It is reported that some of the fatty acid metabolite levels are higher in nocturia patient plasma compared to non-nocturia patient. Especially, Palmitoylethanolamide (PEA) showed the highest level (1), which are known as an agonist of G protein-coupled receptor 55 (GPR55) (2). Recently, a variety of fatty acid metabolites has been reported to regulate in an intracellular signaling, transcription factor, and gene expression.The reason why the pathophysiological roles of lipids have not been unclarified so far is due to the lack of technology for lipid analysis, so research in lipids for regulating lower urinary tract function is considered promising (3). In the present study, we investigated the distribution of GPR55 and effect of PEA on urination trough GPR55 in the mice bladder.

Male C57BL/6 mice were used in the present study. Mice were bred under 12 h light/dark conditions with free access to food and water for 2 weeks. The light period started from 6 am. The distribution of GPR55 was investigated in the mice bladder, pontine micturition center (PMC), and striatum in which GPR55 are reported to be most predominant, using immunofluorescence staining and western blotting. The GPR55 expression level in the mouse primary cultured urothelial cell (UC) and bladder smooth muscle cell (BSMC) was also quantified using western blotting and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).  PEA (10 mg/kg) was administered intraperitoneally (PEA-IP) at the beginning of sleep phase  in mice under the constant dark cycle. Then, urination behavior  was measured before and after PEA-IP using metabolic cages. PEA was also applied to UCs. The media of UCs was collected after 2 h, 6 h, and 12 h of PEA applying to UCs, then, NGF level was quantified using ELISA assay. Data were processed using a Mann-Whitney U-test. Data are presented as means ± SE. ** p < 0.01; n.s., not significant.

GPR55 was more predominant at bladder urothelial cell layer than bladder smooth muscle cells, PMC, and striatum (Fig 1). The voiding frequency was increased, and bladder capacity was decreased after PEA-IP. The ELISA assay showed that NGF level in the media of UCs were increased significantly compared to control after 6 h and 12 h of PEA applying to UCs (Fig. 2).

The higher serum PEA level during sleep may occur in patients with nocturia, in which a regular metabolic rhythm of fatty acids was disrupted. Thus, GPR55 was activated by the PEA in the bladder urothelium, which results in stimulation of micturition reflex through NGF secretion.

GPR55 could be the new therapeutic target for nocturia.

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