Discipline of Human Physiology, Flinders Health & Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia.
Am J Physiol Renal Physiol. 2021 May 1;320(5):F859-F865. doi: 10.1152/ajprenal.00065.2021. Epub 2021 Mar 22.
Bladder afferents play a pivotal role in bladder function such as urine storage and micturition as well as conscious sensations such as urgency and pain. Endocannabinoids are ligands of cannabinoid 1 and 2 (CB1 and CB2) receptors but can influence the activity of a variety of G protein-coupled receptors as well as ligand-gated and voltage-gated channels. It is still not known which classes of bladder afferents are influenced by CB1 and CB2 receptor agonists. This study aimed to determine the role of CB2 receptors in two major classes of afferents in the guinea pig bladder: mucosal and muscular-mucosal. The mechanosensitivity of these two classes was determined by an ex vivo extracellular electrophysiological recording technique. A stable analog of endocannabinoid anandamide, methanandamide (mAEA), potentiated the mechanosensitivity of mucosal bladder afferents in response to stroking. In the presence of a transient receptor potential vanilloid 1 antagonist (capsazepine), the effect of mAEA switched from excitatory to inhibitory. A selective CB2 receptor agonist, 4-quinolone-3-carboxyamide (4Q3C), significantly inhibited the mechanosensitivity of mucosal bladder afferents to stroking. In the presence of a CB2 receptor antagonist, the inhibitory effect of 4Q3C was lost. mAEA and 4Q3C did not affect responses to stretch and/or mucosal stroking of muscular-mucosal afferents. Our findings revealed that agonists of CB2 receptors selectively inhibited the mechanosensitivity of capsaicin-sensitive mucosal bladder afferents but not muscular-mucosal afferents. This may have important implications for understanding of the role of endocannabinoids in modulating bladder function and sensation in health and diseases. This article describes, for the first time, to our knowledge, the direct inhibitory effect of cannabinoid 2 receptor agonists on guinea pig mucosal bladder afferents. The cannabinoid 2 receptor is involved in pain and inflammation, suggesting that this may be a viable target for treatment of bladder disorders such as cystitis.
膀胱传入神经在膀胱功能（如储尿和排尿）以及意识感觉（如尿急和疼痛）中起着关键作用。内源性大麻素是大麻素 1 和 2（CB1 和 CB2）受体的配体，但也可以影响多种 G 蛋白偶联受体以及配体门控和电压门控通道的活性。目前尚不清楚 CB1 和 CB2 受体激动剂影响哪些类型的膀胱传入神经。本研究旨在确定 CB2 受体在豚鼠膀胱两种主要传入神经中的作用：黏膜和肌黏膜。这两种传入神经的机械敏感性通过离体细胞外电生理记录技术来确定。内源性大麻素类似物大麻素甲酰胺（methanandamide，mAEA）增强了黏膜膀胱传入神经对刺激的机械敏感性。在瞬时受体电位香草酸 1 拮抗剂（辣椒素）存在的情况下，mAEA 的作用从兴奋变为抑制。选择性 CB2 受体激动剂 4-喹诺酮-3-羧酰胺（4Q3C）显著抑制了黏膜膀胱传入神经对刺激的机械敏感性。在 CB2 受体拮抗剂存在的情况下，4Q3C 的抑制作用消失。mAEA 和 4Q3C 均不影响对肌黏膜传入神经的拉伸和/或黏膜刺激的反应。我们的研究结果表明，CB2 受体激动剂选择性抑制辣椒素敏感的黏膜膀胱传入神经的机械敏感性，但不影响肌黏膜传入神经。这对于理解内源性大麻素在调节健康和疾病状态下膀胱功能和感觉方面的作用具有重要意义。本文首次描述了，据我们所知，大麻素 2 受体激动剂对豚鼠黏膜膀胱传入神经的直接抑制作用。大麻素 2 受体与疼痛和炎症有关，这表明它可能是治疗膀胱炎等膀胱疾病的可行靶点。
