Can the adrenergic system be implicated in the pathophysiology of bladder pain syndrome/interstitial cystitis? A clinical and experimental study

Neurourol Urodyn. 2015 Jun;34(5):489-96. doi: 10.1002/nau.22542. Epub 2013 Dec 24.


Aims: To evaluate sympathetic system activity in bladder pain syndrome/interstitial cystitis (BPS/IC) patients and to investigate if chronic adrenergic stimulation in intact rats induces BPS/IC-like bladder modifications.

Methods: Clinical study--In BPS/IC patients and aged and body mass index matched volunteers TILT test was undertaken and catecholamines were measured in plasma and 24 hr urine samples. Experimental study--Phenylephrine was injected subcutaneously (14 days) to female Wistar rats. Pain behavior, spinal Fos expression, urinary spotting, number of fecal pellets expelled, frequency of reflex bladder contractions, and urothelial height were analyzed. Urothelium permeability was investigated by trypan blue staining. Immunoreactivity against caspase 3 and bax were studied in the urothelium and against alpha-1-adrenoreceptor and TRPV1 in suburothelial nerves. Mast cell number was determined in the sub-urothelium. In rats with lipopolysaccharide-induced cystitis, urinary catecholamines, and Vesicular Monoamine Transporter 2 (VMAT2) expression in bladder nerves were analyzed.

Results: The TILT test showed an increase of sympathetic activity. Noradrenaline levels in blood at resting conditions and in 24-hr urine samples were higher in BPS/IC patients. Phenylephrine administration increased visceral pain, spinal Fos expression, bladder reflex activity, urinary spotting and the number of expelled fecal pellets. The mucosa showed urothelial thinning and increased immunoreactivity for caspase 3 and bax. Trypan blue staining was only observed in phenylephrine treated animals. Suburothelial nerves co-expressed alpha1 and TRPV1. Mastocytosis was present in the suburothelium. Cystitis increased sympathetic nerve density and urinary noradrenaline levels.

Conclusions: Excessive adrenergic stimulation of the bladder may contribute to the pathophysiological mechanisms of BPS/IC.

Keywords: bladder pain syndrome/interstitial cystitis; primary afferents; sympathetic system; urothelium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Agonists / pharmacology*
  • Afferent Pathways
  • Animals
  • Behavior, Animal / drug effects
  • Caspase 3 / drug effects
  • Caspase 3 / metabolism
  • Cohort Studies
  • Cystitis, Interstitial / metabolism*
  • Cystitis, Interstitial / physiopathology
  • Defecation / drug effects
  • Female
  • Humans
  • Norepinephrine / blood
  • Norepinephrine / metabolism*
  • Norepinephrine / urine
  • Organ Size
  • Peripheral Nerves / metabolism
  • Phenylephrine / pharmacology*
  • Proto-Oncogene Proteins c-fos / drug effects
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Sympathetic Nervous System / metabolism*
  • Sympathetic Nervous System / physiopathology
  • TRPV Cation Channels / metabolism
  • Tilt-Table Test
  • Urinary Bladder / drug effects*
  • Urinary Bladder / innervation
  • Urinary Bladder / metabolism
  • Urinary Bladder / pathology
  • Urothelium / drug effects*
  • Urothelium / innervation
  • Urothelium / metabolism
  • Urothelium / pathology
  • Visceral Pain
  • bcl-2-Associated X Protein / drug effects
  • bcl-2-Associated X Protein / metabolism


  • Adrenergic alpha-1 Receptor Agonists
  • Bax protein, rat
  • Proto-Oncogene Proteins c-fos
  • Receptors, Adrenergic, alpha-1
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • bcl-2-Associated X Protein
  • Phenylephrine
  • Casp3 protein, rat
  • Caspase 3
  • Norepinephrine