Investigation of the role of 5‐HT 2 receptor subtypes in the control of the bladder and the urethra in the anaesthetized female rat

Background and purpose: Micturition is controlled by central 5‐HT‐containing pathways. 5‐HT 2 receptors have been implicated in this system especially in control of the urethra, which is a drug target for treating urinary incontinence. This study investigates the role of each of the three subtypes of this receptor with emphasis on sphincter regulation. Experimental approach: Recordings of urethral and bladder pressure, external urethral sphincter (EUS) EMG, as well as the micturition reflex induced by bladder distension along with blood pressure and heart rate were made in anaesthetized rats. The effects of agonists and antagonists for 5‐HT 2 receptor subtypes were studied on these variables. Key results: The 5‐HT 2C agonists Ro 60‐0175, WAY 161503 and mCPP, i.v., activated the EUS, increased urethral pressure and inhibited the micturition reflex. The effects of Ro 60‐0175 on the EUS were blocked by the 5‐HT 2C antagonist SB 242084 and the 5‐HT 2A antagonists, ketanserin and MDL 100907. SB 242084 also blocked the inhibitory action on the reflex, while the 5‐HT 2B antagonist RS 127445 only blocked the increase in urethral pressure. The 5‐HT 2A receptor agonist DOI given i.v. or i.t. but not i.c.v. activated the EUS. Conclusions and implications: 5‐HT 2A/2C receptors located in the sacral spinal cord activate the EUS, while central 5‐HT 2C receptors inhibit the micturition reflex and 5‐HT 2B receptors, probably at the level of the urethra, increase urethral smooth muscle tone. Furthermore, 5‐HT 2B and 5‐HT 2C receptors do not seem to play an important role in the physiological regulation of micturition. British Journal of Pharmacology (2008) 155 , 343–356; doi: 10.1038/bjp.2008.273 ; published online 7 July 2008