Ramsay Stewart, Spencer Nick J, Zagorodnyuk Vladimir
Discipline of Human Physiology, Flinders Health & Medical Research Institute, College of Medicine and Public Health, Flinders University, South Australia, Australia.
Discipline of Human Physiology, Flinders Health & Medical Research Institute, College of Medicine and Public Health, Flinders University, South Australia, Australia.
Eur J Pharmacol. 2023 Apr 15;945:175624. doi: 10.1016/j.ejphar.2023.175624. Epub 2023 Feb 27.
Bladder afferents play a crucial role in urine storage and voiding, and conscious sensations from the bladder. Endocannabinoids, anandamide (AEA) and 2-arachidonolylglycerol (2-AG), are endogenous ligands of G-protein coupled cannabinoid receptors 1 and 2 (CB1 and CB2) found in the CNS and peripheral organs. They also have off-target effects on some ligand- and voltage-gated channels. The aim of this study is to determine the role of AEA and 2-AG in regulation of mechanosensitivity of probable nociceptive neurons innervating the bladder - capsaicin-sensitive mucosal afferents. The activity of these afferents was determined by ex vivo single unit extracellular recordings in the guinea pig bladder. A stable analogue of anandamide, methanandamide (mAEA) evoked initial excitatory response of mucosal afferents followed by potentiation of their responses to mechanical stimulation. In the presence of TRPV1 antagonist (AMG9810), mAEA's effect on mechanosensitivity switched from excitatory to inhibitory. The inhibitory effect of mAEA is due to activation of both CB1 and CB2 cannabinoid receptors since it was abolished by combined application of selective CB1 (NESS0327) and CB2 (SR144528) antagonists. 2-AG application evoked a brief excitation of mucosal afferents, without potentiation of their mechanosensitivity, followed by the inhibition of their responses to mechanical stimulation. CB2 receptor antagonist, SR144528 abolished the inhibitory effect of 2-AG. Our data indicated that anandamide and 2-AG have opposite effects on mechanosensitivity of mucosal capsaicin-sensitive afferents in the guinea pig bladder; mAEA potentiated while 2-AG inhibited responses of mucosal afferents to mechanical stimulation. These findings are important for understanding of the role of endocannabinoids in regulating bladder sensation and function.
膀胱传入神经在尿液储存、排尿以及膀胱的意识感觉中发挥着关键作用。内源性大麻素，如花生四烯酸乙醇胺（AEA）和2-花生四烯酸甘油酯（2-AG），是在中枢神经系统和外周器官中发现的G蛋白偶联大麻素受体1和2（CB1和CB2）的内源性配体。它们对一些配体门控通道和电压门控通道也有脱靶效应。本研究的目的是确定AEA和2-AG在调节支配膀胱的可能伤害性神经元——辣椒素敏感的黏膜传入神经的机械敏感性中的作用。这些传入神经的活动通过在豚鼠膀胱中进行的离体单单位细胞外记录来确定。花生四烯酸乙醇胺的稳定类似物——甲基花生四烯酸乙醇胺（mAEA）引起黏膜传入神经的初始兴奋反应，随后增强其对机械刺激的反应。在存在TRPV1拮抗剂（AMG9810）的情况下，mAEA对机械敏感性的作用从兴奋转变为抑制。mAEA的抑制作用是由于CB1和CB2大麻素受体的激活，因为联合应用选择性CB1拮抗剂（NESS0327）和CB2拮抗剂（SR144528）可消除该作用。应用2-AG引起黏膜传入神经的短暂兴奋，而不增强其机械敏感性，随后抑制其对机械刺激的反应。CB2受体拮抗剂SR144528消除了2-AG的抑制作用。我们的数据表明，花生四烯酸乙醇胺和2-AG对豚鼠膀胱中黏膜辣椒素敏感传入神经的机械敏感性具有相反的作用；mAEA增强而2-AG抑制黏膜传入神经对机械刺激的反应。这些发现对于理解内源性大麻素在调节膀胱感觉和功能中的作用具有重要意义。
