Orexin-A在晕动症发生中的作用研究

Motion sickness is a physiological response, the main symptoms of which include lethargy, anorexia, sweating, nausea, vomiting. But the precise neurobiological mechanism has not been fully clarified. Many studies have demonstrated that orexin plays an important role in sleep-wakefulness, feeding and gastrointestinal function. Our research showed that bilateral vestibular damage caused the increase of Orexin A (OxA) positive neurons in lateral hypothalamic area (LH), while motion stimulation significantly decrease of those. Intraventricular injection of OxA, however, significantly alleviated the symptoms of motion sickness, promoted the expression of Fos protein in locus coeruleus (LC) and inhibited the expression of Fos protein in the medial amygdala nucleus (MeA). It has been confirmed that orexin neurons can excite the noradrenergic LC, which have the inhibitory effect on MeA neurons. Moreover, anatomy evidence showed Orexin neurons directly project to the noradrenergic LC which has a direct projection to MeA. It suggested that orexin may be involved in alleviating motion sickness symptoms through the LH-LC-MeA pathway. In this study, we would like to investigate expression of OxA and its receptors in motion sickness, to verify the types of orexin receptors and downstream signaling pathway related to motion sickness, to identify the mechanism that OxA may be involved in occurrence of motion sickness through regulation of the LH-LC-MeA pathway activity.

晕动症可引起嗜睡、厌食、出冷汗、恶心、呕吐等反应，但相关神经机制尚不明确。研究证实，Orexin在睡眠-觉醒、摄食及胃肠功能调节中起重要作用。我们发现，双侧前庭器官损毁大鼠下丘脑外侧区（LH）Orexin A（OxA）阳性神经元数量显著增加，而晕动刺激时OxA阳性神经元数量则明显降低；侧脑室注射OxA可明显缓解晕动症症状，促进蓝斑（LC）区Fos蛋白表达，并抑制杏仁内侧核（MeA）区Fos蛋白表达。已证实，LH区Orexin神经元对LC去甲肾上腺素能神经元有兴奋性调控作用；而后者对MeA神经元具有抑制性调节作用，且三者间存在直接的解剖联系。提示Orexin可能通过调节LH-LC-MeA通路活性，缓解晕动症症状的发生。本研究拟观察OxA及其受体表达变化与晕动症发生的关系，明确相关的OxA受体类型及信号通路；初步证明OxA通过调控LH-LC-MeA神经通路活性参与晕动症的发生过程。

晕动症可引起厌食、恶心、呕吐、流涎、嗜睡、出冷汗、体温降低等反应，但相关神经机制尚不明确。研究表明，下丘脑外侧区（LHA） 增食欲素（Orexin）系统在机体摄食、自主神经、心血管系统、昼夜节律、运动及体温方面具有重要的调节作用，Orexin神经元所合成分泌的Orexin-A（OXA）具有增加摄食、抑制恶心呕吐、促进自发活动以及调节体温等作用，这些作用效果与晕动症的症状恰恰相反。研究证实，晕动症的症状表现与前庭内脏反射密切相关，然而Orexin系统是否参与前庭内脏反射的调节，以及是否对晕动症引起的植物神经症状具有缓解作用，目前尚未见报道。该研究发现，侧脑室外源性OXA注射后，可明显缓解晕动症大鼠的厌食、胃肠道反应（条件性张口与排便）、运动障碍（自发活动减少）及低体温症状，使DMV、PVN的神经元活性下降，DMD、PMV的神经元活性升高；在晕动症模型大鼠下丘脑相关区域注射外源性OXA后，可通过激动下丘脑背内侧核（DMH）的OX1R缓解厌食及自发活动降低的症状，激动下丘脑室旁核（PVN）的OX1R缓解恶心、呕吐的症状，激动乳头前核腹侧部（PMV）的OX2R缓解低体温症状；此外，OXA还可能通过OX1R逆向激活CB1R，调节突触前、后的递质释放，改变DMH、PMV的神经元活性，发挥缓解晕动症厌食及低体温症状的作用。进一步通过荧光金逆行标记实验，发现脑干NTS与下丘脑DMH、PMV之间有直接的投射联系， PBN与DMH、PVN、PMV之间有直接的投射联系，表明前庭内脏刺激信号可直接影响下丘脑植物神经上述相关核团的活性，从而引起晕动症相关症状。该研究以Orexin-A对晕动症症状的缓解作用及机制为基础，为后期研究新的晕动症防治手段提供理论依据和实验基础。