Impaired Nociception and Peripheral Opioid Antinociception in Mice Lacking Both Kinin B1 and B2 Receptors
Impaired Nociception and Peripheral Opioid Antinociception in Mice Lacking Both Kinin B1 and B2 Receptors
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DOI：
10.1097/aln.0b013e318242b2ea
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发表时间：
2012-02-01
期刊：
影响因子：
8.8
通讯作者：
Stein, Christoph
中科院分区：
文献类型：
--
作者：
Cayla, Cecile;Labuz, Dominika;Stein, Christoph
背景：激肽（例如，缓激肽）通过组成性表达的B2和损伤诱导的B1受体起作用，参与疼痛和痛觉过敏，如先前通过使用受体选择性拮抗剂和单受体敲除模型所示。由于激肽对疼痛过程的总体贡献尚不清楚，本研究的目的是分析由于缺乏B1和B2受体而无法对激肽作出反应的小鼠的疼痛相关行为。在缺乏B1和B2受体的基因敲除小鼠和野生型小鼠中，（每组n = 8-21）作者评估了对机械和热刺激的伤害性阈值，（分别为von Frey和Hargreaves试验），并在诱导炎性和神经性疼痛，酸诱导的内脏伤害感受，结果：B1和B2受体基因敲除小鼠对热的基础伤害性反应不变，对缓激肽的伤害性反应消失，急性乙酸引起的内脏伤害性反应降低约70%，而对B1受体基因敲除小鼠的基础伤害性反应无明显变化（平均差异：19.5扭体/30分钟）和热过敏性角叉菜胶诱导的足爪炎症在注射后48小时减少（平均差2.88秒），慢性完全弗氏佐剂诱导的爪炎症或坐骨神经慢性压迫性损伤后的超敏反应没有变化，慢性压迫性损伤后外周μ-和δ-阿片样物质诱导的镇痛作用降低了30-35%（平均差异：μ-激动剂：0.495 g，δ-激动剂：0.555 g）。结论：这些数据表明，激肽对于与急性短暂炎症相关的伤害感受是重要的，但在疼痛的慢性阶段不太重要。结果还强调了激肽通过与阿片系统相互作用的新保护功能。
Background: Kinins (e.g., bradykinin) acting through the constitutively expressed B2 and the injury-induced B1 receptors are involved in pain and hyperalgesia, as previously shown by use of receptor-selective antagonists and single-receptor knockout models. Because the overall contribution of kinins to painful processes remains unclear, the aim of this study was to analyze pain-related behaviors of mice unable to respond to kinins because of a lack of both B1 and B2 receptors.Methods: In knockout mice lacking both B1 and B2 receptors and in wild-type mice (n = 8-21 per group) the authors assessed nociceptive thresholds to mechanical and heat stimuli (von Frey and Hargreaves tests, respectively) in healthy animals and after induction of inflammatory and neuropathic pain, acid-induced visceral nociception, and modulation of nociceptive responses by peripherally administered opioid agonists.Results: In knockout mice lacking both B1 and B2 receptors baseline nociceptive responses to heat were unaltered, nocifensive responses to bradykinin were abolished, acute acetic acid-induced visceral nociception was reduced by approximately 70% (mean difference: 19.5 writhes/30 min) and heat hypersensitivity in carrageenan-induced paw inflammation was decreased 48 h after injection (mean difference 2.88 s), hypersensitivities in chronic complete Freund's adjuvant-induced paw inflammation or after chronic constriction injury of the sciatic nerve were unchanged, and peripheral mu- and delta-opioid-induced analgesia after chronic constriction injury was reduced by 30-35% (mean differences: mu-agonist: 0.495 g, delta-agonist: 0.555 g).Conclusions: These data suggest that kinins are important for nociception associated with acute short-lasting inflammation but are less essential in chronic stages of pain. The results also highlight a new protective function of kinins via interactions with the opioid system.