopa increased morphine action and (±)-tryptophan did not influence it significantly.     

罗哌卡因联合吗啡或芬太尼镇痛效果与对肠蠕动影响的临床观察

目的探讨罗哌卡因联合不同镇痛药物对手术后肠蠕动恢复情况的影响。方法对105例普外科择期手术患者,ASAⅠ、Ⅱ级,根据不同的镇痛方案随机等分成3组:(1)吗啡组。0.125%罗哌卡因+0.005%吗啡+0.005%氟哌利多。(2)芬太尼组:0.125%罗哌卡因+0.000 5%芬太尼+0.005%氟哌利多。(3)对照组为不实施患者术后自控镇痛。镇痛治疗后4h、8h、12h、24h、36h进行随访,观察疼痛程度、镇静状态、平均动脉压(MAP)、心率(HR)、呼吸频率(RR)、脉搏氧饱和度(SpO_2),并记录肠蠕动恢复时间。结果吗啡组与芬太尼组均取得较好的镇痛效果,VAS评分显著低于对照组(P<0.01);芬太尼组较吗啡组、对照组肠蠕动恢复时间明显缩短(P<0.05)。结论罗哌卡因联合吗啡、芬太尼组患者术后自控镇痛均能获得良好的效果;罗哌卡因与芬太尼联用可缩短肠蠕动的恢复时间。     

The effect of amfonelic acid or nisoxetine in combination with morphine on brain-stimulation reward

Many drugs of abuse, including stimulants such as cocaine and amphetamine, and opioids like morphine and heroin, will lower threshold at which rats will work to receive electrical stimulation to the medial forebrain bundle-lateral hypothalamic region (MFB-LH). This effect is even greater when the two classes of drugs are coadministered. The underlying mechanisms by which this occurs are not completely understood, however there is considerable evidence suggesting that the catecholamines play a major role in mediating the reinforcing effects of these drugs. The present study was conducted to investigate the effects of amfonelic acid, an indirect dopamine agonist, and nisoxetine, a highly selective norepinephrine uptake blocker, alone and in combination with morphine, on the reward threshold for rewarding electrical intracranial stimulation. As in previous studies, morphine, as well as amfonelic acid, lowered the reward threshold with the amfonelic acid causing greater threshold lowerings than that of morphine. When a low (ineffective) dose of amfonelic acid was administered concomitantly with morphine, the threshold lowerings observed were larger than those seen with either drug alone and were often more than additive. Nisoxetine alone had no effect on the reward threshold and produced inconsistent results when combined with morphine. These findings support the thesis that amfonelic acid has abuse potential, and that its reinforcing effects may, in fact, be even greater than that of the opioids. Further, these results support the hypothesis that dopamine plays a more critical role in mediating brain-stimulation reward than dose norepinephrine.     

Effects of medial raphe and raphe magnus lesions on the analgesic activity of morphine and methadone

The effects of lesions of the raphe nuclei on opiate-induced antinociception and brain serotonin (5-HT) levels were investigated. Lesions of the medial raphe nucleus effectively antagonized the analgesic effects of morphine, but not methadone, and lowered brain 5-HT. The decrement in analgesic activity of morphine was reversed by pretreatment with 5-hydroxytryptophan. Lesions of the raphe magnus, a descending 5-HT system, antagonized the analgesic potency of both morphine and methadone. These experiments indicate a differential effect of 5-HT manipulation on opiate-induced analgesia, suggesting a different mechanism of analgesic action for morphine and methadone.     

Developmental effects of propyphenazone in analgesic and antipyretic combination with caffeine or paracetamol

The aim of the study was to determine the influence of an over-the-counter (OTC) mixture of propyphenazone with caffeine or paracetamol on prenatal development. Propyphenazone:caffeine and propyphenazone:paracetamol mixtures were prepared with constant 3:1 and 3:5 ratios, respectively. Three dose levels of each of the mixtures were administered separately in Tween-80 water suspension once a day to pregnant Wistar rats on gestation days 8-14. The low dose was similar to the OTC preparations, 2.1 mg/kg of propyphenazone, 0.7 mg/kg of caffeine or 3.5 mg/kg of paracetamol. The middle dose was 21.0, 7.0 or 35.0 mg/kg, and the highest 210.0, 70.0 or 350.0 mg/kg for propyphenazone, caffeine or paracetamol, respectively. On day 21 of gestation the fetuses were delivered by hysterectomy. Dead or live fetuses, resorptions and the number of implantation sites were counted. Live fetuses were examined for external, visceral and skeletal malformation. Postimplantation mortality was calculated. Dose-dependent effects in the middle and high dose groups on fetal body weight/length and placental weight were found. No increase in external or internal congenital anomalies was found in any of the mixture-exposed groups. Prenatal coadministration of propyphenazone with caffeine or paracetamol caused intrauterine growth retardation but did not increase external or internal congenital anomalies. The risk of midline defects (umbilical hernia and gastroschisis) is discussed.     

The analgesic action of morphine-N-oxide

1. The analgesic activity of morphine-N-oxide in mice and rats has been investigated and compared with that of morphine.2. Both morphine and morphine-N-oxide were more active when given subcutaneously than when given intraperitoneally.3. Given subcutaneously, morphine was 11-22 times more potent than morphine-N-oxide and when given intraperitoneally it was 39-89 times more potent. The potencies depended on the test situation and the species of animal used.4. In animals pretreated with amiphenazole or tacrine, the analgesic activities of morphine and morphine-N-oxide were increased. The potencies of these analgesic drugs given intraperitoneally were increased to a greater extent than were the potencies obtained by subcutaneous administration.5. A possible explanation for the increase in analgesic potency of morphine-N-oxide produced by pretreatment with amiphenazole or tacrine may be that morphine-N-oxide is rapidly inactivated in the liver and this inactivation is impaired by amiphenazole and tacrine.     

瑞舒伐他汀部分恢复吗啡耐受大鼠的吗啡镇痛效能

目的探讨瑞舒伐他汀对吗啡耐受大鼠的吗啡镇痛效能的影响及其相关的分子机制。方法 48只♂SD大鼠随机分成6组(n=8):Ⅰ组为空白对照组;Ⅱ组为吗啡耐受组;Ⅲ组为10 mg.kg-1瑞舒伐他汀对照组;Ⅳ组、Ⅴ组、Ⅵ组分别为0.4、2、10 mg.kg-1瑞舒伐他汀处理组。Ⅱ、Ⅳ、Ⅴ、Ⅵ组皮下注射吗啡10 mg.kg-1,Ⅰ组和Ⅲ组皮下注射生理盐水,每天8∶00和16∶00各1次,连续10 d。d 6起,上午皮下注射前30 min,Ⅰ、Ⅱ组给予生理盐水灌胃,Ⅲ、Ⅳ、Ⅴ、Ⅵ组给予相应剂量的瑞舒伐他汀灌胃,连续5 d。d 6、11,测定大鼠基础热缩足潜伏期(PWTL)后,计算尾静脉注射吗啡30 min时各组大鼠的MPE值。d 11行为学检测后处死大鼠,留取腰5脊髓,比较各组脊髓内细胞外调节蛋白激酶(ERK)、磷酸化细胞外调节蛋白激酶(p-ERK)及星形胶质细胞表面标志物GFAP的表达水平。结果①d 6,6组的基础PWTL无明显差异。与Ⅰ组相比,Ⅱ、Ⅳ、Ⅴ和Ⅵ组MPE值明显降低(P<0.05)。d 11,6组的基础PWTL无差异。与Ⅰ组相比,Ⅱ、Ⅳ组尾静脉注射吗啡后30 min的MPE值明显降低(P<0.05);与Ⅱ组相比,Ⅴ、Ⅵ组的MPE值明显升高(P<0.05)。②d 11,6组大鼠腰5脊髓内总ERK表达水平差异无显著性。与Ⅰ组相比,Ⅱ、Ⅳ组腰5脊髓内p-ERK表达明显升高(P<0.05);与Ⅱ组相比,Ⅲ、Ⅴ、Ⅵ组腰5脊髓内p-ERK表达明显降低(P<0.05)。与Ⅰ组相比,Ⅱ组腰5脊髓内GFAP的荧光强度明显升高(P<0.05);与Ⅱ组相比,Ⅵ组腰5脊髓内GFAP的强度明显降低(P<0.05)。结论瑞舒伐他汀能够部分恢复吗啡耐受大鼠的吗啡镇痛效果,这可能与其抑制脊髓内ERK的磷酸化,减少星形胶质细胞活化有关。     

Hospital morphine preparation for abstinence syndrome in newborns exposed to buprenorphine or methadone

Objective This study was undertaken to evaluate the adequacy of a hospital formulated oral morphine preparation for management of neonatal abstinence syndrome (NAS) and to compare clinical features in infants exposed to methadone or buprenorphine in utero. Method Between October 1998 and October 2004 all infants born to mothers treated with buprenorphine or methadone during pregnancy were enrolled into this prospective study. Morphine hydrochloride solution (0.2 mg/ml) was prepared without preservatives under a flow laminar air box (class 100). Mean outcome measure Morphine solution: quantitative and qualitative HPLC analysis and microbiological study at regular intervals during storage at 4°C for 6 months. Maternal characteristics: age, opiate dose during pregnancy. Neonatal characteristics: gestational age at delivery, birth weight, Lipsitz scores. Morphine dose: daily morphine dose, maximum morphine dose, duration of NAS, and duration of treatment required to achieve stable Lipsitz scores below 4. Statistics: Kruskal–Wallis test for comparison of median values. Results Microbiological and HPLC analysis showed that the morphine preparation remained stable for 6 months at 4°C. Nine methadone-exposed infants and 13 buprenorphine-exposed infants were included in the study. All infants presented NAS requiring treatment with the morphine solution. Lipsitz scores at birth were significantly different in the methadone and buprenorphine groups (P < 0.05). The methadone group required significantly higher doses of morphine preparation than the buprenorphine group during the first 38 days of treatment (P < 0.05): 0.435 ± 0.150 mg/kg/day vs. 0.257 ± 0.083 mg/kg/day. Conclusion This hospital morphine solution is adequate for management of NAS. Preparations showed good stability and doses could be adjusted with a margin of 0.02 mg. The onset of NAS occurred within 24 h after birth in methadone-exposed infants (range 6–24 h) and within 48 h after birth in buprenorphine-exposed infants (range 24–168 h). Due to the possibility of delayed onset of NAS up to 7 days, infants born to mothers treated with buprenorphine should be kept in the hospital for an appropriate surveillance period. Treatment time was significantly longer (45 vs. 28 days) and the mean morphine doses were higher (1.7 fold) in methadone-exposed than buprenorphine-exposed infants.     

Delimitation of neuronal substrates necessary for the analgesic action of baclofen and morphine

The loci of neuronal substrates necessary for the analgesic action of baclofen and of morphine were determined by systematic transection of the rat cerebrospinal axis. Severe reduction in the analgesic capacity of both drugs, assessed with the tail flick test, occurred after section of the thoracic spinal cord, indicating that necessary substrates are located rostral to this level. These data also suggest that baclofen-induced analgesia does not primarily result from a pharmacological blockade of nociceptive information at the first sensory synapse in the spinal cord. Neither baclofen- nor morphine-induced analgesia was altered by transection of the brain stem between the superior and inferior colliculi, but the action of both drugs was greatly reduced following section of the medulla 3 mm rostral to the obex. Thus, the rostral margin of neuronal substrates mediating the effects of both drugs lies somewhere in the pons or anterior third of the medulla. This observation is compatible with the notion that analgesia induced by baclofen and morphine involves, at least in part, common neuronal substrates.     

The evaluation of the analgesic action of phenaridine when combined with agents used in anesthesiological practice]

A new narcotic analgesic agent phenaridine is superior to fentanyl by the activity and duration of action. It does not cause bronchospasm, exerts no significant influence on the parameters of gas exchange in the blood.