Department of Pharmacology, Faculty of Pharmaceutical Science, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Department of Pharmacology, Faculty of Pharmaceutical Science, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Physiol Behav. 2018 Mar 15;186:52-61. doi: 10.1016/j.physbeh.2018.01.010. Epub 2018 Jan 12.
Many studies have associated sleep alterations with the severity of irritable bowel syndrome (IBS) symptoms, but the direct pathophysiological relationship has not been clarified. In addition, alterations in noradrenergic signaling have been implicated in the pathophysiology of IBS, and alpha2-adrenoceptors are potential treatment targets. We have previously shown that acceleration of gastrointestinal transit (GIT) elicited by intermittent rapid eye movement (REM) sleep deprivation stress may fulfill the profile of a model of IBS. Moreover, we showed hypernoradrenergic function in the brain of sleep-deprived mice. On the other hand, acetic acid-induced writhes indicate visceral pain features of IBS model animals. In this study, using mice, we investigated whether intermittent REM sleep deprivation stress causes changes in acetic acid-induced writhing and whether the number of writhes and GIT are improved by administration of the hydrophilic clonidine analogue, ST-91. Mice were deprived of REM sleep intermittently using the small-platform method (20h/day) for 3days. The intermittent REM sleep deprivation stress elicited acceleration of GIT and the increased number of writhes was significantly improved by ST-91 treatment. The ID50 values of ST-91 on the GIT in cage-control mice and intermittent REM sleep-deprived mice were 0.24 and 0.70mg/kg, respectively. In addition, the ID50 values of ST-91 on the writhes in cage-control mice and intermittent REM sleep-deprived mice were 0.52 and 0.73mg/kg, respectively. Further, the expression of alpha2A-adrenoceptor was decreased in the distal ileum of intermittent REM sleep-deprived mice compared to that in cage-control mice. Moreover, the effects of ST-91 on GIT and writhes in cage-control and intermittent REM sleep-deprived mice were decreased by the administration of BRL44408 (6mg/kg, i.p.), a selective alpha2A-adrenoceptor antagonist, and not by the administration of imiloxan (3mg/kg, i.p.), or JP-1302 (3mg/kg, i.p.), selective alpha2B-and alpha2C-adrenoceptor antagonists, respectively. These results suggest that the increase in GIT and writhes induced by intermittent REM sleep deprivation stress may serve as a model of diarrhea and visceral pain symptoms in IBS. Further, the onset of these symptoms may be related to the hypofunction of peripheral alpha2A-adrenoceptor.
许多研究表明，睡眠紊乱与肠易激综合征（IBS）症状的严重程度有关，但直接的病理生理关系尚未阐明。此外，去甲肾上腺素能信号的改变与 IBS 的病理生理学有关，α2-肾上腺素能受体是潜在的治疗靶点。我们之前已经证明，间歇 REM 睡眠剥夺应激引起的胃肠道转运（GIT）加速可能符合 IBS 模型的特征。此外，我们还发现睡眠剥夺小鼠的大脑中存在去甲肾上腺素能功能亢进。另一方面，乙酸诱导的扭动表明 IBS 模型动物的内脏疼痛特征。在这项研究中，我们使用小鼠研究了间歇 REM 睡眠剥夺应激是否会导致乙酸诱导的扭动次数发生变化，以及亲水性可乐定类似物 ST-91 是否会改善扭动次数和 GIT。使用小平台方法（每天 20 小时），将小鼠间歇 REM 睡眠剥夺 3 天。间歇 REM 睡眠剥夺应激引起 GIT 加速，并且 ST-91 处理可显著改善扭动次数增加。在笼养对照小鼠和间歇 REM 睡眠剥夺小鼠中，ST-91 对 GIT 的 ID50 值分别为 0.24 和 0.70mg/kg。此外，在笼养对照小鼠和间歇 REM 睡眠剥夺小鼠中，ST-91 对扭动的 ID50 值分别为 0.52 和 0.73mg/kg。此外，与笼养对照小鼠相比，间歇 REM 睡眠剥夺小鼠的回肠远端α2A-肾上腺素能受体表达减少。此外，ST-91 对 GIT 和扭动的作用在笼养对照和间歇 REM 睡眠剥夺小鼠中，由选择性α2A-肾上腺素能受体拮抗剂 BRL44408（6mg/kg，ip）给药减弱，而由选择性α2B-和α2C-肾上腺素能受体拮抗剂 imiloxan（3mg/kg，ip）或 JP-1302（3mg/kg，ip）给药不减弱。这些结果表明，间歇 REM 睡眠剥夺应激引起的 GIT 和扭动增加可能作为 IBS 腹泻和内脏疼痛症状的模型。此外，这些症状的发作可能与外周α2A-肾上腺素能受体功能低下有关。
