• 【亚马逊椰子油的抗伤害活性。】 复制标题 收藏 收藏
    DOI:10.1016/j.jep.2006.08.018 复制DOI
    作者列表:Gomes NM,Rezende CM,Fontes SP,Matheus ME,Fernandes PD
    BACKGROUND & AIMS: :Copaiba oil resins are extensively commercialized in Brazil as capsules or crude oil and used as anti-inflammatory and anti-septic. Comparative pharmacological studies between different species of Copaiba oils are scarce. In the present work we compared the antinociceptive activity of two Amazonian Copaiba oils (Copaifera multijuga Hayne and Copaifera reticulata Ducke, Fabaceae) administered by oral route using peripheral (acetic acid-induced abdominal writhing and formalin), spinal (tail flick) and supra-spinal (hot plate) models. Results demonstrated that the Copaiba oils did not develop toxic effects. Doses ranging from 30 to 150 mg/kg were enough to significantly develop peripheral antinociceptive effect. All Copaiba oils demonstrate central activity but with less effect on supra-spinal regions of the brain. Administration of the opioid receptor antagonist, naloxone completely inhibited the antinociceptive effect induced by both Copaiba oils. Our results indicate that Copaiba oils demonstrate peripheral and central antinociceptive effect. This new comprobate effect may be useful in the treatment of algesic disorders.
    背景与目标: : Copaiba油树脂在巴西作为胶囊或原油广泛商业化,并用作抗炎和防腐。缺乏不同种类的Copaiba油之间的比较药理学研究。在目前的工作中,我们比较了两种亚马逊Copaiba油 (Copaifera multijuga Hayne和Copaifera reticulata Ducke,Fabaceae) 的抗伤害感受活性,该方法通过口服途径使用外周 (乙酸诱导的腹部扭动和福尔马林),脊柱 (甩尾) 和脊髓上 (热板) 模型。结果表明,Copaiba油不会产生毒性作用。30至150 mg/kg的剂量足以显着发展外周抗伤害感受作用。所有Copaiba油均表现出中枢活性,但对大脑脊髓上区域的影响较小。服用阿片受体拮抗剂,纳洛酮完全抑制了两种Copaiba油诱导的抗伤害感受作用。我们的结果表明,Copaiba油具有外围和中央抗伤害作用。这种新的药物作用可能有助于治疗痛觉障碍。
  • 【人阿片样蛋白,阿片依赖途径的天然抗伤害感受调节剂。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.0605865103 复制DOI
    作者列表:Wisner A,Dufour E,Messaoudi M,Nejdi A,Marcel A,Ungeheuer MN,Rougeot C
    BACKGROUND & AIMS: :Mammalian zinc ectopeptidases play important roles in turning off neural and hormonal peptide signals at the cell surface, notably those processing sensory information. We report here the discovery of a previously uncharacterized physiological inhibitor of enkephalin-inactivating zinc ectopeptidases in humans, which we have named Opiorphin. It is a QRFSR peptide that inhibits two enkephalin-catabolizing ectoenzymes, human neutral ecto-endopeptidase, hNEP (EC 3.4.24.11), and human ecto-aminopeptidase, hAP-N (EC 3.4.11.2). Opiorphin displays potent analgesic activity in chemical and mechanical pain models by activating endogenous opioid-dependent transmission. Its function is closely related to the rat sialorphin peptide, which is an inhibitor of pain perception and acts by potentiating endogenous mu- and delta-opioid receptor-dependent enkephalinergic pathways. Here we demonstrate the functional specificity in vivo of human Opiorphin. The pain-suppressive potency of Opiorphin is as effective as morphine in the behavioral rat model of acute mechanical pain, the pin-pain test. Thus, our discovery of Opiorphin is extremely exciting from a physiological point of view in the context of endogenous opioidergic pathways, notably in modulating mood-related states and pain sensation. Furthermore, because of its in vivo properties, Opiorphin may have therapeutic implications.
    背景与目标: : 哺乳动物锌外肽酶在关闭细胞表面的神经和激素肽信号中起重要作用,尤其是那些处理感觉信息的信号。我们在这里报告了在人类中发现了一种以前未表征的脑啡肽失活锌外肽酶的生理抑制剂,我们将其命名为Opiorphin。它是一种QRFSR肽,可抑制两种脑啡肽分解代谢的外胚酶,人中性外胚肽内肽酶hNEP (EC 3.4.24.11) 和人外胚肽氨基肽酶hAP-N (EC 3.4.11.2)。Opiorphin通过激活内源性阿片样物质依赖性传递在化学和机械疼痛模型中显示出有效的镇痛活性。其功能与大鼠唾液酸肽密切相关,唾液酸肽是一种疼痛感的抑制剂,可通过增强内源性mu和 δ 阿片受体依赖性脑啡肽途径发挥作用。在这里,我们证明了人Opiorphin在体内的功能特异性。在急性机械性疼痛的行为大鼠模型 (pin-pain测试) 中,Opiorphin的疼痛抑制作用与吗啡一样有效。因此,从生理学的角度来看,在内源性阿片样肽途径的背景下,特别是在调节情绪相关状态和疼痛感方面,我们对阿片样肽的发现非常令人兴奋。此外,由于其体内特性,Opiorphin可能具有治疗意义。
  • 【大麻素的抗伤害和运动作用的性别差异。】 复制标题 收藏 收藏
    DOI:10.1016/s0014-2999(01)01267-5 复制DOI
    作者列表:Tseng AH,Craft RM
    BACKGROUND & AIMS: :Cannabinoids are currently used for the treatment of excessive weight loss and nausea; however, there are very few studies that have examined cannabinoid effects in females of any species. A previous study has shown that there are sex differences in cannabinoid pharmacokinetics in rats, suggesting that there could be sex differences in cannabinoid-induced behaviors. To address this issue, Delta9-tetrahydrocannabinol, 11-hydroxy-Delta9-tetrahydrocannabinol (natural cannabinoids) or (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP55940, a synthetic cannabinoid) was administered i.p. to male and female Sprague-Dawley rats, who were tested on the 50 degrees C warm water tail withdrawal, paw pressure, catalepsy bar and spontaneous locomotor activity tests at various times post-injection. At the doses tested, all three cannabinoid agonists produced greater effects in females than males in two or more behavioral tests. This study demonstrates that there are sex differences in the behavioral effects of cannabinoids in the rat.
    背景与目标: : 大麻素目前用于治疗过度减肥和恶心; 然而,很少有研究检查大麻素对任何物种的女性的影响。先前的研究表明,大鼠大麻素的药代动力学存在性别差异,这表明大麻素诱导的行为可能存在性别差异。为了解决这个问题,Delta9-tetrahydrocannabinol,11-hydroxy-Delta9-tetrahydrocannabinol (天然大麻素) 或 (-)-cis-3-[2-羟基-4-(1,1-二甲基庚基)-苯基]-trans-4-(3-羟丙基) 环己醇) (CP55940,合成大麻素) 被i.p.对于雄性和雌性Sprague-Dawley大鼠,在注射后的不同时间对50摄氏度的温水尾巴戒断,爪子压力,僵直性棒和自发运动能力测试进行了测试。在测试的剂量下,在两个或多个行为测试中,所有三种大麻素激动剂对女性的影响均大于男性。这项研究表明,大麻素对大鼠的行为影响存在性别差异。
  • 【比较 α-肾上腺素受体参与替扎尼定和可乐定在小鼠中的抗伤害感受作用。】 复制标题 收藏 收藏
    DOI:10.1016/0014-2999(86)90035-x 复制DOI
    作者列表:Kameyama T,Nabeshima T,Matsuno K,Sugimoto A
    BACKGROUND & AIMS: :The effect of drugs that influence the opioidergic and monoaminergic neuronal systems on the antinociceptive action of tizanidine [5-chloro-4-(2-imidazolin-2-yl-amino)-2,1, 3-benzothiodiazole] was compared with their effect on the action of clonidine. The potency of the clonidine-induced antinociceptive action was 1.83 and 7.75 times greater than that of tizanidine in the tail-flick and acetic acid-induced writhing tests, respectively. The action of tizanidine and clonidine was completely antagonized by pretreatment with yohimbine, an alpha 2-adrenoceptor blocker, but not by prazosin, an alpha 1-adrenoceptor blocker. Other alpha-adrenoceptor blockers, phenoxybenzamine and phentolamine, also attenuated the action of tizanidine and clonidine but the potency of these drugs was less than that of yohimbine. An opioid antagonist (naloxone), drugs influencing the serotonergic neuronal system (p-chlorophenylalanine, 5,6-dihydroxytryptamine, cyproheptadine), and drugs influencing the catecholaminergic system (alpha-methyl-p-tyrosine, diethyl-dithiocarbamate, 6-hydroxydopamine, haloperidol) showed no effect on the action of tizanidine and clonidine. From these results, it appears that alpha 2-adrenoceptors might be of importance in mediating the tizanidine and clonidine antinociceptive action in the tail-flick test.
    背景与目标: : 比较了影响碘化和单胺能神经元系统的药物对替扎尼定 [5-氯-4-(2-咪唑啉-2-基-氨基)-2,1,3-苯并硫二唑] 的抗伤害作用的影响。对可乐定的作用。在甩尾和乙酸诱导的扭动试验中,可乐定诱导的抗伤害感受作用的效力分别是替扎尼定的1.83倍和7.75倍。tizanidine和可乐定的作用通过用 α2-肾上腺素受体阻滞剂育亨宾进行预处理而完全拮抗,而不用 α1-肾上腺素受体阻滞剂哌唑嗪。其他 α-肾上腺素受体阻滞剂苯氧基苯甲胺和酚妥拉明也减弱了替扎尼定和可乐定的作用,但这些药物的效力低于育亨宾。阿片类药物拮抗剂 (纳洛酮),影响5-羟色胺能神经元系统的药物 (对氯苯丙氨酸,5,6-二羟色胺,赛庚啶) 和影响儿茶酚胺能系统的药物 (α-甲基-对-酪氨酸,二乙基-二硫代氨基甲酸,6-羟基多巴胺,氟哌啶醇) 对替扎尼定和可乐定的作用没有影响。从这些结果看来,在甩尾试验中,α2-肾上腺素受体在介导tizanidine和可乐定的抗伤害作用中可能很重要。
  • 【鞘内注射大鼠脑啡肽酶抑制剂SCH32615的抗伤害作用。】 复制标题 收藏 收藏
    DOI:10.1016/0006-8993(90)90588-3 复制DOI
    作者列表:Oshita S,Yaksh TL,Chipkin R
    BACKGROUND & AIMS: :The presence of opioid receptors and enkephalin-releasing neurons in the spinal dorsal horn prompted us to examine whether an enkephalinase inhibitor, SCH32615, given intrathecally would alter the response of the rat on several nociceptive endpoints: 49 degrees C hot plate (HP), 52 degrees C HP; tail flick (TF) and the paw pressure (PP) test. SCH (16-320 nmol, i.t.) resulted in a submaximal dose-dependent increase in the 49 degrees C HP, 52 degrees C HP, TF, and PP measures with the respective ED50 values being 40, 74, 68 and 83 nmol, respectively. AT 320 nmol, no additional increment in effect was observed. Concurrent examination of the effects of 0.1-10 nmol morphine on the 49 degrees C HP, 52 degrees C HP, TF and PP measures revealed i.t. ED50 values of 0.2, 0.8, 0.9 and 0.6 nmol, respectively, with the maximum dose leading to a complete block on all measures. The effects of SCH were totally reversed by naloxone (1 mg/kg, i.p.), a dose which had no detectable effect upon baseline nociceptive response measures. The effects of SCH, even at the highest dose were not accompanied by motor dysfunction or catalepsy. These results are consistent with the hypothesis that high-threshold thermal and mechanical stimuli will evoke the release of an opioid in the spinal space, the metabolism of which is significantly influenced by enkephalinase inhibition.
    背景与目标: : 脊髓背角阿片受体和脑啡肽释放神经元的存在促使我们检查鞘内给予的脑啡肽酶抑制剂SCH32615是否会改变大鼠在几个伤害性终点上的反应: 49 ℃ 热板 (HP),52 ℃ HP; 甩尾 (TF) 和爪子压力 (PP) 测试。SCH (16-320 nmol,i.t.) 导致49摄氏度HP、52摄氏度HP、TF和PP量度的次最大剂量依赖性增加,各自的ED50值分别为40、74、68和83 nmol。在320 nmol时,没有观察到额外的效应增量。同时检查0.1-10 nmol吗啡对49 ℃ HP,52 ℃ HP,TF和PP措施的影响,揭示了i.t.ED50值分别为0.2,0.8,0.9和0.6 nmol,最大剂量导致所有措施的完全阻滞。SCH的作用被纳洛酮 (1 mg/kg,ip) 完全逆转,该剂量对基线伤害性反应措施没有可检测到的作用。即使在最高剂量下,SCH的作用也不伴有运动功能障碍或僵直。这些结果与以下假设一致: 高阈值的热刺激和机械刺激会引起阿片类物质在脊柱间隙中的释放,其代谢受到脑啡肽酶抑制的显着影响。
  • 【精氨酸加压素是大鼠下丘脑室旁核抗伤害感受调节的重要调节剂。】 复制标题 收藏 收藏
    DOI:10.1016/j.npep.2006.12.005 复制DOI
    作者列表:Yang J,Yang Y,Chen JM,Xu HT,Liu WY,Wang CH,Lin BC
    BACKGROUND & AIMS: :Our previous study has proven that hypothalamic paraventricular nucleus (PVN) stimulation increases pain threshold and PVN cauterization decreases pain threshold. The studied neuropeptides in PVN were investigated to involve to pain modulation in the rat. The results showed that (1) intraventricular injection (icv) of anti-arginine vasopressin (AVP) serum completely reversed pain threshold increase induced by l-glutamate sodium (Glu) injection into the PVN, and local administration (icv) of anti-leucine-enkephalin (L-Ek) serum or anti-beta-endorphin (beta-Ep) serum partly attenuated pain threshold increase induced by Glu injection into the PVN, but pre-treatment of anti-oxytocin (OXT), dynorphinA(1-13) (DynA(1-13)), cholecystokinin-like peptide (CCK), neurotensin (NT), corticotrophin-releasing hormone (CRH), adrenocorticotrophin (ACTH), somatostatin (SST), prolactin-releasing hormone (PRH), angiotensinII (AngII), vasoactive intestinal polypeptide (VIP), melanotropin-releasing hormone (MRH), thyrotropin-releasing hormone (TRH), substance P (SP) or growth hormone-releasing hormone (GHRH) serum (icv) did not influence the analgesic effect of PVN administration with Glu; (2) PVN stimulation with Glu elevated the concentrations of AVP, OXT, CCK, NT, CRH, SST, PRH and DynA(1-13) in PVN perfusion liquid, and could not change the concentrations of L-Ek, beta-Ep, AngII, ACTH, VIP, MRH, TRH, SP and GHRH in PVN perfusion liquid; (3) Pain stimulation increased the concentrations of AVP, L-Ek, beta-Ep, DynA(1-13), CRH and ACTH in PVN perfusion liquid, and did not alter the concentrations of OXT, CCK, NT, SST, PRH, AngII, VIP, MRH, TRH, SP and GHRH in PVN perfusion liquid. The data suggested that AVP played a more important role than the other studied peptides (OXT, L-Ek, beta-Ep, DynA(1-13), CCK, NT, CRH, ACTH, SST, PRH, AngII, VIP, MRH, TRH, SP and GHRH) in PVN antinociceptive progress.
    背景与目标: : 我们先前的研究已经证明,下丘脑室旁核 (PVN) 刺激会增加疼痛阈值,而PVN烧灼会降低疼痛阈值。研究了PVN中研究的神经肽与大鼠疼痛调节有关。结果表明 :( 1) 脑室内注射 (icv) 抗精氨酸加压素 (AVP) 血清完全逆转左旋谷氨酸钠 (Glu) 注入PVN引起的痛阈升高,局部给药 (icv) 抗亮氨酸脑啡肽 (l-ek) 血清或抗 β-内啡肽 (beta-Ep) 血清部分减轻了Glu注射到PVN中引起的疼痛阈值增加,但预治疗抗-催产素 (OXT),强啡肽 (1-13) (DynA(1-13)),胆囊收缩素样肽 (CCK),神经降压素 (NT),促肾上腺皮质激素释放激素 (CRH),促肾上腺皮质激素 (ACTH),生长抑素 (SST),催乳素释放激素 (PRH),血管紧张素 (AngII),血管活性肠多肽 (VIP),促甲状腺素释放激素 (MRH),促甲状腺激素释放激素 (TRH),p物质 (SP) 或生长激素释放激素 (GHRH) 血清 (icv) 不影响PVN与Glu的镇痛作用; (2) 用Glu刺激PVN可提高PVN灌注液中AVP,OXT,CCK,NT,CRH,SST,PRH和DynA(1-13) 的浓度,并且不能改变L-Ek,β-Ep,AngII,ACTH,VIP,MRH,PVN灌注液中的TRH,SP和GHRH; (3) 疼痛刺激增加了PVN灌注液中AVP,L-Ek,β-Ep,DynA(1-13),CRH和ACTH的浓度,并且没有改变OXT,CCK,NT,SST,PVN灌注液中的PRH、AngII、VIP、MRH、TRH、SP和GHRH。数据表明,AVP比其他研究的肽 (OXT,l-ek,beta-Ep,DynA(1-13),CCK,NT,CRH,ACTH,SST,PRH,AngII,VIP,MRH,TRH,SP和GHRH) 在PVN抗伤害感受方面的进展。
  • 【二十二碳六烯酸对小鼠各种疼痛刺激的抗伤害作用。】 复制标题 收藏 收藏
    DOI:10.1248/bpb.33.1070 复制DOI
    作者列表:Nakamoto K,Nishinaka T,Mankura M,Fujita-Hamabe W,Tokuyama S
    BACKGROUND & AIMS: :Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (n-3 PUFAs), is an essential polyunsaturated fatty acid in the central nervous system, and possesses many physiological functions in neurodegenerative diseases. Previously, there are some reports that n-3 PUFAs contribute to pain relief. As the antinociceptive effect of DHA alone has not been reported, this study examined the antinociceptive effect of DHA on various pain stimuli. To evaluate the antinociceptive effect of DHA on thermal and chemical nociception, we employed the tail flick test, acetic acid writhing test and formalin test in mice. DHA was orally administrated at 5, 15 and 25 mmol/kg at 30 min before measurement. DHA administration dose-dependently exerted an antinociceptive effect against thermal and chemical stimulation in comparison to the control olive oil administration. These effects of DHA were abolished when mice were pretreated with naloxone, an opioid receptor antagonist. These findings suggest that DHA has opiod receptor-mediated pain control activities, and may provide valuable information towards an advanced therapeutic approach for pain control.
    背景与目标: 二十二碳六烯酸 (DHA) 是一种 ω-3多不饱和脂肪酸 (n-3 PUFAs),是中枢神经系统中必需的多不饱和脂肪酸,在神经退行性疾病中具有许多生理功能。以前,有一些报道称n-3 PUFAs有助于缓解疼痛。由于尚未报道单独使用DHA的抗伤害感受作用,因此本研究检查了DHA对各种疼痛刺激的抗伤害感受作用。为了评估DHA对热和化学伤害感受的抗伤害作用,我们在小鼠中进行了甩尾试验,乙酸扭体试验和福尔马林试验。DHA在测量前30分钟以5、15和25 mmol/kg口服给药。与对照橄榄油相比,DHA给药对热和化学刺激具有剂量依赖性的抗伤害作用。当用阿片受体拮抗剂纳洛酮预处理小鼠时,DHA的这些作用被消除了。这些发现表明DHA具有阿片受体介导的疼痛控制活性,并可能为疼痛控制的先进治疗方法提供有价值的信息。
  • 【脊髓背角抗伤害感受腺苷A1受体的分布,以及与初级传入神经和神经元亚群的关系。】 复制标题 收藏 收藏
    DOI:10.1016/s0306-4522(03)00480-9 复制DOI
    作者列表:Schulte G,Robertson B,Fredholm BB,DeLander GE,Shortland P,Molander C
    BACKGROUND & AIMS: :Adenosine can reduce pain and allodynia in animals and man, probably via spinal adenosine A1 receptors. In the present study, we investigate the distribution of the adenosine A1 receptor in the rat spinal cord dorsal horn using immunohistochemistry, in situ hybridization, radioligand binding, and confocal microscopy. In the lumbar cord dorsal horn, dense immunoreactivity was seen in the inner part of lamina II. This was unaltered by dorsal root section or thoracic cord hemisection. Confocal microscopy of the dorsal horn revealed close anatomical relationships but no or only minor overlap between A1 receptors and immunoreactivity for markers associated with primary afferent central endings: calcitonin gene-related peptide, or isolectin B4, or with neuronal subpopulations: mu-opioid receptor, neuronal nitric oxide synthase, met-enkephalin, parvalbumin, or protein kinase Cgamma, or with glial cells: glial fibrillary acidic protein. A few adenosine A1 receptor positive structures were double-labeled with alpha-amino-3-hydroxy-5-methyl-4-isoaxolepropionic acid glutamate receptor subunits 1 and 2/3. The results indicate that most of the adenosine A1 receptors in the dorsal horn are located in inner lamina II postsynaptic neuronal cell bodies and processes whose functional and neurochemical identity is so far unknown. Many adenosine A1 receptor positive structures are in close contact with isolectin B4 positive C-fiber primary afferents and/or postsynaptic structures containing components of importance for the modulation of nociceptive information.
    背景与目标: : 腺苷可以减轻动物和人的疼痛和异常性疼痛,可能通过脊髓腺苷A1受体。在本研究中,我们使用免疫组织化学,原位杂交,放射性配体结合和共聚焦显微镜研究了腺苷A1受体在大鼠脊髓背角中的分布。在腰索背角中,在椎板II的内部可见密集的免疫反应性。背根节或胸脊髓半切没有改变。背角的共聚焦显微镜显示出密切的解剖关系,但A1受体与与初级传入中心末端相关的标记物的免疫反应性之间没有或只有轻微的重叠: 降钙素基因相关肽或isolectin B4,或与神经元亚群: mu-阿片受体,神经元一氧化氮合酶,met-脑啡肽,小白蛋白或蛋白激酶Cgamma,或与神经胶质细胞: 神经胶质纤维酸性蛋白。一些腺苷A1受体阳性结构被alpha-amino-3-hydroxy-5-methyl-4-isoaxolepropionic谷氨酸受体亚基1和2/3双重标记。结果表明,背角中的大多数腺苷A1受体位于椎板II突触后神经元细胞体中,其功能和神经化学特性迄今尚不清楚。许多腺苷A1受体阳性结构与异结素B4阳性C纤维初级传入和/或突触后结构密切接触者,这些结构包含对调节伤害性信息至关重要的成分。
  • 【对小白豆,三角酸浆和罗莎杂交的抗炎和抗伤害感受活性的研究。】 复制标题 收藏 收藏
    DOI:10.1016/s0378-8741(03)00280-0 复制DOI
    作者列表:Choi EM,Hwang JK
    BACKGROUND & AIMS: :The anti-inflammatory activities of Piper cubeba (fruit), Physalis angulata (flower) and Rosa hybrida (flower) were determined by carrageenan-induced paw edema, arachidonic acid-induced ear edema and formaldehyde-induced arthritis in mice. The anti-allergic and analgesic activities of these plants were also studied by using 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity reaction (type IV) and hot plate test in mice, respectively. These plant extracts clearly exhibited inhibitory effects against acute and subacute inflammation by oral administration (200 mg/kg). Also, administration (200 mg/kg, p.o.) of plant extracts for 1 week significantly inhibited type IV allergic reaction in mice (P<0.05). Rosa hybrida showed an analgesic effect against hot plate-induced thermal stimulation at a dose of 200 mg/kg. These results provide support for the use of Rosa hybrida in relieving inflammatory pain, and insight into the development of new agents for treating inflammatory diseases.
    背景与目标: : 通过角叉菜胶引起的爪子水肿,花生四烯酸引起的耳水肿和甲醛引起的关节炎,测定了小白鼠 (果实),板豆酸浆 (花) 和蔷薇 (花) 的抗炎活性。还通过分别在小鼠中使用2,4-二硝基氟苯 (DNFB) 诱导的接触超敏反应 (IV型) 和热板试验研究了这些植物的抗过敏和镇痛活性。这些植物提取物通过口服给药 (200 mg/kg) 明显表现出对急性和亚急性炎症的抑制作用。此外,施用 (200 mg/kg,p.o.) 植物提取物1周显著抑制小鼠的IV型过敏反应 (P<0.05)。Rosa hybrida在200 mg/kg的剂量下显示出对热板诱导的热刺激的镇痛作用。这些结果为使用Rosa hybrida缓解炎性疼痛提供了支持,并深入了解了治疗炎性疾病的新药物的开发。
  • 【Κ-阿片受体激动剂U50的钠通道阻断作用488有助于其内脏抗伤害感受作用。】 复制标题 收藏 收藏
    DOI:10.1152/jn.00624.2001 复制DOI
    作者列表:Su X,Joshi SK,Kardos S,Gebhart GF
    BACKGROUND & AIMS: The goal of the present study was to determine whether the kappa-opioid receptor agonist (ORA) U50,488 attenuates behavioral and primary afferent nerve responses to noxious colorectal distension (CRD) by sodium channel blockade. We tested the analgesic kappa-ORA (+/-)-trans U50,488, its enantiomers (-)-trans (1S,2S)-U50,488 and non kappa-ORA (+)-trans (1R,2R)-U50,488, and/or its diastereomer (-)-cis (1S,2R)-U50,488 for their ability to attenuate visceromotor and pelvic nerve afferent fiber responses to noxious CRD in vivo and voltage-activated sodium current in colon sensory neurons in vitro. In unanesthetized rats, subcutaneous administration of U50,488, (1S,2S)-U50,488, and (1R,2R)-U50,488 attenuated the behavioral visceromotor response to noxious CRD; the rank order of potency was(1S,2S)-U50,488 > U50,488 angle quotation mark, right (1R,2R)-U50,488. U50,488 and its stereoisomers also inhibited responses of decentralized pelvic nerve afferent fibers to noxious CRD in a dose-dependent manner. Cumulative doses of 16 mg/kg of (1S,2S)-U50,488, (1S,2R)-U50,488, and (1R,2R)-U50,488 reduced responses to a mean 29, 30, and 47% of control, respectively.

    The mean inhibitory doses of these drugs were not different (range6.6-10.8 mg/kg). Sodium channel blockers mexiletine and carbamazepine mimicked the effect of U50,488. In contrast, the kappa-ORAs dynorphin (1-13) and ICI 204,488 were ineffective in attenuating pelvic nerve activity. Perfusion of (1S,2S)-U50,488, (1S,2R)-U50,488, or (1R,2R)-U50,488 on colon sensory neurons in vitro decreased voltage-activated sodium currents. This inhibition by U50,488 and its stereoisomers was not opioid receptor-mediated because it could not be reversed by the opioid receptor antagonist naloxone and was also not a G protein-mediated effect. The results reported here suggest that the visceral antinociceptive effects of U50,488 and its stereoisomers are contributed to by their peripheral sodium channel blocking actions.

    背景与目标: 本研究的目的是确定 κ-阿片受体激动剂 (ORA) U50是否488通过钠通道阻断减弱对伤害性结直肠扩张 (CRD) 的行为和初级传入神经反应。我们测试了镇痛药kappa-ORA (+/-)-反式U50,488,其对映异构体 (-)-反式 (1S,2S)-U50,488和非kappa-ORA (+)-反式 (1R,2R)-U50,488,和/或其非对映体 (-)-顺式 (1S,2R)-U50,488它们在体内减弱内脏运动和骨盆神经传入纤维对伤害性CRD的反应的能力以及在体外结肠感觉神经元中的电压激活钠电流。在未麻醉的大鼠中,皮下注射U50,488,(1S,2S)-U50,488和 (1R,2R)-U50 488减弱了对伤害性CRD的行为内脏运动反应; 效力的等级顺序为 (1S,2S)-U50,488> U50,488角引号,右 (1R,2R)-U50,488。U50、488及其立体异构体还以剂量依赖性方式抑制分散的盆腔神经传入纤维对伤害性CRD的反应。(1S,2S)-U50,488,(1S,2R)-U50,488和 (1R,2R)-U50的累积剂量为16 mg/kg,488降低了对平均29、30和47% 的控制,
    这些药物的平均抑制剂量没有差异 (范围6.6-10.8 mg/kg)。钠通道阻滞剂美西律和卡马西平模拟U50,488的作用。相反,kappa-ORAs强啡素 (1-13) 和ICI 204,488在减弱骨盆神经活动方面无效。(1S,2S)-U50,488,(1S,2R)-U50,488或 (1R,2R)-U50,488在结肠感觉神经元上的体外灌注降低了电压激活的钠电流。U50、488及其立体异构体的这种抑制不是阿片受体介导的,因为它不能被阿片受体拮抗剂纳洛酮逆转,并且也不是g蛋白介导的作用。此处报道的结果表明,U50,488及其立体异构体的内脏抗伤害作用是由其周围的钠通道阻断作用引起的。
  • 【MD-354增强可乐定在小鼠甩尾试验中的抗伤害感受作用,而不是热板试验。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2004.05.028 复制DOI
    作者列表:Wesolowska A,Young S,Dukat M
    BACKGROUND & AIMS: :Albeit conflicting, evidence suggests that 5-HT3 receptor partial agonists as well as alpha2NON-A-adrenoceptor agonists might be involved in antinociception. MD-354 (m-chlorophenylguanidine) can be viewed as the first example of a rather selective 5-HT3/alpha2B-adrenergic ligand. In a tail-flick test in mice, subcutaneous administration of MD-354 doses up to 30 mg/kg did not produce antinociception and failed to antagonize the effect of clonidine (ED50=0.5 mg/kg), but a combination of an inactive de of clonidine (0.25 mg/kg) that produced only 13% maximal possible effect (MPE) with an inactive dose of MD-354 (10 mg/kg, MPE=8%) produced an antinociceptive effect (MPE=83%). In the hot-plate assay, neither subcutaneous administration of MD-354 (3 to 30 mg/kg) alone nor in combination with clonidine (ED50=0.8 mg/kg) produced an antinociceptive effect. MD-354 was demonstrated to potentiate the antinociceptive effect of clonidine in the tail-flick assay, but its underlying mechanism remains to be determined.
    背景与目标: : 尽管相互矛盾,但证据表明5-HT3受体部分激动剂以及alpha2NON-A-adrenoceptor激动剂可能参与了抗伤害感受。MD-354 (间氯苯基胍) 可以被视为相当选择性的5-HT3/alpha2B-adrenergic配体的第一个例子。在小鼠的甩尾试验中,皮下施用高达30 mg/kg的MD-354剂量不会产生抗伤害感受,也不能拮抗可乐定的作用 (ED50 = 0.5 mg/kg),但是,仅产生13% 最大可能效应 (MPE) 的非活性可乐定de (0.25 mg/kg) 与非活性剂量的MD-354 (10 mg/kg,MPE = 8%) 的组合产生抗伤害感受效应 (MPE = 83%)。在热板测定中,单独皮下施用MD-354 (3至30 mg/kg) 或与可乐定 (ED50 = 0.8 mg/kg) 组合均不产生抗伤害感受作用。在甩尾试验中,已证明MD-354增强可乐定的抗伤害感受作用,但其潜在机制仍有待确定。
  • 【在佐剂诱导的慢性炎症大鼠模型中,卡马西平对脊髓水平的热过敏疼痛的抗伤害感受作用。】 复制标题 收藏 收藏
    DOI:10.1007/s00540-010-1046-7 复制DOI
    作者列表:Iwamoto T,Takasugi Y,Higashino H,Ito H,Koga Y,Nakao S
    BACKGROUND & AIMS: PURPOSE:Systemic carbamazepine, a voltage-gated sodium channel blocker, has been reported to dose-dependently reduce inflammatory hyperalgesia. However, the antinociceptive effects of carbamazepine on the spinal cord in inflammatory conditions are unclear. The aim of the present study was to evaluate the antinociceptive effects of carbamazepine on the spinal cord in a chronic inflammatory condition. METHODS:In Sprague-Dawley rats, a chronic inflammatory condition was induced by complete Freund's adjuvant (CFA) inoculation into the tail. Tail flick (TF) latencies were measured following intraperitoneal carbamazepine, or intrathecal carbamazepine or tetrodotoxin injection in intact rats and in the chronic inflammatory rats. From the values of TF latency at 60 min after drug injection, the effective dose required to produce 50% response (ED(50)) of each drug was derived. RESULTS:Carbamazepine attenuated thermal responses with both systemic and intrathecal administration. The effect was more evident in rats with chronic inflammation than in intact rats; the ED(50s) of intraperitoneal carbamazepine in intact and inflamed rats were 12.39 and 1.54 mg/kg, and those of intrathecal carbamazepine were 0.311 and 0.048 nmol, respectively. Intrathecal tetrodotoxin also clearly inhibited the response, with ED(50s) of 1.006 pmol in intact rats and 0.310 pmol in inflamed rats. The relative potencies of intrathecal carbamazepine versus tetrodotoxin for inhibition were approximately 1:150-1:300 in intact and inflamed rats. CONCLUSION:These results indicate that the inhibition of voltage-gated sodium channels, at least tetrodotoxin-sensitive channels, may contribute to the antinociceptive effect of carbamazepine on CFA-induced inflammatory pain, since lower doses of intrathecal carbamazepine and tetrodotoxin attenuated thermal responses to a greater extent in inflamed rats than in intact rats.
    背景与目标:
  • 【P物质 (1-7) 在p物质代谢中的发生及其在小鼠脊髓水平的抗伤害感受活性。】 复制标题 收藏 收藏
    DOI:10.1358/mf.2004.26.3.809722 复制DOI
    作者列表:Sakurada C,Watanabe C,Sakurada T
    BACKGROUND & AIMS: :Substance P (SP), which is known as a pain transmitter or modulator in the spinal cord, was degraded by the synaptic membranes of the mouse spinal cord. The major metabolites of SP were phenylalanine, SP(1-6), SP(1-7), SP(1-9), SP(8-9) and SP(10-11). Degradation of SP was inhibited by a metal chelator, o-phenanthroline, and also by specific inhibitors of endopeptidase-24.11, thiorphan and phosphoramidon. In contrast, captopril (a specific inhibitor of angiotensin-converting enzyme), bestatin (a specific inhibitor of aminopeptidase) and Z-321 (a specific inhibitor of prolylendopeptidase) showed little effect on the degradation of SP. The accumulation of the major cleavage products was strongly inhibited by phosphoramidon and thirophan, as well as the initial cleavage of SP. Thus, endopeptidase-24.11 plays a major role in SP degradation in the mouse spinal cord. Additional in vivo experiments were performed to investigate the antinociceptive effect of SP(1-7), a major product of SP that was detected after incubation with spinal synaptic membranes. In the mouse tail-flick test, the intrathecal administration of SP(1-7) (1.0-4.0 pmol) increased tail-flick latency in a dose-dependent manner. These results suggest that degradation of SP by spinal endopeptidase-24.11 may lead to the formation of SP(1-7), which has an ability to produce antinociceptive effects at the mouse spinal cord level.
    背景与目标: : p物质 (SP) 被称为脊髓中的疼痛递质或调节剂,被小鼠脊髓的突触膜降解。SP的主要代谢产物为苯丙氨酸,SP(1-6),SP(1-7),SP(1-9),SP(8-9) 和SP(10-11)。SP的降解被金属螯合剂邻菲咯啉以及endopeptidase-24.11,硫代吗啡和磷酰胺的特异性抑制剂抑制。相反,卡托普利 (血管紧张素转化酶的特定抑制剂),bestatin (氨肽酶的特定抑制剂) 和Z-321 (脯氨酸内肽酶的特定抑制剂) 对SP的降解几乎没有影响。磷酰胺和thirophan以及SP的初始裂解强烈抑制了主要裂解产物的积累。因此,endopeptidase-24.11在小鼠脊髓的SP降解中起主要作用。进行了其他体内实验以研究SP(1-7) 的抗伤害感受作用,SP是与脊髓突触膜孵育后检测到的SP的主要产物。在小鼠甩尾试验中,鞘内施用SP(1-7) (1.0-4.0 pmol) 以剂量依赖性方式增加甩尾潜伏期。这些结果表明,脊髓endopeptidase-24.11对SP的降解可能导致SP(1-7) 的形成,SP具有在小鼠脊髓水平产生抗伤害感受作用的能力。
  • 【(+/-)-顺式-(6-乙基-四氢吡喃-2-基)-甲酸对小鼠的抗伤害作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejphar.2006.06.067 复制DOI
    作者列表:Marinho BG,Miranda LS,Gomes NM,Matheus ME,Leitão SG,Vasconcellos ML,Fernandes PD
    BACKGROUND & AIMS: :The objective of this study was to investigate spinal and supraspinal antinociceptive effects of a new synthetic compound, (+/-)-cis-(6-ethyl-tetrahydropyran-2-yl)-formic acid (tetrahydropyran derivative). Its activity was compared with those from morphine. In peripheral models of inflammation and hyperalgesia, tetrahydropyran derivative significantly reduced nociceptive effect induced by acetic acid or formalin in mice. Tetrahydropyran derivative developed antinociceptive effect on the tail-flick and hot-plate tests with a long-acting curve maintaining the effect for 4 h longer than morphine. The opioid receptor antagonist naloxone totally reverted tetrahydropyran derivative effects on both models. Morphine as well as tetrahydropyran derivative induced tolerance and sedation in mice. However, tetrahydropyran derivative-induced tolerance had its onset retarded and the sedative activity was lower when compared to that induced by morphine. These results indicate that this new substance develops an antinociceptive activity and may be used in the future as a substitute for traditional opioids.
    背景与目标: : 这项研究的目的是研究一种新的合成化合物 (/-)-顺式-(6-乙基-四氢吡喃-2-基)-甲酸 (四氢吡喃衍生物) 的脊柱和脊髓上镇痛作用。将其活性与吗啡的活性进行了比较。在炎症和痛觉过敏的外周模型中,四氢吡喃衍生物显着降低了乙酸或福尔马林对小鼠的伤害感受作用。四氢吡喃衍生物对甩尾和热板试验产生了抗伤害感受作用,其长效曲线比吗啡保持作用4小时。阿片受体拮抗剂纳洛酮在两种模型上都完全恢复了四氢吡喃衍生物的作用。吗啡以及四氢吡喃衍生物可诱导小鼠耐受和镇静。然而,与吗啡相比,四氢吡喃衍生物诱导的耐受性的发作延迟,镇静活性较低。这些结果表明,这种新物质具有抗伤害感受活性,将来可能用作传统阿片类药物的替代品。
  • 【在抗伤害感受试验中比较 (-)-eseroline与 ()-eseroline和二氢seco类似物: 通过x射线分析确认rubreserine结构。】 复制标题 收藏 收藏
    DOI:10.1021/jm00161a023 复制DOI
    作者列表:Schönenberger B,Jacobson AE,Brossi A,Streaty R,Klee WA,Flippen-Anderson JL,Gilardi R
    BACKGROUND & AIMS: :The enantiomers of eseroline bind to opiate receptors of rat brain membranes with equal affinities and show opiate agonist properties as inhibitors of adenylate cyclase in vitro. However, only (-)-eseroline shows potent narcotic agonist activity in vivo, similar to that of morphine. Neither (-)-noreseroline, (+)-eseroline, nor the open dihydroseco analogue (-)-8 shows analgetic effects in vivo. The structure of rubreserine being a resonance hybrid of an o-quinone with its zwitterionic mesomer is confirmed by solid-state X-ray diffraction analysis.
    背景与目标: : eseroline的对映体以相同的亲和力与大鼠脑膜的阿片受体结合,并在体外显示阿片激动剂作为腺苷酸环化酶抑制剂的特性。然而,只有 (-)-eseroline在体内显示出有效的麻醉激动剂活性,类似于吗啡。(-)-noreseroline,()-eseroline和开放的二氢seco类似物 (-)-8在体内均未显示出镇痛作用。通过固态x射线衍射分析证实了rubreserine的结构是邻醌与其两性离子介体的共振杂种。

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