Sites Of Drug Action For Inhibition Of Micturition Reflexes

Drugs that suppress the micturition reflex could be useful for treating overactive bladder and urge Ul. Targets for suppressing the overactive bladder are divided into 6 sites (Figure 1, Table 1): primary afferent neurons (and their peripheral terminals in the bladder); the sacral dorsal horn; the periaqueductal gray/pontine micturition center; the sacral parasympathetic nucleus; the pelvic parasympathetic ganglion; and the detrusor smooth muscle neuroeffector junction.

Therapeutic agents that suppress action potential initiation and/or propagation along primary afferent fibers, through manipulation of ion channels or G proteincoupled receptors (GPCR), would be expected to increase the volume (i.e. stretch) threshold for activation of the micturition reflex and thus reduce bladder overactivity and urgency. Because C-fibers are responsible for pathological bladder activity, while AS-fibers are responsible for normal micturition, it would be beneficial to find targets that are preferentially associated with C-flbers (e.g. VR1 vanilloid receptors).

Once the action potential from the primary afferent fiber reaches its spinal synaptic terminal or "en passanf boutons, an influx of calcium is necessary to cause fusion of the synaptic vesicles with the plasma membrane and subsequent release of the primary afferent neurotransmitters. Thus, compounds that can reduce the flow of calcium through blockade of N-type calcium channels or through activation of GPCR receptors (e.g. opioid) will reduce release of transmitters and subsequent excitation of 2nd order neurons in the reflex pathway. Another strategy for blocking 2nd order neuron activation is to block the postsynaptic receptors on the 2nd order neurons that respond to the transmitters of the primary afferent neurons (e.g. NK1 receptor antagonists to block substance P-induced excitation). However, because there is a redundancy of transmitters in primary afferent neurons (e.g. glutamate, substance P, vasoactive intestinal polypeptide), it remains to be shown that blocking a single receptor subtype will completely prevent transmission of afferent input. A final way to block transmission is to directly activate inhibitory receptors on the 2nd order neurons (e.g. opioids). Because this would reduce their

pathways. Dotted lines represent the afferent pathway previously shown in Figure 1. Solid lines represent novel somatic storage pathways. Numbers refer to the regions listed on Table 3.
Table 1. Sites and targets for inhibition of the micturition reflex.



Function (+ indicates excitatory; - indicates inhibitory)


1. Primary Afferent Neurons

Na* channels (Nav1.8)

+ peripheral

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