Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, MSRB III, Room 9315, Ann Arbor, Michigan 48109, USA.
Gastroenterology. 2011 Feb;140(2):627-637.e4. doi: 10.1053/j.gastro.2010.11.003. Epub 2010 Nov 9.
BACKGROUND & AIMS: Chronic stress is associated with visceral hyperalgesia in functional gastrointestinal disorders. We investigated whether corticosterone plays a role in chronic psychological stress-induced visceral hyperalgesia.
Male rats were subjected to 1-hour water avoidance (WA) stress or subcutaneous corticosterone injection daily for 10 consecutive days in the presence or absence of corticoid-receptor antagonist RU-486 and cannabinoid-receptor agonist WIN55,212-2. The visceromotor response to colorectal distension was measured. Receptor protein levels were measured and whole-cell patch-clamp recordings were used to assess transient receptor potential vanilloid type 1 (TRPV1) currents in L6-S2 dorsal root ganglion (DRG) neurons. Mass spectrometry was used to measure endocannabinoid anandamide content.
Chronic WA stress was associated with visceral hyperalgesia in response to colorectal distension, increased stool output and reciprocal changes in cannabinoid receptor 1 (CB1) (decreased) and TRPV1 (increased) receptor expression and function. Treatment of WA stressed rats with RU-486 prevented these changes. Control rats treated with serial injections of corticosterone in situ showed a significant increase in serum corticosterone associated with visceral hyperalgesia, enhanced anandamide content, increased TRPV1, and decreased CB1 receptor protein levels, which were prevented by co-treatment with RU-486. Exposure of isolated control L6-S2 DRGs in vitro to corticosterone reproduced the changes in CB1 and TRPV1 receptors observed in situ, which was prevented by co-treatment with RU-486 or WIN55,212-2.
These results support a novel role for corticosterone to modulate CB1 and TRPV1-receptor pathways in L6-S2 DRGs in the chronic WA stressed rat, which contributes to visceral hyperalgesia observed in this model.
慢性应激与功能性胃肠疾病的内脏痛觉过敏有关。我们研究了皮质酮是否在慢性心理应激引起的内脏痛觉过敏中发挥作用。
雄性大鼠在存在或不存在皮质激素受体拮抗剂 RU-486 和大麻素受体激动剂 WIN55,212-2 的情况下，每天接受 1 小时水回避（WA）应激或皮下皮质酮注射，连续 10 天。测量结肠扩张的内脏运动反应。测量受体蛋白水平，并使用全细胞膜片钳记录评估 L6-S2 背根神经节（DRG）神经元中瞬时受体电位香草酸类型 1（TRPV1）电流。质谱法用于测量内源性大麻素大麻素。
慢性 WA 应激与结肠扩张时的内脏痛觉过敏、粪便排出量增加以及大麻素受体 1（CB1）（减少）和 TRPV1（增加）受体表达和功能的相互变化有关。用 RU-486 治疗 WA 应激大鼠可预防这些变化。用原位连续注射皮质酮处理的对照大鼠与内脏痛觉过敏相关的血清皮质酮水平显著升高，大麻素含量增加，TRPV1 增加，CB1 受体蛋白水平降低，用 RU-486 共同处理可预防这些变化。体外暴露于皮质酮的分离对照 L6-S2 DRG 重现了原位观察到的 CB1 和 TRPV1 受体变化，用 RU-486 或 WIN55,212-2 共同处理可预防这些变化。
这些结果支持皮质酮在慢性 WA 应激大鼠 L6-S2 DRG 中调节 CB1 和 TRPV1 受体途径的新作用，这有助于该模型中观察到的内脏痛觉过敏。
