Neuroscience 2005 Abstract
| Presentation Number: | 48.14 |
|---|---|
| Abstract Title: | Identification of 5-HT<sub>2C</sub>-mediated mechanisms involved in urethral sphincter reflexes. |
| Authors: |
Conlon, K.*1
; Miner, W.1
; Christy, C.1
; McCleary, S.1
; Brinkman, H.1
; Rees, H.1
; McMurray, G.1
1Discovery Biology, Pfizer Global Research and Development, Sandwich, United Kingdom |
| Primary Theme and Topics |
Homeostatic and Neuroendocrine Systems - Gastrointestinal and Urogenital Regulation |
| Session: |
48. GI and Urogenital Regulation I Poster |
| Presentation Time: | Saturday, November 12, 2005 2:00 PM-3:00 PM |
| Location: | Washington Convention Center - Hall A-C, Board # O7 |
| Keywords: |
Stress urinary incontinence (SUI) is the involuntary loss of urine on exertion due to impaired urethral tone. Drugs which enhance serotonergic and adrenergic drive and urethral function in pre-clinical animal models are effective in treating SUI, but are known to have undesirable side-effects such as nausea. Presently, in dog sacral spinal cord, we identified Onuf’s nucleus (ON), which is known to contain neurones responsible for the somatic innervation of the external urethral sphincter (EUS), and utilised laser `capture micro-dissection and reverse transcriptase-polymerase chain reaction techniques to show high levels of 5-HT2C receptors within these neurones. Subsequently, we investigated the effects of known 5-HT2C agonists mCPP, Ro 60-0175 and YM 348 in guinea pig and canine models of urethral function. In terminally anaesthetised female guinea pigs all agonists (0.01- 1 mg kg-1 iv.) induced dose-dependent increases in EUS electromyographic (EMG) activity during normal bladder filling, compared to controls. This effect was reversed by the selective 5-HT2C antagonist, SB 242084 (0.1-1mg kg-1 iv.). In addition, urethral pull-through pressure profile measurements in terminally anaesthetised female beagle dogs, using a Millar transducer catheter (7Fr) showed dose-dependent increases in peak urethral pressure in response to mCPP, Ro 60-0175 and YM 348 (0.01-1 mg kg-1 iv.). Canine measures of urethral function using this method have been shown to have good translation to the clinic using clinical agents (e.g duloxetine).
In conclusion, the clinical benefit of drugs used to treat SUI through enhanced serotonergic and adrenergic drive may be mediated, at least in part, via 5-HT2C receptors expressed in EUS motor neurones located in ON. Selective 5-HT2C agonism increases urethral tone, and, hence, provides an opportunity to develop new pharmacotherapies for SUI with reduced side-effects.
In conclusion, the clinical benefit of drugs used to treat SUI through enhanced serotonergic and adrenergic drive may be mediated, at least in part, via 5-HT2C receptors expressed in EUS motor neurones located in ON. Selective 5-HT2C agonism increases urethral tone, and, hence, provides an opportunity to develop new pharmacotherapies for SUI with reduced side-effects.
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2005 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2005. Online.
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