Moloney Rachel D, Golubeva Anna V, O'Connor Richard M, Kalinichev Mikhail, Dinan Timothy G, Cryan John F
Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Ireland; Department of Psychiatry, University College Cork, Ireland.
Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Ireland.
Neurobiol Stress. 2015 Apr 4;2:28-33. doi: 10.1016/j.ynstr.2015.04.001. eCollection 2015.
Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect through ionotropic and metabotropic receptors. Of these, group III mGlu receptors (mGlu 4, 6, 7, 8) are among the least studied due to a lack of pharmacological tools. mGlu7 receptors, the most highly conserved isoform, are abundantly distributed in the brain, especially in regions, such as the amygdala, known to be crucial for the emotional processing of painful stimuli. Visceral hypersensitivity is a poorly understood phenomenon manifesting as an increased sensitivity to visceral stimuli. Glutamate has long been associated with somatic pain processing leading us to postulate that crossover may exist between these two modalities. Moreover, stress has been shown to exacerbate visceral pain. ADX71743 is a novel, centrally penetrant, negative allosteric modulator of mGlu7 receptors. Thus, we used this tool to explore the possible involvement of this receptor in the mediation of visceral pain in a stress-sensitive model of visceral hypersensitivity, namely the Wistar Kyoto (WKY) rat. ADX71743 reduced visceral hypersensitivity in the WKY rat as exhibited by increased visceral sensitivity threshold with concomitant reductions in total number of pain behaviours. Moreover, AD71743 increased total distance and distance travelled in the inner zone of the open field. These findings show, for what is to our knowledge, the first time, that mGlu7 receptor signalling plays a role in visceral pain processing. Thus, negative modulation of the mGlu7 receptor may be a plausible target for the amelioration of stress-induced visceral pain where there is a large unmet medical need.
谷氨酸是中枢神经系统中的主要兴奋性神经递质，它通过离子型受体和代谢型受体发挥作用。其中，III组代谢型谷氨酸受体（mGlu 4、6、7、8）由于缺乏药理学工具，是研究最少的受体之一。mGlu7受体是最保守的亚型，在大脑中广泛分布，尤其是在杏仁核等已知对疼痛刺激的情绪处理至关重要的区域。内脏超敏反应是一种理解不足的现象，表现为对内脏刺激的敏感性增加。谷氨酸长期以来一直与躯体疼痛处理相关，这使我们推测这两种模式之间可能存在交叉。此外，压力已被证明会加剧内脏疼痛。ADX71743是一种新型的、可穿透中枢的mGlu7受体负变构调节剂。因此，我们使用这个工具，在一种内脏超敏反应的应激敏感模型即Wistar京都（WKY）大鼠中，探索该受体在介导内脏疼痛中的可能作用。ADX71743降低了WKY大鼠的内脏超敏反应，表现为内脏敏感性阈值升高，同时疼痛行为总数减少。此外，AD71743增加了旷场试验中总距离和在内区行走的距离。据我们所知，这些发现首次表明mGlu7受体信号传导在内脏疼痛处理中起作用。因此，对mGlu7受体的负调节可能是缓解应激诱导的内脏疼痛的一个合理靶点，而这方面存在大量未满足的医疗需求。
