Central nervous system targets for micturition control

University dissertation from Department of Clinical Pharmacology, Lund University Hospital, S-221 85 Lund, Sweden

Abstract: Normal urine storage and bladder emptying are controlled by the central (CNS) as well as the peripheral nervous system. Dysfunction of these mechanisms can lead to urinary incontinence. Urinary tract dysfunctions have symptomatically been treated mainly with drugs acting peripherally. However, in the CNS, drug targets for pharmacological intervention may be found. The present study deals with effects on micturition of drugs active on receptors for GABA, 5-HT and enkephalins. Rat models of normal and dysfunctional micturition were used. Reuptake inhibition of GABA (tiagabine), as well as stimulation of GABAb receptors (baclofen) inhibited micturition. The sites of actions were the spinal cord and/or brain. Tiagabine depressed neurogenic contractions and acetylcholine release in rat detrusor strips. Blockade of GABAb receptors (CGP62349) increased the frequency of micturitions. Stimulation of receptors for 5-HT, in particular the 5-HT1a receptor subtype, facilitated micturition. Blockade of this receptor subtype (NAD-299 and WAY100635) increased bladder storage capacity via a supraspinal mechanism. Tramadol, a mixed opioid receptor agonist and reuptake inhibitor of 5-HT and noradrenaline, in analgesic doses increased bladder storage capacity, without impairing bladder emptying. The effect was dependent on the (+)-enantiomer, which stimulates m-opioid receptors and inhibits 5-HT reuptake. Tramadol and GABAb receptor stimulation reversed detrusor overactivity due to C-fibre activation in the bladder. Activation of CNS dopamine receptors, as well as experimental cerebral-infarction, induced detrusor overactivity which could be reversed by tramadol. Drugs influencing the CNS micturition control may offer new possibilities to treat lower urinary tract disorders, including detrusor overactivity.

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