• 【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。
  • 【强啡肽A通过mu1-opioid受体释放可能参与endomorphin-2的脊髓上抗伤害感受。】 复制标题 收藏 收藏
    DOI:10.1016/j.peptides.2008.04.012 复制DOI
    作者列表:Sakurada S,Sawai T,Mizoguchi H,Watanabe H,Watanabe C,Yonezawa A,Morimoto M,Sato T,Komatsu T,Sakurada T
    BACKGROUND & AIMS: :It has been demonstrated that the antinociception induced by i.t. or i.c.v. administration of endomorphins is mediated through mu-opioid receptors. Moreover, though endomorphins do not have appreciable affinity for kappa-opioid receptors, pretreatment with the kappa-opioid receptor antagonist nor-binaltorphimine markedly blocks the antinociception induced by i.c.v.- or i.t.-injected endomorphin-2, but not endomorphin-1. These evidences propose the hypothesis that endomorphin-2 may initially stimulate the mu-opioid receptors, which subsequently induces the release of dynorphins acting on kappa-opioid receptors to produce antinociception. The present study was performed to determine whether the release of dynorphins by i.c.v.-administered endomorphin-2 is mediated through mu-opioid receptors for producing antinociception. Intracerebroventricular pretreatment with an antiserum against dynorphin A, but not dynorphin B or alpha-neo-endorphin, and s.c. pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine dose-dependently attenuated the antinociception induced by i.c.v.-administered endomorphin-2, but not endomorphin-1 and DAMGO. The attenuation of endomorphin-2-induced antinociception by pretreatment with antiserum against dynorphin A or nor-binaltorphimine was dose-dependently eliminated by additional s.c. pretreatment with a selective mu-opioid receptor antagonist beta-funaltrexamine or a selective mu1-opioid receptor antagonist naloxonazine at ultra low doses, which are inactive against micro-opioid receptor agonists in antinociception, suggesting that endomorphin-2 stimulates distinct subclass of micro1-opioid receptor that induces the release of dynorphin A acting on kappa-opioid receptors in the brain. It concludes that the antinociception induced by supraspinally administered endomorphin-2 is in part mediated through the release of endogenous kappa-opioid peptide dynorphin A, which is caused by the stimulation of distinct subclass of micro1-opioid receptor.
    背景与目标: : 已经证明了由i.t.诱导的抗伤害感受。或者静脉注射。内啡肽的给药是通过 μ-阿片受体介导的。此外,尽管内吗啡对 κ-阿片受体没有明显的亲和力,但用 κ-阿片受体拮抗剂nor-binaltorphimine进行预处理可显着阻断i.c.v.-或i.t.-注射的endomorphin-2诱导的抗伤害感受,但不是endomorphin-1的。这些证据提出了这样的假设,即endomorphin-2可能最初刺激 μ 阿片受体,随后诱导作用于 κ 阿片受体的强啡肽释放产生抗伤害感受。进行本研究以确定由i.c.v.给药的endomorphin-2释放的强啡肽是否通过 μ-阿片受体介导产生抗伤害感受。脑室内用抗强啡肽A的抗血清预处理,但不抗强啡肽B或 α-新内啡肽和s.C。用 κ 阿片受体拮抗剂nor-binaltorphimine进行预处理剂量依赖性地减弱了i.c.v.给药的endomorphin-2,但不endomorphin-1和DAMGO诱导的抗伤害感受。通过额外的s.C剂量依赖性地消除了抗强啡肽A或nor-binaltorphimine抗血清预处理对endomorphin-2-induced抗伤害感受的减弱。用选择性 μ 阿片受体拮抗剂 β-funaltrexamine或选择性mu1-opioid受体拮抗剂纳洛酮嗪进行超低剂量预处理,在抗伤害感受方面对微阿片受体激动剂无效,表明endomorphin-2刺激micro1-opioid受体的不同亚类,从而诱导强啡肽A的释放,作用于大脑中的 κ-阿片受体。结论是,上皮下给药的endomorphin-2诱导的抗伤害感受部分是通过内源性 κ 阿片肽强啡肽A的释放介导的,这是由micro1-opioid受体的不同亚类刺激引起的。
  • 【大麻素介导的抗伤害感受在大鼠骨关节炎膝盖中增强。】 复制标题 收藏 收藏
    DOI:10.1002/art.23156 复制DOI
    作者列表:Schuelert N,McDougall JJ
    BACKGROUND & AIMS: OBJECTIVE:To determine whether local administration of the cannabinoid 1 (CB(1)) receptor agonist arachidonyl-2-chloroethylamide (ACEA) can modulate joint nociception in control rat knee joints and in experimental osteoarthritis (OA). METHODS:OA was induced in male Wistar rats by intraarticular injection of 3 mg of sodium mono-iodoacetate, with a recovery period of 14 days. Electrophysiologic recordings were made of knee joint primary afferent nerve fibers in response to normal rotation and noxious hyperrotation of the joint both before and after close intraarterial injection of different doses of ACEA. RESULTS:Local application of the CB(1) agonist significantly reduced the firing rate of afferent nerve fibers by up to 50% in control knee joints (n=19) and up to 62% in OA knee joints (n=29; P<0.01). Coadministration of the CB(1) receptor antagonist AM251 or the transient receptor potential vanilloid 1 (TRPV-1) ion channel antagonist SB366791 significantly reduced the desensitizing effect of ACEA. The CB(1) receptor antagonist AM251 by itself had no effect in the control joint but significantly increased the firing rate of afferent nerve fibers in the OA joint. CONCLUSION:These findings indicate that activation of peripheral CB(1) receptors reduces the mechanosensitivity of afferent nerve fibers in control and OA knee joints. Blockade of either the CB(1) receptor or the TRPV-1 channel significantly reduced the efficacy of ACEA, which suggests that both receptors are involved in cannabinoid-mediated antinociception. The increased nerve activity observed following CB(1) receptor antagonism suggests a tonic release of endocannabinoids during OA. As such, peripheral CB(1) receptors may be important targets in controlling OA pain.
    背景与目标:
  • 【辣椒素对辣椒素的选择性拮抗作用: 辣椒素诱导的抗伤害感受中脊髓受体位点的证据。】 复制标题 收藏 收藏
    DOI:10.1111/j.1476-5381.1991.tb12547.x 复制DOI
    作者列表:Dickenson AH,Dray A
    BACKGROUND & AIMS: :1. Capsazepine has recently been described as a competitive capsaicin antagonist. We have used this compound to test the hypotheses that the in vitro and in vivo effects of capsaicin are due to interactions with a specific receptor. 2. In an in vitro preparation of the neonatal rat spinal cord with functionally connected tail, the activation of nociceptive afferent fibres by the application of capsaicin, bradykinin or noxious heat (48 degrees C) to the tail could be measured by recording a depolarizing response from a spinal ventral root. Application of capsaicin or substance P to the spinal cord also evoked a depolarizing response which was recorded in a ventral root. 3. When capsazepine (50 nM-20 microM) was administered to the tail or spinal cord it did not evoke any measurable response. However on the tail, capsazepine reversibly antagonized (IC50 = 254 +/- 28 nM) the responses to capsaicin but not to heat or bradykinin administered to the same site. Similarly capsazepine administration to the spinal cord antagonized the responses evoked by capsaicin (IC50 = 230 +/- 20 nM) applied to the cord but not responses evoked by substance P on the cord or by noxious heat and capsaicin on the tail. 4. In halothane anaesthetized rats, C-fibre responses evoked by transcutaneous electrical stimulation of the receptive field were recorded from single wide dynamic range neurones located in the spinal dorsal horn. C-fibre evoked discharges were consistently reduced by the systemic administration of capsaicin (20 mumol kg-1, s.c.) and this action of capsaicin was antagonized by capsazepine (100 mumol kg-1) administered by the same route. In addition the systemic effect of capsaicin was antagonized by a spinal intrathecal administration of capsazepine (5-50 nmol). 5. Intradermal injections of capsaicin, localized to the peripheral receptive field, usually one toe of the ipsilateral hind-paw, produced a transient increase in C-fibre-evoked activity followed by a prolonged period of localized insensitivity to transcutaneous C-fibre stimulation. These effects of capsaicin were significantly reduced by the concommitant administration of capsazepine to the same site. 6. These data demonstrate that capsazepine is a selective antagonist of capsaicin on nociceptive neurones in vitro and in vivo and suggest that the effects of capsaicin were mediated by activation of a specific receptor. Since the antinociceptive effect produced by systemically administered capsaicin was antagonised by spinal intrathecal capsazepine this further supports the hypothesis that capsaicin exerts its antinociceptive effect by acting on specific receptors localized to sensory nerve fibres in the spinal cord.
    背景与目标: : 1。辣椒素最近被描述为一种竞争性辣椒素拮抗剂。我们已经使用该化合物来检验以下假设: 辣椒素的体外和体内作用是由于与特定受体的相互作用所致。2.在具有功能连接的尾巴的新生大鼠脊髓的体外制备中,可以通过记录去极化反应来测量通过向尾巴施用辣椒素,缓激肽或有害热 (48摄氏度) 对伤害性传入纤维的激活来自脊髓腹侧根。将辣椒素或p物质应用于脊髓也引起了去极化反应,该反应在腹侧根部记录。3.当将capsazepine (50 nM-20 microM) 施用于尾部或脊髓时,它不会引起任何可测量的反应。然而,在尾部,辣椒素可逆地拮抗对辣椒素的反应 (IC50 = 254 +/-28 nm),但对给予相同位点的热或缓激肽不应答。类似地,向脊髓施用辣椒素可拮抗施加到脊髓的辣椒素 (IC50 = 230 +/-20 nm) 引起的反应,但不拮抗脊髓上的p物质或有害的热量和尾部的辣椒素引起的反应。4.在氟烷麻醉的大鼠中,从位于脊髓背角的单个宽动态范围神经元记录了经皮电刺激感受野引起的C纤维反应。通过全身施用辣椒素 (20 mumol kg-1,s.C.) 持续减少C纤维诱发的放电,并且辣椒素的这种作用被通过相同途径施用的辣椒素 (100 mumol kg-1) 拮抗。此外,通过鞘内注射辣椒素 (5-50 nmol) 来拮抗辣椒素的全身作用。5.皮内注射辣椒素,定位于外周感受野,通常是同侧后爪的一个脚趾,导致C纤维诱发的活动短暂增加,随后对经皮C纤维刺激的局部不敏感性延长。辣椒素的这些作用通过将辣椒素同时施用到同一部位而显着降低。6.这些数据表明,辣椒素是辣椒素在体外和体内对伤害性神经元的选择性拮抗剂,并表明辣椒素的作用是由特定受体的激活介导的。由于鞘内注射辣椒素产生的抗伤害感受作用被脊髓内注射辣椒素拮抗,这进一步支持了辣椒素通过作用于脊髓中感觉神经纤维的特定受体来发挥其抗伤害感受作用的假说。
  • 【在小鼠脊髓中植入AtT-20或基因修饰的AtT-20/hENK细胞可诱导抗伤害感受和阿片类药物耐受。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Wu HH,Wilcox GL,McLoon SC
    BACKGROUND & AIMS: AtT-20 cells, which make and release beta-endorphin, or AtT-20/hENK cells, an AtT-20 cell line transfected with the human proenkephalin gene and secreting enkephalin as well as presumably beta-endorphin, were implanted in mouse spinal subarachnoid space. Cell implants did not affect the basal response to thermal nociceptive stimuli. Administration of isoproterenol, believed to stimulate secretion from these cells, produced antinociception in groups receiving AtT-20 or AtT-20/hENK cell implants but not in control groups receiving no cells. The antinociceptive effect of isoproterenol was dose related and could be blocked by the opioid antagonist naloxone. Implantation of these cells offers a novel approach for the study of tolerance. Mice receiving AtT-20 cell implants developed tolerance to beta-endorphin and the mu-opioid agonist DAMGO, whereas mice receiving genetically modified AtT-20/hENK cell implants developed tolerance to the delta-opioid agonist DPDPE. Genetically modified AtT-20/hENK cell implants, but not AtT-20 cell implants, reduced the development of acute morphine tolerance in the host mice. This finding is consistent with the suggestion that enkephalin alters development of opioid tolerance. These results suggest that opioid-releasing cells implanted around mouse spinal cord can produce antinociception and may provide an alternative therapy for chronic intractable pain.

    背景与目标: 制造和释放 β-内啡肽或AtT-20/亨克细胞的AtT-20细胞被植入小鼠脊髓蛛网膜下腔,该细胞是一种用人脑啡肽基因转染并分泌脑啡肽以及可能的 β-内啡肽的AtT-20细胞系。细胞植入物不会影响对热伤害性刺激的基础反应。异丙肾上腺素的施用 (据信刺激这些细胞的分泌) 在接受AtT-20或AtT-20/亨克细胞植入物的组中产生了抗伤害感受,但在接受无细胞的对照组中没有。异丙肾上腺素的抗伤害作用与剂量有关,可被阿片类拮抗剂纳洛酮阻断。这些细胞的植入为耐受性的研究提供了一种新的方法。接受AtT-20细胞植入物的小鼠对 β-内啡肽和 μ-阿片激动剂DAMGO产生耐受性,而接受基因修饰的AtT-20/hENK细胞植入物的小鼠对 δ-阿片激动剂DPDPE产生耐受性。基因修饰的AtT-20/亨克细胞植入物 (而非AtT-20细胞植入物) 减少了宿主小鼠中急性吗啡耐受性的发展。这一发现与脑啡肽改变阿片类药物耐受性发展的建议一致。这些结果表明,植入小鼠脊髓周围的阿片类释放细胞可以产生抗伤害感受,并可能为慢性顽固性疼痛提供替代疗法。
  • 【LipoxinA(4) 诱导大鼠慢性背根神经节压迫后的抗伤害感受并降低NF-κ b和促炎细胞因子的表达。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejpain.2011.05.005 复制DOI
    作者列表:Sun T,Yu E,Yu L,Luo J,Li H,Fu Z
    BACKGROUND & AIMS: :Inflammatory and immune responses following nerve injury have been shown to play an important role in neuropathic pain. Lipoxins are endogenous lipoxygenase-derived eicosanoids performing protective roles in a range of pathophysiologic processes. Here, we examined the effects of intrathecal lipoxinA4 (LXA4) on NF-κB activation and pro-inflammatory cytokine (TNF-α, IL-1β and IL-6) expression in dorsal root ganglia (DRG) following chronic compression of DRG (CCD), a model of neuropathic pain. Daily intrathecal injection of vehicle or LXA4 (10 ng or 100 ng) was performed for three successive days post-CCD. CCD induced both mechanical allodynia and thermal hyperalgesia, and increased the expression of TNF-α, IL-1β, IL-6 and NF-κB. Intrathecal injection of LXA4 prevented the development of neuropathic pain and inhibited NF-κB activation and pro-inflammatory cytokine upregulation in a dose-dependent manner. In this study, we have shown the strong protective effect of intrathecal LXA4 on the development of nociceptive behaviors induced by CCD and that these effects might be associated with its anti-inflammatory and pro-resolution properties.
    背景与目标: : 神经损伤后的炎症和免疫反应已被证明在神经性疼痛中起重要作用。脂氧素是内源性脂氧合酶衍生的类花生酸,在一系列病理生理过程中发挥保护作用。在这里,我们研究了鞘内注射lipoxinA4 (LXA4) 对慢性压迫DRG (CCD) 后背根神经节 (DRG) 中NF-κ b活化和促炎性细胞因子 (TNF-α,IL-1β 和IL-6) 表达的影响。神经病理性疼痛。在CCD后连续三天进行每天鞘内注射赋形剂或LXA4 (10 ng ng或100  ng)。CCD引起机械痛觉异常和热痛觉过敏,并增加TNF-α,IL-1β,IL-6和NF-κ b的表达。鞘内注射LXA4可防止神经性疼痛的发展,并以剂量依赖性方式抑制NF-κ b活化和促炎性细胞因子上调。在这项研究中,我们已经证明鞘内LXA4对CCD诱导的伤害感受行为的发展具有很强的保护作用,并且这些作用可能与其抗炎和促分辨特性有关。
  • 【氯胺酮激活L-精氨酸/一氧化氮/环鸟苷单磷酸途径,诱导大鼠外周抗伤害感受。】 复制标题 收藏 收藏
    DOI:10.1213/ANE.0b013e3182285dda 复制DOI
    作者列表:Romero TR,Galdino GS,Silva GC,Resende LC,Perez AC,Côrtes SF,Duarte ID
    BACKGROUND & AIMS: BACKGROUND:The involvement of the L-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway in antinociception has been implicated as a molecular mechanism of antinociception produced by several antinociceptive agents, including μ-, κ-, or δ-opioid receptor agonists, nonsteroidal analgesics, cholinergic agonist, and α2C adrenoceptor agonist. In this study, we investigated whether ketamine, a dissociative anesthetic N-methyl-D-aspartate receptor antagonist, was also capable of activating the L-arginine/NO/cGMP pathway and eliciting peripheral antinociception. METHODS:The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2. All drugs were locally administered into the right hindpaw of male Wistar rats. RESULTS:Ketamine (10, 20, 40, 80 μg/paw) elicited a local antinociceptive effect that was antagonized by the nonselective NOS inhibitor L-NOARG (12, 18, and 24 μg/paw) and by the selective neuronal NOS inhibitor L-NPA (12, 18, and 24 μg/paw). In another experiment, we used the inhibitors L-NIO and L-NIL (24 μg/paw) to selectively inhibit endothelial and inducible NOS, respectively. These 2 drugs were ineffective at blocking the effects of the peripheral ketamine injection. In addition, the level of nitrite in the homogenized paw indicated that exogenous ketamine is able to induce NO release. The soluble guanylyl cyclase inhibitor ODQ (25, 50, and 100 μg/paw) blocked the action of ketamine, and the cGMP-phosphodiesterase inhibitor zaprinast (50 μg/paw) enhanced the antinociceptive effects of low-dose ketamine (10 μg/paw). CONCLUSIONS:Our results suggest that ketamine stimulates the L-arginine/NO/cyclic GMP pathway via neuronal NO synthase to induce peripheral antinociceptive effects.
    背景与目标:
  • 【催产素受体拮抗剂atosiban阻断了雌性大鼠交配诱导的抗伤害感受。】 复制标题 收藏 收藏
    DOI:10.1016/j.yhbeh.2018.12.001 复制DOI
    作者列表:Gómora-Arrati P,Gonzalez-Flores O,Galicia-Aguas YL,Hoffman KL,Komisaruk B
    BACKGROUND & AIMS: AIMS:We hypothesized that copulation-induced temporary anti-nociception in female rats is mediated by the activation of central and/or peripheral oxytocin receptors. To test this hypothesis, we assessed the effects of intraperitoneal (ip), intrathecal (it), and intra-cerebroventricular (icv) administration of an oxytocin receptor antagonist (atosiban), on copulation-induced temporary anti-nociception in estrous rats. MAIN METHODS:The treatment groups were ovariectomized rats pre-treated subcutaneously (sc) with 10 μg of estradiol benzoate (EB) followed 24 h later by an sc injection of 5 μg EB, and 4 h later, by an sc injection of 2 mg progesterone (P4). Rats were then administered saline vehicle (ip, it, or icv: control groups) or atosiban (500 μg/kg ip; 500 ng it; or 500 ng icv: experimental groups). Thirty minutes after drug or saline administration, their sexual behavior was tested by pairing with a sexually-experienced male rat. Brief pulse trains of 50 Hz, 300 ms duration, supra-threshold tail electrical shocks (STS) were delivered before and during copulatory activity i.e., while the female was receiving mounts, intromissions, or ejaculations, and we recorded whether vocalization occurred in response to each STS. KEY FINDINGS:Replicating our previous findings, the vocalization response to STS in control rats was significantly attenuated during intromissions and ejaculations, compared to their baseline (pre-mating) response, indicative of anti-nociception. By contrast, rats pre-treated with atosiban (each route of administration) failed to show an attenuation of the vocalization response to shock. SIGNIFICANCE:These findings provide evidence that the temporary anti-nociceptive effect of copulation in female rats is mediated by copulation-induced release of endogenous oxytocin in brain, spinal cord and periphery.
    背景与目标:
  • 【神经元NO合酶参与几种镇痛药物诱导的外周抗伤害感受机制。】 复制标题 收藏 收藏
    DOI:10.1016/j.niox.2011.08.002 复制DOI
    作者列表:Romero TR,Resende LC,Duarte ID
    BACKGROUND & AIMS: :The production of nitric oxide (NO) from l-arginine is catalyzed by NO synthase (NOS), which exists as the following three isoforms: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). The participation of this pathway in peripheral antinociception has been extensively established by our group with the use of several types of drugs, including opioids, cannabinoids, cholinergic, and α(2C) adrenoceptor agonists and nonsteroidal anti-inflammatory drugs (NSAIDS), and even non-pharmacological procedures such as electroacupuncture. In this study, we aimed to refine the previous data to investigate which type of NOS isoform is involved in the peripheral antinociception mechanism induced by anandamide, morphine, SNC80, bremazocine, acetylcholine, xylazine, baclofen, dipyrone, and diclofenac. After hyperalgesia was induced by intraplantar injection of prostaglandin E(2) in male Wistar rats, we measured peripheral nociception with the paw pressure test. All drugs that were used induced a peripheral antinociception effect that was completely blocked by injection of the selective neuronal NO synthase inhibitor, L-NPA (24μg/paw). The exception was the GABA(B) agonist baclofen, which induced an effect that was not antagonized. We used the inhibitors L-NIO and -NIL (24μg/paw) to exclude the involvement of endothelial and inducible NO synthase, respectively. These drugs were ineffective against the antinociception effect induced by all analgesic drugs that we utilized. Based on the experimental evidence, we conclude that the local injection of analgesic drugs activates nNOS to release NO and induce peripheral antinociception.
    背景与目标: : 由l-精氨酸产生一氧化氮 (NO) 是由NO合酶 (NOS) 催化的,NO合酶 (NOS) 以以下三种同工型存在: 内皮 (eNOS),神经元 (nNOS) 和诱导型 (iNOS)。我们的小组已经广泛建立了这种途径参与外周抗伤害感受的方法,其中包括阿片类药物,大麻素,胆碱能和 α(2C) 肾上腺素受体激动剂以及非甾体类抗炎药 (NSAIDS),甚至非药理学程序,例如电针。在这项研究中,我们旨在完善以前的数据,以研究哪种类型的NOS亚型参与由anandamide,吗啡,SNC80,bremazocine,乙酰胆碱,赛拉嗪,巴氯芬,双吡喃酮和双氯芬酸诱导的外周抗伤害感受机制。在雄性Wistar大鼠中通过足底内注射前列腺素E(2) 引起痛觉过敏后,我们通过paw压力测试测量了外周伤害感受。所有使用的药物均会诱导外周抗伤害感受作用,并通过注射选择性神经元NO合酶抑制剂L-NPA (24 μ g/paw) 完全阻断。唯一的例外是GABA(B) 激动剂巴氯芬,其诱导的作用没有拮抗。我们分别使用抑制剂L-NIO和-NIL (24 μ g/paw) 来排除内皮细胞和诱导型NO合酶的参与。这些药物对我们使用的所有镇痛药引起的抗伤害感受作用无效。根据实验证据,我们得出结论,局部注射镇痛药会激活nNOS释放NO并诱导外周抗伤害感受。
  • 【向健康志愿者静脉注射吗啡后morphine-6-glucuronide对抗伤害感受的贡献。】 复制标题 收藏 收藏
    DOI:10.1177/00912700222011508 复制DOI
    作者列表:Murthy BR,Pollack GM,Brouwer KL
    BACKGROUND & AIMS: :This study was performed to develop an integrated pharmacokinetic-pharmacodynamic model for estimating the contribution of morphine-6-glucuronide (M6G) to morphine-associated antinociception in humans. Healthy volunteers (n = 8) received 10 mg of morphine sulfate as a 5-minute i.v. infusion. A Contact Thermode heat probe was placed on the volar forearm to elicitpain. Thermal threshold, defined as the temperature at which pain was first perceived, was measured at fixed time intervals over 8 hours. Serum concentrations of morphine and M6G were determined by LC/MS. Concentration- and effect-time data were analyzed by stepwise nonlinear least-squares regression. The pharmacodynamic parameter estimates were recovered with a linear effect-compartment model and were used to assess the contribution of M6G to morphine-associated analgesia. The estimates (mean +/- SEM) for morphine total clearance and steady-state volume of distribution were 1.0 +/- 0.07 L/h/kg and 1.6 +/- 0.1 L/kg, respectively. The AUC ratio of M6G to morphine was 0.73 +/- 0.06. The contribution of M6G to analgesia ranged from < 0.1% to 66% and was inversely related to the overall effect elicited by the morphine dose (r2 = 0.776). Differences in gender were observed where the contribution (mean +/- SEM) of M6G to analgesia was 32% +/- 19% in males (n = 3) and 13% +/- 8% in females (n = 5). These results suggest that as the overall effect of morphine increases, the fractional contribution of M6G declines and the contribution of M6G to analgesia may differ between males and females. Alterations in the M6G/morphine system may have clinically significant pharmacodynamic consequences.
    背景与目标: : 进行这项研究是为了开发一种综合的药代动力学-药效学模型,用于估计morphine-6-glucuronide (M6G) 对人类吗啡相关抗伤害感受的贡献。健康志愿者 (n = 8) 接受10毫克硫酸吗啡5分钟静脉输注。将接触式热模热探针放在前臂上,以引起疼痛。在8小时内以固定的时间间隔测量热阈值 (定义为首次感觉到疼痛的温度)。通过LC/MS测定吗啡和M6G的血清浓度。通过逐步非线性最小二乘回归分析浓度和效应时间数据。用线性效应室模型恢复药效学参数估计值,并用于评估M6G对吗啡相关镇痛的贡献。吗啡总清除率和稳态分布体积的估计值 (平均值/- SEM) 分别为1.0/- 0.07 L/h/kg和1.6/- 0.1 L/kg。M6G与吗啡的AUC比为0.73 +/- 0.06。M6G对镇痛的贡献范围为 <0.1% 至66%,并且与吗啡剂量引起的总体效果成反比 (r2 = 0.776)。观察到性别差异,其中M6G对镇痛的贡献 (平均/- SEM) 在男性 (n = 3) 中32%/- 19%,在女性 (n = 5) 中13%/- 8%。这些结果表明,随着吗啡的总体作用增加,M6G的分数贡献下降,而M6G对镇痛的贡献在男性和女性之间可能有所不同。M6G/吗啡系统的改变可能具有临床上显着的药效学后果。

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