Involvement of cholecystokininergic systems in anxiety-induced hyperalgesia in male rats: Behavioral and biochemical studies
Involvement of cholecystokininergic systems in anxiety-induced hyperalgesia in male rats: Behavioral and biochemical studies
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DOI：
10.1523/jneurosci.0743-05.2005
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发表时间：
2005-08-31
影响因子：
5.3
通讯作者：
Becker, C
中科院分区：
文献类型：
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作者：
Andre, J;Zeau, B;Becker, C
考虑到焦虑或抑郁患者报告的疼痛主诉有所增加，我们的目标是在大鼠中研究实验引发的焦虑/抑郁状态对疼痛行为及其潜在机制的影响。因此，我们使用了一种社会失败模型，包括 30 分钟的受保护对抗，然后是 15 分钟的身体对抗，在 4 天内重复，这引发了与焦虑或抑郁人类中观察到的症状相似的症状。事实上，5天后，遭受社交失败对抗的动物的特征是甜水消耗量和体重下降，以及下丘脑-垂体-肾上腺轴过度活跃，这表明社交失败过程会引起长期的焦虑状态。在最后一次对抗后 5 天，接受社交失败程序的大鼠对皮下注射福尔马林表现出增强的伤害性行为。由于用已知的抗焦虑药氯氮卓（10mg (.) kg(-1) (.) d(-1)）长期治疗可预防痛觉过敏，这强烈表明该实验过程可能是“焦虑引起的痛觉过敏”的合适动物模型。与焦虑相关的痛觉过敏不仅与额叶皮层微透析液中 CCKLM [胆囊收缩素 (CCK) 样物质] 的显着增加有关，而且还可以通过 CCK-B 受体拮抗剂来预防[4-[[2-[[3-(1H-吲哚-3-基)-2-甲基-1-氧代2[[(三环[3.3[12,17]癸-2-基氧基)-羰基]氨基]-丙基]氨基]-1-苯乙基]氨基]-4-氧代-[R-(R*,R*)]-丁酸酯-N-甲基-D-葡萄糖胺(CI-988)](2 mg/kg），强烈支持中央 CCKergic 系统参与这些现象。最后，CI-988 和吗啡的联合治疗完全抑制了疼痛相关行为，这支持了以下观点：两种化合物的结合可能代表一种新的治疗方法，可以减少焦虑或抑郁患者中普遍存在的疼痛抱怨的增加。
Keeping in mind the increased pain complaints reported in anxious or depressive patients, our goal was to investigate in rats the consequences of an experimentally provoked state of anxiety/depression on pain behavior and on its underlying mechanisms. We therefore used a model of social defeat consisting of a 30 min protected confrontation followed by a 15 min physical confrontation, repeated during 4 d, that elicited symptoms close to those observed in humans with anxiety or depression. Indeed, 5 d later, animals subjected to social-defeat confrontation were characterized by a decrease of sweet-water consumption and of body weight, and a hyperactivity of the hypothalamic-pituitary-adrenal axis, suggesting that the social-defeat procedure induced a prolonged state of anxiety. Rats subjected to the social-defeat procedure showed an enhanced nociceptive behavior to the subcutaneous administration of formalin, 5 d after the last confrontation session. Because chronic treatment with the established anxiolytic chlordiazepoxide (10mg (.) kg(-1) (.) d(-1)) prevented hyperalgesia, this strongly suggested that this experimental procedure might be a suitable animal model of "anxiety-inducedhyperalgesia." Hyperalgesia associated with anxiety not only was related to a significant increase of CCKLM [ cholecystokinin (CCK)-like material] in frontal cortex microdialysates but also was prevented by a CCK-B receptor antagonist [4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo2[[(tricyclo[3.3[12,17]dec-2-yloxy)-carbonyl]amino]-propyl]amino]-1-phenyethyl]amino]-4-oxo-[R-(R*,R*)]-butanoate-N-methyl- D-glucamine (CI-988)] (2 mg/kg), strongly supporting the involvement of central CCKergic systems in these phenomena. Finally, combined treatments with CI-988 and morphine completely suppressed pain-related behavior, supporting the idea that the association of both compounds might represent a new therapeutic approach to reduce the increase of pain complaints highly prevalent among anxious or depressive patients.