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WATER AND ELECTROLYTE HOMEOSTASIS

Impact of state of arousal and stress neuropeptides on urodynamic function in freely moving rats

¹Department of Surgery, ²Department of Anesthesiology and Critical Care Medicine, and ³Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; and ⁴Neurocrine Biosciences, Inc., San Diego, California

Submitted 20 October 2005 ; accepted in final form 25 January 2006

Corticotropin-releasing factor (CRF) is a neurotransmitter in Barrington’s nucleus neurons. These neurons can coregulate parasympathetic tone to the bladder (to modulate micturition) and brain noradrenergic activity (to affect arousal). To identify the role of CRF in the regulation of micturition, the effects of CRF agonists and antagonists on urodynamics in the unanesthetized rat were characterized. Rats were implanted with bladder and intrathecal or intraperitoneal catheters under isoflurane anesthesia. Cystometry was performed in the unanesthetized, unrestrained state at least 24 h later. In some cases, cortical electroencephalographic activity (EEG) was recorded simultaneously to assess arousal state. During cystometry, the state of arousal often shifted between waking and sleeping and urodynamic function changed depending on the state. Micturition threshold, bladder capacity, and micturition volume were all increased during sleep. The CRF₁/CRF₂ receptor agonists CRF and urocortin 2 increased bladder capacity and micturition volume in awake but not in sleeping rats. Conversely, the CRF₁ receptor antagonists antalarmin and NBI-30775 increased urinary frequency and decreased bladder capacity in awake rats. The present results demonstrate a profound effect of the state of arousal on urodynamic function and suggest that simultaneous monitoring of EEG and cystometry may provide a useful model for studying nocturnal enuresis and other urinary disorders. In addition, the results provide evidence for an inhibitory influence of CRF in the spinal pathway on micturition. Targeting the CRF system in the spinal cord may provide a novel approach for treating urinary disorders.

corticotropin-releasing factor; cystometry; micturition; electroencephalographic activity

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