Identification of 5‐HT2C mediated mechanisms involved in urethral sphincter reflexes in a guinea‐pig model of urethral function

Abstract

Preclinically, studies investigating urethral function have shown that the clinical benefit of agents such as duloxetine may partly reflect increases in urethral striated muscle activity via a central mode of action. Duloxetine has been shown to inhibit the presynaptic reuptake of 5-HT and norepinephrine in Onuf's nucleus, leading to an increased activity of pudendal motor neurones and a subsequent increase in the strength of urethral sphincter contractions. Preclinical studies have postulated a role for both 5-HT(2C) receptors and 5-HT(2A) receptors in external urethral sphincter (EUS) function, with differences between species that may reflect the differing physiological roles of the EUS in different preclinical species. The present study therefore aimed to investigate the 5-HT receptor subtype involved in EUS function in the guinea-pig. The in vivo data reported in the present study suggest that the effects of clinical agents used to treat stress urinary incontinence, which enhance serotonergic drive, may be mediated, at least in part, via 5-HT(2C) receptors. To elucidate the subtype of 5-HT receptor involved in urethral function using a preclinical model of urethral function. The effects of the 5-HT(2C) agonist Ro 600-175 were investigated by measuring the urethral pressure profile in anaesthetized guinea-pigs together with antagonists at 5-HT(2A) , 5-HT(2B) and 5-HT(2C) receptor subtypes. Ro 600-175 increased peak urethral pressure in a dose-dependent manner. This effect was reversed by the selective 5-HT(2C) antagonist SB 242084. Neither the 5-HT(2A) antagonist MDL 100907, nor the 5-HT(2B) antagonist SB 240741 had any significant effect on the response. The clinical benefit of drugs used to treat stress urinary incontinence through enhanced serotonergic and adrenergic drive may be mediated, at least in part, via 5-HT(2C) receptors. Selective 5-HT(2C) agonism increases urethral tone, and hence provides an opportunity for developing new pharmacotherapies for stress urinary incontinence with reduced side-effects.