The Neuro-Urological Connection Martin C. Michel, Matthias Oelke, Stephan L.M. Peters  European Urology Supplements  Volume 4, Issue 1, Pages 18-28 (January 2005) DOI: 10.1016/j.eursup.2004.10.004 Copyright © 2004 Elsevier B.V. Terms and Conditions

Fig. 1 Proposed model of the role of glutamate, serotonin (5-HT) and noradrenaline (NA) in the control of urethral function at the organ level. Panel A: Storage phase. Activity of the pudendal nerve is primarily controlled in the sacral spinal cord, i.e. Onuf's nucleus, by descending nerve fibres releasing glutamate. Neurones releasing 5-HT or NA act to potentiate the effects of glutamate, resulting in an enhanced tone of the urethral rhabdosphincter. Duloxetine increases synaptic 5-HT and NA concentrations and hence enhances the facilitatory role of 5-HT and NA. Panel B: During voiding glutamate is turned off, eliminating pudendal nerve activity and allowing the urethral rhabdosphincter to relax, even in the presence of duloxetine. (Adapted from Viktrup et al. [70], reproduced with permission of Physicians Postgraduate Press, Inc.). European Urology Supplements 2005 4, 18-28DOI: (10.1016/j.eursup.2004.10.004) Copyright © 2004 Elsevier B.V. Terms and Conditions

Fig. 2 Effect of duloxetine on the synapse of a serotonin (5-HT) releasing neurone at the molecular level. Panel A: Situation in the absence of duloxetine. Released 5-HT is rapidly and efficiently inactivated by reuptake into the neurone releasing it. This limits duration and magnitude of the 5-HT signal. Panel B: In the presence of duloxetine the neuronal 5-HT reuptake mechanism is blocked and hence 5-HT inactivation in the synaptic cleft is markedly reduced. This results in increased and prolonged 5-HT concentrations in the synapse and hence enhanced activation of the post-junctional neurone, e.g. of the motor neurone of the rhabdosphincter originating from Onuf's nucleus in the sacral spinal cord. A similar situation exists for the effect of duloxetine in the synapse of noradrenaline-releasing neurones. (Adapted from Thor [71], reproduced with permission of Elsevier). European Urology Supplements 2005 4, 18-28DOI: (10.1016/j.eursup.2004.10.004) Copyright © 2004 Elsevier B.V. Terms and Conditions

Fig. 3 Effect of duloxetine in cats challenged with trans-vesical acetic acid infusion [64]. Duloxetine administration significantly and dose-dependently increased the EMG activity of the rhabdosphincter muscle (up to 8-fold) and restored bladder capacity to pre-treatment values. Micturition was not adversely affected. European Urology Supplements 2005 4, 18-28DOI: (10.1016/j.eursup.2004.10.004) Copyright © 2004 Elsevier B.V. Terms and Conditions