title: Role of spinal serotonergic pathways in sneeze-induced urethral continence reflex in rats.
abstract: To clarify the role of spinal serotonergic mechanisms in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of intrathecal (it) application of 8-OH-DPAT (a 5-HT(1A) agonist), mCPP (a 5-HT(2B/2C) agonist), and fluoxetine (a serotonin reuptake inhibitor) using a rat model that can examine the neurally evoked continence reflex during sneezing. Amplitudes of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats and rats with SUI induced by vaginal distention (VD). In normal rats, 8-OH-DPAT decreased A-URS by 48.9%, whereas mCPP increased A-URS by 33.6%. However, A-URS was not changed after fluoxetine. 8-OH-DPAT, mCPP, or fluoxetine did not alter UBP. The effect of 8-OH-DPAT and mCPP was antagonized by WAY-100635 (it), a selective 5-HT(1A) antagonist, and RS-102221 (it), a selective 5-HT(2C) antagonist, respectively. Fluoxetine in the presence of WAY-100635 did not change either A-URS or UBP, but fluoxetine in the presence of RS-102221 decreased A-URS. In VD rats, S-LPP was decreased by 14.6 cmH2O after 8-OH-DPAT, whereas it was increased by 12.8 cmH2O after mCPP. However, S-LPP was not changed after fluoxetine. These results indicate that activation of 5-HT(2C) receptors enhances the active urethral closure reflex during sneezing at the spinal level, whereas 5-HT(1A) inhibits it and that no apparent changes in the sneeze-induced continence reflex after fluoxetine treatment are due to coactivation of excitatory 5-HT(2C) receptors and inhibitory 5-HT receptors other than the 5-HT(1A) subtype. Thus, activation of excitatory 5-HT receptor subtypes such as 5-HT(2C) could be effective for the treatment of SUI.
authors.affiliation: Dept. of Urology, Univ. of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Minoru
authors.initials: M
authors.lastname: Miyazato
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kaiho
authors.forename: Izumi
authors.initials: I
authors.lastname: Kamo
authors.forename: Takeya
authors.initials: T
authors.lastname: Kitta
authors.forename: Michael B
authors.initials: MB
authors.lastname: Chancellor
authors.forename: Kimio
authors.initials: K
authors.lastname: Sugaya
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Arai
authors.forename: William C
authors.initials: WC
authors.lastname: de Groat
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimura
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D005260:Female; D005473:Fluoxetine; D010879:Piperazines; D011312:Pressure; D011725:Pyridines; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012912:Sneezing; D013141:Spiro Compounds; D013449:Sulfonamides; D014521:Urethra / Q000502:physiology*; D014550:Urinary Incontinence, Stress / Q000378:metabolism / Q000503:physiopathology*
chemical_list: C107821:8-(5-(5-amino-2,4-dimethoxyphenyl)-5-oxopentyl)-1,3,8-triazaspiro(4.5)decane-2,4-dione; D010879:Piperazines; D011725:Pyridines; D044348:Receptors, Serotonin, 5-HT2; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D013141:Spiro Compounds; D013449:Sulfonamides; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C015068:1-(3-chlorophenyl)piperazine