• 【从泰国草药mitramyna speciosa中分离出的7-羟基雌米霉素诱导的抗伤害感受和抑制胃肠道转运的mu-阿片受体参与。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2006.08.013 复制DOI
    作者列表:Matsumoto K,Hatori Y,Murayama T,Tashima K,Wongseripipatana S,Misawa K,Kitajima M,Takayama H,Horie S
    BACKGROUND & AIMS: :7-hydroxymitragynine, a constituent of the Thai herbal medicine Mitragyna speciosa, has been found to have a potent opioid antinociceptive effect. In the present study, we investigated the mechanism of antinociception and the inhibitory effect on gastrointestinal transit of 7-hydroxymitragynine, and compared its effects with those of morphine. When administered subcutaneously to mice, 7-hydroxymitragynine produced antinociceptive effects about 5.7 and 4.4 times more potent than those of morphine in the tail-flick (ED50=0.80 mg/kg) and hot-plate (ED50=0.93 mg/kg) tests, respectively. The antinociceptive effect of 7-hydroxymitragynine was significantly blocked by the mu1/mu2-opioid receptor antagonist beta-funaltrexamine hydrochloride (beta-FNA) and the mu1-opioid receptor-selective antagonist naloxonazine in both tests. Thus, 7-hydroxymitragynine acts predominantly on mu-opioid receptors, especially on mu1-opioid receptors. Isolated tissue studies further supported its specificity for the mu-opioid receptors. Further, 7-hydroxymintragynine dose-dependently (ED50=1.19 mg/kg, s.c.) and significantly inhibited gastrointestinal transit in mice, as morphine does. The inhibitory effect was significantly antagonized by beta-FNA pretreatment, but slightly antagonized by naloxonazine. The ED50 value of 7-hydroxymitragynine on gastrointestinal transit was larger than its antinociceptive ED50 value. On the other hand, morphine significantly inhibits gastrointestinal transit at a much smaller dose than its antinociceptive dose. These results suggest that mu-opioid receptor mechanisms mediate the antinociceptive effect and inhibition of gastrointestinal transit. This compound induced more potent antinociceptive effects and was less constipating than morphine.
    背景与目标: : 7-hydroxyymyramynine,泰国草药mitramyna speciosa的一种成分,已被发现具有有效的阿片类药物抗伤害作用。在本研究中,我们研究了7-羟基雌米雌酮的抗伤害感受机制和对胃肠道转运的抑制作用,并将其与吗啡的作用进行了比较。当皮下给药小鼠时,在甩尾 (ED50 = 0.80 mg/kg) 和热板 (ED50 = 0.93 mg/kg) 测试中,7-羟基肌酸产生的抗伤害感受作用比吗啡的作用强约5.7和4.4倍。在两次测试中,mu1/mu2-opioid受体拮抗剂 β-氟曲胺盐酸盐 (β-FNA) 和mu1-opioid受体选择性拮抗剂纳洛酮嗪均显着阻断了7-羟基酪氨酸的抗伤害感受作用。因此,7-羟甲基主要作用于 μ-阿片受体,尤其是mu1-opioid受体。孤立的组织研究进一步支持了其对 μ 阿片受体的特异性。此外,7-羟基喹啉呈剂量依赖性 (ED50 = 1.19 mg/kg,s.C.),并显著抑制小鼠的胃肠转运,如吗啡。Β-FNA预处理可显着拮抗抑制作用,但纳洛酮嗪可轻微拮抗。7-羟基雌杆菌在胃肠道运输中的ED50值大于其抗伤害感受ED50值。另一方面,吗啡以比其抗伤害感受剂量小得多的剂量显着抑制胃肠道转运。这些结果表明,μ 阿片受体机制介导了抗伤害感受作用和抑制胃肠道转运。与吗啡相比,该化合物可产生更有效的抗伤害感受作用,并且便秘更少。
  • 【福尔马林试验中吗啡诱导的抗伤害感受: 与D1和D2多巴胺受体和一氧化氮剂的敏化和相互作用。】 复制标题 收藏 收藏
    DOI:10.1097/FBP.0b013e32813c5462 复制DOI
    作者列表:Zarrindast MR,Asgari-Afshar A,Sahebgharani M
    BACKGROUND & AIMS: :In this study, the effects of dopamine receptor antagonists and nitric oxide agents on morphine-induced sensitization in the formalin test in mice have been investigated. Repeated daily intraperitoneal administration of morphine (30 mg/kg for 3 days) followed by a 11-day wash out period increased morphine-induced antinociception in the formalin test, which may be due to sensitization. The antinociceptive response to higher doses of morphine (6 and 9 mg/kg) but not 3 mg/kg was significantly increased in sensitized animals compared with control groups. Pretreatment of animals with an opioid receptor antagonist, naloxone (4 mg/kg), during repeated administration of morphine, attenuated the morphine-induced sensitization. In the second part of the study, the animals received SCH23390 (D1 receptor antagonist), sulpiride (D2 receptor antagonist), L-Arg (nitric oxide precursor) and NG-nitro-L-Arg methylester (nitric oxide synthase inhibitor) during repeated morphine administration, to evaluate the role of dopamine receptor antagonists and nitric oxide agents in this phenomenon. Pretreatment of animals with NG-nitro-L-Arg methylester (20 mg/kg) and sulpiride (100 mg/kg) during morphine sensitization decreased the antinociceptive response to higher doses of morphine in the formalin test. It is concluded that D2 dopamine receptor and nitric oxide mechanisms may be involved at least partly in morphine-induced sensitization in the formalin test.
    背景与目标: : 在这项研究中,研究了多巴胺受体拮抗剂和一氧化氮对小鼠福尔马林试验中吗啡诱导的致敏作用。每天重复腹膜内施用吗啡 (30 mg/kg,持续3天),然后进行11天的冲洗期,增加了福尔马林试验中吗啡诱导的抗伤害感受,这可能是由于致敏所致。与对照组相比,致敏动物对较高剂量吗啡 (6和9 mg/kg) 而不是3 mg/kg的抗伤害反应显着增加。在重复施用吗啡期间,用阿片样物质受体拮抗剂纳洛酮 (4 mg/kg) 对动物进行预处理会减弱吗啡诱导的敏化作用。在研究的第二部分中,动物在重复吗啡给药期间接受了SCH23390 (D1受体拮抗剂),舒必利 (D2受体拮抗剂),L-Arg (一氧化氮前体) 和NG-硝基-L-Arg甲基酯 (一氧化氮合酶抑制剂),评估多巴胺受体拮抗剂和一氧化氮剂在这种现象中的作用。在吗啡致敏过程中,用NG-硝基-L-Arg甲基酯 (20 mg/kg) 和舒必利 (100 mg/kg) 对动物进行预处理会降低福尔马林测试中对较高剂量吗啡的抗伤害感受反应。结论是,在福尔马林测试中,D2多巴胺受体和一氧化氮机制可能至少部分参与吗啡诱导的致敏。
  • 【CC12是一种P450/环氧合酶抑制剂,在大鼠的延髓腹内侧延髓中起作用,以减轻吗啡的抗伤害感受。】 复制标题 收藏 收藏
    DOI:10.1016/j.brainres.2012.12.030 复制DOI
    作者列表:Conroy JL,Nalwalk JW,Phillips JG,Hough LB
    BACKGROUND & AIMS: :Brain cytochrome P450 epoxygenases were recently shown to play an essential role in mediating the pain-relieving properties of morphine. To identify the CNS sites containing the morphine-relevant P450s, the effects of intracerebral (ic) microinjections of the P450 inhibitor CC12 were determined on morphine antinociception in rats. CC12 inhibited morphine antinociception when both drugs were injected into the rostral ventromedial medulla (RVM), but not following co-injections into the periaqueductal gray (PAG) or into the spinal subarachnoid space. In addition, intra-RVM CC12 pretreatment nearly completely blocked the effects of morphine following intracerebroventricular (icv) administration. Although morphine is thought to act in both the PAG and RVM by pre-synaptic inhibition of inhibitory GABAergic transmission, the present findings show that 1) the mechanism of morphine action differs between these two brainstem areas, and 2) P450 activity within the RVM is important for supraspinal morphine antinociception. Characterization of morphine-P450 interactions within RVM circuits will further enhance the understanding of the biochemistry of pain relief.
    背景与目标: : 脑细胞色素P450环氧合酶最近被证明在介导吗啡的止痛特性中起重要作用。为了鉴定含有吗啡相关P450的CNS位点,确定了脑内 (ic) 微注射P450抑制剂CC12对大鼠吗啡抗伤害感受的影响。当将两种药物注射到延髓腹内侧髓质 (RVM) 中时,CC12抑制了吗啡的抗伤害感受,但在将两种药物注射到导水管周围灰色 (PAG) 或脊髓蛛网膜下腔后不进行。此外,RVM内CC12预处理几乎完全阻断了脑室内 (icv) 给药后吗啡的作用。尽管吗啡被认为通过突触前抑制抑制性gaba能传递而在PAG和RVM中起作用,但目前的发现表明: 1) 吗啡作用的机制在这两个脑干区域之间有所不同,并且2) RVM内的P450活性对于脊髓上吗啡抗伤害感受很重要。RVM回路内morphine-P450相互作用的表征将进一步增强对缓解疼痛的生物化学的理解。
  • 【孟鲁司特是半胱氨酰白三烯受体拮抗剂,通过L-精氨酸/一氧化氮/环GMP/KATP通道途径和ppar γ 受体在疼痛动物模型中发挥局部抗伤害作用。】 复制标题 收藏 收藏
    DOI:10.1080/00207454.2020.1769618 复制DOI
    作者列表:Alizamani E,Ghorbanzadeh B,Naserzadeh R,Mansouri MT
    BACKGROUND & AIMS: :Objective: The leukotrienes are inflammatory mediators. In the present study, the analgesic role of local montelukast, a cysteinyl leukotriene receptor antagonist, and the possible involvement of L-arginine/NO/cGMP/KATP channel pathway and PPARγ receptors was assessed in the formalin test in rats.Methods and results: The local administration of montelukast into the hind paw produced dose-related analgesia during both phases of the formalin test. Furthermore, pre-treatment with L-NAME, methylene blue, and glibenclamide prevented montelukast (10 μg/paw)-induced antinociception in both early and late phases of the test. Moreover, the local L-arginine and diazoxide before the sub-effective dose of montelukast (3 μg/paw) produced an analgesic effect. Also, local GW-9662 blocked antinociception induced by montelukast plus pioglitazone (10 μg/paw).Conclusion: In conclusion, montelukast produced peripheral analgesia through PPARγ receptors and activation of the L-arginine/NO/cGMP/KATP channel pathway, with potential for a new topical analgesic drug.
    背景与目标: 目的: 白三烯是炎症介质。在本研究中,在大鼠福尔马林试验中评估了局部孟鲁司特 (半胱氨酰白三烯受体拮抗剂) 的镇痛作用以及L-精氨酸/NO/cGMP/KATP通道途径和ppar γ 受体的可能参与。方法和结果: 在福尔马林试验的两个阶段,将孟鲁司特局部施用到后爪中会产生剂量相关的镇痛作用。此外,在试验的早期和晚期,用L-NAME,亚甲蓝和格列本脲进行预处理可防止孟鲁司特 (10 μ g/paw) 诱导的抗伤害感受。此外,在次有效剂量孟鲁司特 (3  μ g/paw) 之前,局部L-精氨酸和二氮嗪产生镇痛作用。此外,局部GW-9662阻断了孟鲁司特联合吡格列酮 (10 μ g/paw) 诱导的抗伤害感受。结论: 孟鲁司特通过ppar γ 受体和L-精氨酸/NO/cGMP/KATP通道通路的激活产生外周镇痛作用,有可能成为一种新的局部镇痛药物。
  • 【神经元一氧化氮合酶在扭体试验中对低压缺氧诱导的抗伤害感受的作用。】 复制标题 收藏 收藏
    DOI:10.1007/s12272-010-0717-0 复制DOI
    作者列表:Choi SM,Chung SY,Seol CA,Sul JG,Kwon MS
    BACKGROUND & AIMS: :It has been reported that hypobaric hypoxia exposure by high altitude is responsible for neuropsychological impairment. In the present study, we examined an effect of hypobaric hypoxia on the writhing test. The ICR mice were exposed in hypobaric chamber with several altitudes (5000, 10,000 or 20,000 ft) for 1 or 2 h, and then immediately injected intraperitoneally (i.p.) with 1% acetic acid for writhing test. Our results show that both 10,000 ft and 20,000 ft exposure induce antinociceptive effect in writhing test, but 5,000 ft does not. In addition, this antinociceptive effect was abolished by L-NAME (nitric oxide synthase inhibitor) pre-treated intraperitoneally, but not naloxone (non-specific opioid receptor antagonist). Furthermore, we examined that neuronal NOS immunoreactivities in the hypothalamus (paraventricular nucleus and arcuate nucleus) were increased by hypobaric hypoxic exposure (10,000ft). These results suggest that hypobaric hypoxic-induced antinociception may be associated with neuronal NOS IR in the hypothalamus.
    背景与目标: : 据报道,高空低压缺氧是造成神经心理障碍的原因。在本研究中,我们检查了低压缺氧对扭曲试验的影响。将ICR小鼠暴露在几个海拔高度 (5000、10,000或20,000英尺) 的低压室中1或2小时,然后立即腹膜内 (i.p.) 注射1% 乙酸用于扭体试验。我们的结果表明,10,000英尺和20,000英尺的暴露在扭体试验中均引起抗伤害感受作用,而5,000英尺则没有。此外,腹膜内预处理的l-name (一氧化氮合酶抑制剂) 消除了这种抗伤害感受作用,而纳洛酮 (非特异性阿片受体拮抗剂) 则没有。此外,我们检查了低压低氧暴露 (10,000ft) 增加了下丘脑 (室旁核和弓状核) 中的神经元NOS免疫反应性。这些结果表明,低压缺氧诱导的抗伤害感受可能与下丘脑中的神经元NOS IR有关。
  • 【大鼠阿片类药物抗伤害感受性别差异的药物遗传学分析。】 复制标题 收藏 收藏
    影响因子 :
    发表时间:2003-12-01
    来源期刊:Pain
    DOI:10.1016/j.pain.2003.08.008 复制DOI
    作者列表:Terner JM,Lomas LM,Smith ES,Barrett AC,Picker MJ
    BACKGROUND & AIMS: :Sex differences in opioid antinociception have been reported in rodents and monkeys, with opioids being more potent in males than females. In the present study, the influence of rat strain on sex differences in opioid antinociception was examined in a warm water tail-withdrawal procedure. Antinociceptive tests were conducted with the high-efficacy micro-opioid morphine, and the less efficacious opioids buprenorphine, butorphanol and nalbuphine. Baseline nociceptive latencies were consistently higher in males than their female counterparts. Sex differences in opioid antinociception were observed in all strains tested, with the opioids being more potent and/or effective in males. The magnitude of the sex differences was related to the relative efficacy of the opioid, with morphine, buprenorphine, butorphanol and nalbuphine being on average 2.2-, 2.6-, 15.9- and 11.9-fold more potent in males. Sex differences also varied markedly across strains, with large differences consistently obtained in the F344 and F344-Sasco strains, moderate differences in the ACI, DA, Lewis, Sprague Dawley, Wistar and Wistar-Kyoto strains, and small differences in the Long Evans-Blue Spruce, Long Evans, Brown Norway and Holtzman strains. When compared across strains, there was no relationship between sex differences in nociceptive sensitivity and opioid sensitivity. These findings provide strong support for the role of genetic factors in determining sex differences in opioid antinociception, and suggest that the use of low-efficacy opioids, coupled with the use of rat strains that display small and large sex differences in opioid antinociception, may provide a sensitive tool to investigate the mechanisms underlying sex differences in opioid antinociception.
    背景与目标: : 据报道,啮齿动物和猴子在阿片类药物抗伤害感受方面存在性别差异,其中阿片类药物在男性中比女性更有效。在本研究中,在温水戒尾程序中检查了大鼠应变对阿片类药物抗伤害感受性别差异的影响。用高效的微阿片类吗啡和效率较低的阿片类药物丁丙诺啡,布托啡诺和纳布啡进行抗伤害试验。男性的基线伤害性潜伏期始终高于女性。在所有测试的菌株中均观察到阿片类药物抗伤害感受的性别差异,其中阿片类药物在男性中更有效和/或更有效。性别差异的大小与阿片类药物的相对功效有关,吗啡,丁丙诺啡,布托啡诺和纳布啡在男性中的平均效力是2.2,2.6,15.9和11.9倍。不同菌株的性别差异也显着不同,在F344和F344-Sasco菌株中始终存在较大差异,在ACI,DA,Lewis,Sprague Dawley,Wistar和Wistar-Kyoto菌株中存在中等差异,在Long Evans-Blue云杉中存在较小差异,Long Evans,Brown Norway和Holtzman菌株。当比较不同菌株时,伤害性敏感性和阿片类药物敏感性的性别差异之间没有关系。这些发现为遗传因素在确定阿片类抗伤害感受中的性别差异方面的作用提供了有力的支持,并表明使用低效阿片类药物,再加上使用在阿片类抗伤害感受中表现出小而大的性别差异的大鼠品系,可以提供一个敏感的工具来研究阿片类药物抗伤害感受中性别差异的潜在机制。
  • 【在福尔马林试验中,早期的抗伤害感受会延迟水肿,但不会降低持续性疼痛的程度。】 复制标题 收藏 收藏
    DOI:10.1054/jpai.2000.7308 复制DOI
    作者列表:Taylor BK,Basbaum AI
    BACKGROUND & AIMS: :Intraplantar formalin injection produces early (Phase 1, 0- to 5-minute) and late (Phase 2, 15-plus minutes after injection) nociceptive responses, including painlike behavior and activation of primary afferents and dorsal horn neurons. Although we and others have reported that opioid analgesia or local anesthesia during Phase 1 does not reduce the overall magnitude of behavioral and/or neuronal responses during Phase 2, recent studies concluded that spinal sensitization during Phase 1 significantly contributes to the magnitude of painlike behavior during Phase 2. In this article, we provide additional evidence that Phase 1 and Phase 2 behaviors are independent. We found that remifentanil analgesia during Phase 1 does not reduce Phase 2, regardless of route of administration, duration of analgesia, types of behavior assessed, formalin concentration, concomitant use of general anesthesia, or concomitant administration of an N-methyl-D-aspartate (NMDA) antagonist. We suggest that Phase 1 behaviors compared with Phase 2 behaviors in the formalin test are not an appropriate model of spinal sensitization or preemptive opioid analgesia. Instead, early opioid administration delayed the onset of edema produced by formalin. Because the antiedema effect of remifentanil was reversed with a peripherally acting opioid receptor antagonist, we suggest that opioids interact with peripheral receptors to temporarily delay the onset and offset of formalin-induced edema.
    背景与目标: : 足底福尔马林注射产生早期 (第1阶段,0至5分钟) 和晚期 (第2阶段,注射后15分钟以上) 的伤害性反应,包括疼痛行为和初级传入神经元和背角神经元的激活。尽管我们和其他人报告说,第1阶段的阿片类镇痛或局部麻醉不会降低第2阶段的行为和/或神经元反应的总体幅度,但最近的研究得出结论,第1阶段的脊柱敏化显着有助于疼痛行为的幅度在第2阶段。在本文中,我们提供了其他证据,表明阶段1和阶段2的行为是独立的。我们发现,无论给药途径,镇痛持续时间,评估行为类型,福尔马林浓度,全身麻醉的同时使用或N-甲基-D-天冬氨酸 (NMDA) 拮抗剂的同时给药,瑞芬太尼在1期镇痛不会减少2期镇痛。我们建议,福尔马林试验中的1期行为与2期行为相比,不是脊柱致敏或先发制人阿片类镇痛的合适模型。相反,早期使用阿片类药物会延迟福尔马林产生的水肿的发作。由于瑞芬太尼的抗水肿作用被外周作用的阿片受体拮抗剂逆转,因此我们建议阿片类药物与外周受体相互作用以暂时延迟福尔马林诱导的水肿的发作和抵消。
  • 【关于福尔马林试验中卡马西平诱导的抗伤害感受的机制。】 复制标题 收藏 收藏
    DOI:10.1080/00207450600808669 复制DOI
    作者列表:Sahebgharani M,Hossein-Abad AA,Zarrindast MR
    BACKGROUND & AIMS: :In the present study, the effect of lidocaine (a sodium channel blocker) on carbamazepine-induced antinociception, in formalin test was investigated. Intraperitoneal (i.p.) administration of different doses of carbamazepine (3.5, 7, 15, and 30 mg/kg) induced a dose-dependent antinociception in mice, in the first and second phases of the test. Different doses of lidocaine as a sodium channel blocker (5, 10, and 20 mg/kg, i.p.) also induced antinociception in both phases of the formalin test. It is noted that lidocaine could potentiate the response of carbamazepine in the first, but not in the second, phase of the formalin test. Meanwhile i.p. administration of different doses of Prazosin, alpha1 adrenoceptor antagonist (0.125, 0.25, and 0.5 mg/kg), Yohimbine, alpha2 adrenoceptor antagonist (0.25, 0.5, and 1 mg/kg), Bicuculline, GABAA receptor antagonist (1.5 and 3 mg/kg), and CGP 35348, GABAB receptor antagonist (100 and 200 mg/kg) exert dose-dependent antinociceptive effect in both phases of the formalin test. It should be noted that bicuculline 0.75 mg/kg by itself increased pain score in the second phase of the formalin test, indicating that blockade of GABAA receptor subtype may induce chronic pain. None of the aforementioned drugs could alter the antinociceptive response of carbamazepine in the formalin test. It is concluded that sodium channel mechanisms may be involved partly in the antinociceptive induced by carbamazepine.
    背景与目标: : 在本研究中,在福尔马林试验中研究了利多卡因 (钠通道阻滞剂) 对卡马西平诱导的抗伤害感受的影响。在试验的第一和第二阶段,腹膜内 (i.p.) 施用不同剂量的卡马西平 (3.5、7、15和30 mg/kg) 在小鼠中诱导剂量依赖性抗伤害感受。在福尔马林试验的两个阶段,不同剂量的利多卡因作为钠通道阻滞剂 (5、10和20 mg/kg,i.p.) 也诱导了抗伤害感受。请注意,利多卡因可以在福尔马林测试的第一阶段 (但不能在第二阶段) 增强卡马西平的反应。同时,i.p.给予不同剂量的哌唑嗪,α1肾上腺素受体拮抗剂 (0.125,0.25和0.5 mg/kg),育亨宾,α2肾上腺素受体拮抗剂 (0.25,0.5和1 mg/kg),双古林,GABAA受体拮抗剂 (1.5和3 mg/kg) 和CGP 35348,GABAB受体拮抗剂 (100和200 mg/kg) 在福尔马林试验的两个阶段均发挥剂量依赖性的抗伤害感受作用。应该注意的是,双小分子0.75 mg/kg本身增加了福尔马林试验第二阶段的疼痛评分,表明阻断GABAA受体亚型可能诱发慢性疼痛。上述药物均不能改变福尔马林试验中卡马西平的抗伤害反应。结论是,钠通道机制可能部分参与了卡马西平诱导的抗伤害感受。
  • 【美托咪啶诱导的抗伤害感受中脊髓和脊髓节段 α-2-肾上腺素能机制的参与。】 复制标题 收藏 收藏
    DOI:10.1016/0306-4522(91)90089-7 复制DOI
    作者列表:Pertovaara A,Kauppila T,Jyväsjärvi E,Kalso E
    BACKGROUND & AIMS: :The effect of systemically administered medetomidine, a selective alpha-2-adrenoceptor agonist, was studied by electrophysiological recordings of the peripherally evoked responses of three different types of sensory neuronal populations in the rat: medial thalamic neurons exclusively responding to mechanical cutaneous stimuli at noxious intensities, spinothalamic tract neurons of the spinal cord responding exclusively or differentially to mechanical cutaneous stimuli at noxious intensities, and low-threshold mechanoreceptive spinal dorsal horn neurons with ascending projections. The neuronal effects were compared with the behavioral data obtained in mechanically and thermally induced nociceptive tail reflex tests in intact and spinal rats. A reversal of the antinociceptive effects was attempted by systemically (1.5 mg/kg, i.p.) or intrathecally (25 micrograms) administered atipamezole, a selective alpha-2-adrenoceptor antagonist. Systemically administered medetomidine produced an atipamezole-reversible, dose-dependent suppressive effect on the evoked responses of nociceptive medial thalamic and spinothalamic tract neurons. A lower dose of medetomidine was needed to suppress significantly (half-maximally) evoked responses of the nociceptive medial thalamic neurons (100 micrograms/kg) than those of the nociceptive spinothalamic tract neurons (300 micrograms/kg). The decrease of evoked responses of the nociceptive spinothalamic tract neurons was accompanied by a decrease in spontaneous activity. The responses of the low-threshold mechanoreceptive projection neurons of the spinal cord were not influenced by medetomidine (30-300 micrograms/kg). The reflex studies with a (anesthetic) medetomidine dose of 300 micrograms/kg indicated that in intact and otherwise drug-free rats, medetomidine produced a significant prolongation of the nociceptive reflex response latency to a tail-pinch and heat; these antinociceptive effects of systemic medetomidine were reversed by systemically and intrathecally applied atipamezole. In spinal rats systemically applied medetomidine (300 micrograms/kg) also produced a significant prolongation of the tail-flick latency, which was reversed by systemically applied atipamezole. The results suggest that a high anesthetic dose of systemically applied medetomidine (300 micrograms/kg) can suppress nociceptive sensory neuronal and reflex responses due to spinal segmental mechanisms through an action on alpha-2-adrenoceptors. This spinal effect is selective to responses of nociceptive neurons, and at least partly postsynaptic as indicated by the concomitant decrease in spontaneous activity. At a lower, subanesthetic (but sedative) dose (100 micrograms/kg) the antinociceptive effect of systemically applied medetomidine can be explained by supraspinal alpha-2-adrenergic mechanisms.
    背景与目标: : 通过电生理记录大鼠三种不同类型的感觉神经元群体的外周诱发反应,研究了全身给药的选择性alpha-2-adrenoceptor激动剂美托咪啶的作用: 内侧丘脑神经元仅对有害强度下的机械皮肤刺激作出反应,脊髓的脊髓丘脑束神经元对有害强度下的机械皮肤刺激仅响应或差异响应,以及具有上升投影的低阈值机械感受性脊髓背角神经元。将神经元效应与完整和脊髓大鼠的机械和热诱导的伤害性尾巴反射测试中获得的行为数据进行了比较。通过全身 (1.5 mg/kg,i.p.) 或鞘内 (25微克) 施用选择性alpha-2-adrenoceptor拮抗剂atipamezole,尝试逆转抗伤害感受作用。系统给药美托咪啶对伤害性丘脑内侧和脊髓丘脑道神经元的诱发反应产生了阿替帕美唑可逆的剂量依赖性抑制作用。与伤害性脊髓丘脑道神经元 (300微克/千克) 相比,需要较低剂量的美托咪啶来显着 (最大一半) 抑制伤害性丘脑内侧神经元的诱发反应 (100微克/千克)。伤害性脊髓丘脑束神经元诱发反应的减少伴随着自发活动的减少。脊髓低阈值机械感受投射神经元的反应不受美托咪啶 (30-300微克/千克) 的影响。(麻醉) 美托咪啶剂量为300微克/千克的反射研究表明,在完整的和其他无药物的大鼠中,美托咪啶产生了明显延长的伤害感受反射反应潜伏期,以尾捏和热; 全身和鞘内施用阿替帕美唑可逆转全身性美托咪啶的这些抗伤害感受作用。在脊髓大鼠中,全身应用美托咪啶 (300微克/千克) 也产生了明显的甩尾潜伏期延长,这被全身应用阿替帕美唑逆转。结果表明,高麻醉剂量的全身性美托咪啶 (300微克/千克) 可以通过对alpha-2-adrenoceptors的作用抑制脊髓节段机制引起的伤害性感觉神经元和反射反应。这种脊柱效应对伤害性神经元的反应是选择性的,并且至少部分是突触后的,如自发活动的伴随减少所表明的那样。在较低的亚麻醉 (但镇静) 剂量 (100微克/千克) 下,全身应用美托咪啶的抗伤害作用可以通过脊髓上 α-2-肾上腺素能机制来解释。
  • 【在冷水甩尾试验中,伤害肽/孤儿院蛋白FQ可阻断mu,kappa和 δ 阿片激动剂诱导的抗伤害感受。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2006.11.001 复制DOI
    作者列表:Chen X,Geller EB,Adler MW
    BACKGROUND & AIMS: :Nociceptin/orphanin FQ (N/OFQ), a 17-amino-acid peptide, is an endogenous agonist whose receptor is similar in sequence to mu, delta and kappa opioid receptors. It has been reported that N/OFQ can block antinociceptive effects induced by opioid receptor agonists in the radiant heat tail-flick test and warm water tail-withdrawal test. The present study was designed to see the effect of N/OFQ on antinociception induced by opioid receptor agonists in the cold water tail-flick (CWT) test, which measures a different type of pain. In adult male Sprague-Dawley (S-D) rats given subcutaneous (s.c.) injections of saline or morphine (8 mg/kg), intracerebroventricular (i.c.v.) injection of N/OFQ (18 microg) 15 min later produced a significant reversal of morphine antinociception (P<0.01, ANOVA followed by Duncan's test), compared to the corresponding saline control group. Saline (t=+15 min, i.c.v.) had no effect on s.c. morphine antinociception (P>0.01), compared to the corresponding saline control group. When the kappa opioid receptor agonist spiradoline (80 mg/kg, s.c.) was used instead of morphine, similar results were observed. In another series of experiments, it was found that i.c.v. injection of N/OFQ (18 microg) reversed the antinociception induced by i.c.v. injection of the selective mu opioid agonist PL017 (2 microg), delta opioid agonist DPDPE (50 ng) and kappa opioid agonist dynorphin (21.5 microg), respectively. These results indicate that N/OFQ may be an endogenous anti-opioid peptide in the brain of rats in the CWT test.
    背景与目标: : Nociceptin/orphorin FQ (N/OFQ) 是一种17个氨基酸的肽,是一种内源性激动剂,其受体的顺序与mu,delta和kappa阿片受体相似。据报道,在辐射热甩尾试验和温水抽尾试验中,N/OFQ可以阻断阿片受体激动剂诱导的抗伤害感受作用。本研究旨在观察N/OFQ对冷水甩尾 (CWT) 测试中阿片受体激动剂诱导的抗伤害感受的影响,该测试可测量不同类型的疼痛。在成年雄性Sprague-Dawley (S-D) 大鼠皮下 (s.c.) 注射生理盐水或吗啡 (8 mg/kg),与相应的生理盐水对照组相比,脑室内 (i.c.v.) 注射N/OFQ (18微克) 15分钟后产生吗啡抗伤害感受的显著逆转 (P<0.01,ANOVA随后进行Duncan's检验)。生理盐水 (t = + 15 min,i.c.v.) 对s.c.没有影响。吗啡抗伤害感受 (P>0.01),与相应生理盐水对照组比较。当使用kappa阿片受体激动剂spiradoline (80 mg/kg,s.C.) 代替吗啡时,观察到类似的结果。在另一系列实验中,发现i.c.v.注射N/OFQ (18 microg) 可逆转i.c.v.诱导的抗伤害感受。分别注射选择性 μ 阿片激动剂PL017 (2 μ g) 、 δ 阿片激动剂DPDPE (50 ng) 和 κ 阿片激动剂强啡肽 (21.5 μ g)。这些结果表明,在CWT测试中,N/OFQ可能是大鼠脑内的内源性抗阿片肽。
  • 【反复的新生儿母体分离会改变雄性大鼠吗啡诱导的抗伤害感受。】 复制标题 收藏 收藏
    DOI:10.1016/s0361-9230(01)00485-3 复制DOI
    作者列表:Kalinichev M,Easterling KW,Holtzman SG
    BACKGROUND & AIMS: :Recent studies indicate that Long-Evans rats separated from their dam for 3 h daily over the first 2 weeks of life (maternally separated [MS] rats) exhibit exaggerated behavioral and neuroendocrine responses to stress as adults compared to handled (H) or non-handled (NH) control animals. Our aim was to determine whether repeated neonatal maternal separation results in altered sensitivity to the opioid agonist morphine in male and female adult rats. Sensitivity to morphine was assessed using hot-plate and tail-flick tests. Morphine was less potent inducing antinociception in MS males compared to same-sex controls in the hot-plate, but not in the tail-flick test. Decrease in sensitivity to morphine in MS females compared to same-sex controls was present only as a trend in the hot-plate, but not in the tail-flick test. These results suggest that neonatal maternal separation results in long-lasting changes in opioid responsiveness primarily in male rats.
    背景与目标: : 最近的研究表明,与成年 (h) 相比,Long-Evans大鼠在生命的前2周内每天与大坝分离3小时 (母体分离的 [MS] 大鼠) 表现出对成年压力的行为和神经内分泌反应过度或非-处理 (NH) 对照动物。我们的目的是确定反复的新生儿母体分离是否会导致成年雄性和雌性成年大鼠对阿片类激动剂吗啡的敏感性改变。使用热板和甩尾试验评估对吗啡的敏感性。与热板中的同性对照相比,吗啡在MS男性中诱导抗伤害感受的作用较小,但在甩尾测试中却没有。与同性对照相比,MS女性对吗啡的敏感性降低仅在热板中呈趋势,而在甩尾测试中则没有。这些结果表明,新生儿母体分离主要导致雄性大鼠阿片类药物反应性的长期变化。
  • 【一氧化氮环GMP蛋白激酶g-k通道途径可能参与褪黑激素的外周抗伤害感受。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2008.07.068 复制DOI
    作者列表:Hernández-Pacheco A,Araiza-Saldaña CI,Granados-Soto V,Mixcoatl-Zecuatl T
    BACKGROUND & AIMS: :The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG)-K(+) channel pathway on melatonin-induced local antinociception was assessed during the second phase of the formalin test. The local peripheral ipsilateral, but not contralateral, administration of melatonin (150-600 microg/paw) produced a dose-related antinociception during both phases of the formalin test in rats. Moreover, local pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, NO synthesis inhibitor, 10-100 microg/paw), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 5-50 microg/paw), (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo [1,2,3-fg:3',2',1'-kl]pyrrolo [3,4-i][1,6] benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor, 50-500 ng/paw), glibenclamide (ATP-sensitive K(+) channel blocker, 5-50 microg/paw), apamin (small-conductance Ca(2+)-activated K(+) channel blocker, 0.1-1 microg/paw) or charybdotoxin (large- and intermediate-conductance Ca(2+)-activated K(+) channel blocker, 0.03-0.3 microg/paw), but not N(G)-D-nitro-arginine methyl ester (D-NAME, inactive isomer of L-NAME, 100 microg/paw) or vehicle, significantly prevented melatonin (300 microg/paw)-induced antinociception. Data suggest that melatonin-induced local peripheral antinociception during the second phase of the test could be due to activation of the NO-cyclic GMP-PKG-ATP-sensitive and Ca(2+)-activated K(+) channels pathway.
    背景与目标: : 在福尔马林试验的第二阶段评估了一氧化氮 (NO)-环状GMP-蛋白激酶G (PKG)-K () 通道途径对褪黑激素诱导的局部抗伤害感受的可能参与。在大鼠福尔马林试验的两个阶段,褪黑激素 (150-600 microg/paw) 的局部外周同侧而不是对侧施用产生了剂量相关的抗伤害感受。此外,用N(G)-L-硝基精氨酸甲酯 (L-NAME,NO合成抑制剂,10-100微G/paw),1H-(1,2,4)-恶二唑 (4,2-a)quinoxalin-1-one (ODQ,鸟苷酸环化酶抑制剂,5-50微克/爪),(9S,10R,12R)-2,3,9,10,11,12-六氢-10-甲氧基-2,9-二甲基-1-氧代-9,12-环氧-1h-二吲哚 [1,2,3-fg:3 ',2',1 '-kl] 吡咯 [3,4-i][1,6] benzodiazocine-10-carboxylic甲酯 (KT-5823,特异性PKG抑制剂,50-500 ng/paw),格列本脲 (ATP敏感的K(+) 通道阻滞剂,5-50 microg/paw),apamin (小电导Ca(2 +) 激活的K(+) 通道阻滞剂,0.1-1 microg/paw) 或charybdotoxin (大电导Ca(2 +) 激活的K(+) 通道阻滞剂,0.03-0.3 microg/paw),但不是N(G)-D-硝基精氨酸甲酯 (D-NAME,L-NAME的非活性异构体,100 microg/paw) 或媒介物,显著阻止了褪黑素 (300微克/爪) 诱导的抗伤害感受。数据表明,褪黑素在测试的第二阶段诱导的局部外周抗伤害感受可能是由于激活了非环GMP-PKG-ATP敏感和Ca(2 +) 激活的K(+) 通道途径。
  • 【YFa是一种嵌合阿片肽,在慢性治疗的6天内诱导kappa特异性抗伤害感受而无耐受性。】 复制标题 收藏 收藏
    DOI:10.1002/jnr.21605 复制DOI
    作者列表:Vats ID,Dolt KS,Kumar K,Karar J,Nath M,Mohan A,Pasha MA,Pasha S
    BACKGROUND & AIMS: :Our previous study showed that YGGFMKKKFMRFamide (YFa), a chimeric peptide of Met-enkephalin, and Phe-Met-Arg-Phe-NH2 induced naloxone-reversible antinociception and attenuated the development of tolerance to morphine analgesia. In continuation, the present study investigated which specific opioid receptors-mu, delta or kappa-mediate the observed YFa antinociception pharmacologically using specific antagonists and whether chronic administration of YFa at 26.01 micromol/kg per day induces tolerance and its effect on the expression of mu and kappa opioid receptors from day 4 to day 6, with endomorphine-1 (EM-1) and saline taken as positive and negative controls, respectively. Quantitative differential expression analysis was carried out by real-time reverse-transcriptase polymerase chain reaction, and the corresponding changes in protein levels were assessed by Western blot. A pharmacological investigation revealed that nor-binaltorphimine, a specific kappa opioid receptor-1 (KOR1) antagonist, completely antagonized the antinociception induced by 39.01 micromol/kg of YFa. Importantly, its chronic intraperitoneal administration did not result in significant tolerance over 6 days, whereas EM-1 induced significant tolerance after day 4. Differential expression analysis revealed that EM-1 caused up-regulation of mu opioid receptor-1 on day 4, followed by down-regulation on later days. Interestingly, YFa treatment caused a decrease on day 4, followed by an increase in the expression of KOR1 from day 5 onward. In conclusion, YFa induces kappa-specific antinociception, with no development of tolerance during 6 days of chronic treatment, which further articulates new directions for improved designing of peptide-based analgesics that may be devoid of adverse effects like tolerance.
    背景与目标: : 我们先前的研究表明,甲基脑啡肽的嵌合肽ygsfkkfmrfamide (YFa) 和Phe-Met-Arg-Phe-NH2诱导了纳洛酮可逆的抗伤害感受,并减弱了对吗啡镇痛的耐受性。在继续,本研究调查了哪种特定的阿片受体-mu,delta或kappa-介导使用特异性拮抗剂在药理学上观察到的YFa抗伤害感受,以及从第4天到第6天以每天26.01微mol/kg的YFa慢性给药是否诱导耐受性及其对mu和kappa阿片受体表达的影响,endomorphine-1 (EM-1) 和生理盐水分别作为阳性和阴性对照。通过实时逆转录酶聚合酶链反应进行定量差异表达分析,并通过Western blot评估蛋白质水平的相应变化。一项药理学研究表明,诺比亚托芬 (nor-binaltorphimine) 是一种特定的 κ 阿片受体1 (KOR1) 拮抗剂,完全拮抗由39.01微摩尔/千克YFa诱导的抗伤害感受。重要的是,它的慢性腹膜内给药在6天内没有导致明显的耐受性,而EM-1在第4天后诱导了明显的耐受性。差异表达分析表明,EM-1在第4天引起mu阿片受体1的上调,随后在随后的几天下调。有趣的是,YFa处理在第4天引起减少,然后从第5天开始增加KOR1的表达。总之,YFa诱导kappa特异性抗伤害感受,在慢性治疗的6天内没有耐受性的发展,这进一步阐明了改善基于肽的镇痛药设计的新方向,这些镇痛药可能没有耐受性等不良影响。
  • 【两种NMDA受体拮抗剂: MK-801和硫酸镁对大鼠胆汁淤积诱导的抗伤害感受的调节。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2006.10.026 复制DOI
    作者列表:Hasanein P,Parviz M,Keshavarz M,Javanmardi K,Allahtavakoli M,Ghaseminejad M
    BACKGROUND & AIMS: :Acute cholestasis is associated with increased activity of the endogenous opioid system that results to changes including analgesia. N-methyl-d-aspartate (NMDA) receptors are involved in the nociceptive pathway and play a major role in the development of morphine induced analgesia. The magnesium acts as a non-competitive NMDA receptor antagonist by blocking the NMDA receptor channel. Considering the reported antinociceptive effect of magnesium sulfate as a NMDA receptor antagonist and the existence of close functional links between NMDA receptor antagonists and magnesium with the opioid system, we studied the effect of acute and chronic administration of MK-801 as a NMDA antagonist and magnesium sulfate on modulation of nociception in an experimental model of elevated endogenous opioid tone, acute cholestasis, using the tail-flick paradigm. Cholestasis was induced by ligation of the main bile duct using two ligatures and then transsection of the duct at the midpoint between them. A significant increase (P<0.001) in nociception threshold was observed in bile duct ligated rats compared to unoperated and sham-operated animals. In acute treatment, MK-801 (0.1 mg/kg, b.i.d), but not magnesium (150 mg/kg magnesium sulfate, i.e. 30 mg/kg of Mg(+2), i.p., b.i.d.) increased antinociception in cholestatic rats compared to saline treated cholestatics (P<0.05). In chronic treatment, administration of MK-801 or magnesium sulfate for 7 consecutive days, increased tail-flick latency (P<0.05, P<0.01) in cholestatic animals compared to saline treated cholestatics. These data showed that NMDA receptor pathway is involved in modulation of cholestasis-induced antinociception in rats and that repeated dosages of magnesium sulfate similar to MK-801 is able to modulate nociception in cholestasis.
    背景与目标: : 急性胆汁淤积与内源性阿片系统活性增加有关,导致包括镇痛在内的变化。N-甲基-d-天冬氨酸 (NMDA) 受体参与伤害性途径,并在吗啡诱导的镇痛过程中起主要作用。镁通过阻断NMDA受体通道充当非竞争性NMDA受体拮抗剂。考虑到已报道的硫酸镁作为NMDA受体拮抗剂的抗伤害作用,以及NMDA受体拮抗剂和镁与阿片系统之间存在密切的功能联系,我们使用甩尾范例,在内源性阿片样物质紧张,急性胆汁淤积的实验模型中,研究了作为NMDA拮抗剂和硫酸镁的MK-801的急性和慢性给药对伤害感受调节的影响。胆汁淤积是通过使用两个结扎结扎主胆管,然后在它们之间的中点横穿胆管而引起的。与未手术和假手术的动物相比,在胆管结扎的大鼠中观察到伤害感受阈值显着增加 (P<0.001)。在急性治疗中,MK-801 (0.1 mg/kg,b.i.d),但不包括镁 (150 mg/kg硫酸镁,即30 mg/kg mg (+ 2),i.p.,b.i.d.) 与盐水处理的胆汁淤积剂相比,胆汁淤积大鼠的抗伤害感受增加 (P<0.05)。在慢性治疗中,与盐水治疗的胆汁淤积动物相比,MK-801或硫酸镁连续7天给药增加了甩尾潜伏期 (P<0.05,P<0.01)。这些数据表明,NMDA受体途径参与了大鼠胆汁淤积诱导的抗伤害感受的调节,并且与MK-801相似的重复剂量硫酸镁能够调节胆汁淤积中的伤害感受。
  • 【免疫来源的阿片类药物和外周抗伤害感受。】 复制标题 收藏 收藏
    DOI:10.1046/j.1440-1681.2001.03425.x 复制DOI
    作者列表:Cabot PJ
    BACKGROUND & AIMS: :1. Recent findings have suggested a significant involvement of the immune system in the control of pain. Immune cells contain opioid peptides that are released within inflamed tissue and act at opioid receptors on peripheral sensory nerve endings. It is also apparent that different types of lymphocytes contain beta-endorphin, memory T cells containing more beta-endorphin than naïve cells. 2. These findings highlight an integral link between immune cell migration and inflammatory pain. The present review highlights immune system involvement in the site-directed control of inflammatory pain. 3. Full-length mRNA transcripts for opioid precursor proteins are expressed in immune cells. Increased expression of pro-opiomelanocortin mRNA and beta-endorphin has been demonstrated in stimulated lymphocytes and lymphocytes from animals with inflammation. 4. Cytokines and corticotropin-releasing factor (CRF) release opioids from immune cells. Potent peripheral analgesia due to direct injection of CRF can be blocked by antagonists to CRF, antibodies to opioid peptides, antisense to CRF and opioid receptor-specific antagonists. The release of opioid peptides from lymphocytes is calcium dependent and opioid receptor specific. Furthermore, endogenous sources of opioid peptides produce potent analgesia when implanted into the spinal cord. 5. Activated immune cells migrate directly to inflamed tissue using cell adhesion molecules to adhere to the epithelial surface of the vasculature in inflamed tissue. Lymphocytes that have been activated can express opioid peptides. Memory type T cells that contain opioid peptides are present within inflamed tissue; naive cells are not present in inflamed tissue and do not contain opioid peptides. Inhibiting the migration of memory type T cells into inflamed tissue by blocking selectins results in reduced numbers of beta-endorphin-containing cells, a reduced quantity of beta-endorphin in inflamed paws and reduced stress- and CRF-induced peripheral analgesia. 6. Immunosuppression is associated with increased pain in patients. Moreover, immunosuppression results in decreased lymphocyte numbers as well as decreased analgesia in animal models.
    背景与目标: : 1。最近的发现表明免疫系统在控制疼痛方面有很大的参与。免疫细胞含有阿片肽,这些肽在发炎的组织中释放,并作用于周围感觉神经末梢的阿片受体。同样明显的是,不同类型的淋巴细胞含有 β-内啡肽,记忆T细胞含有比幼稚细胞更多的 β-内啡肽。2.这些发现突出了免疫细胞迁移和炎性疼痛之间不可或缺的联系。本综述强调了免疫系统参与炎性疼痛的定点控制。3.阿片前体蛋白的全长mRNA转录本在免疫细胞中表达。在患有炎症的动物的受刺激的淋巴细胞和淋巴细胞中,已证明了亲黑皮素mRNA和 β-内啡肽的表达增加。4.细胞因子和促肾上腺皮质激素释放因子 (CRF) 从免疫细胞中释放阿片类药物。由于直接注射CRF而产生的有效的外周镇痛作用可被CRF拮抗剂,阿片肽抗体,CRF反义和阿片受体特异性拮抗剂阻断。阿片肽从淋巴细胞的释放是钙依赖性和阿片受体特异性的。此外,当植入脊髓时,阿片肽的内源性来源会产生有效的镇痛作用。5.活化的免疫细胞利用细胞黏附分子直接迁移到发炎组织中,粘附到发炎组织的脉管系统的上皮表面。已经被激活的淋巴细胞可以表达阿片肽。含有阿片肽的记忆型T细胞存在于发炎的组织中; 幼稚细胞不存在于发炎的组织中,也不包含阿片肽。通过阻断选择素来抑制记忆型T细胞向发炎组织的迁移,导致含 β-内啡肽的细胞数量减少,发炎的爪子中 β-内啡肽的数量减少,并减少压力和CRF引起的外周镇痛。6.免疫抑制与患者疼痛增加有关。此外,免疫抑制会导致动物模型中淋巴细胞数量减少以及镇痛作用降低。

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