Characterization of bladder sensory neurons in the context of myelination, receptors for pain modulators, and acute responses to bladder inflammation

Shelley L Forrest,Janet R Keast,Peregrine B Osborne

doi:10.3389/fnins.2013.00206

Abstract

Bladder sensation is mediated by lumbosacral dorsal root ganglion neurons and is essential for normal voiding and nociception. Numerous electrophysiological, structural, and molecular changes occur in these neurons following inflammation. Defining which neurons undergo these changes is critical for understanding the mechanism underlying bladder pain and dysfunction. Our first aim was to define the chemical classes of bladder sensory neurons that express receptors for the endogenous modulators of nociceptor sensitivity, glial cell line-derived neurotrophic factor (GDNF), the related neurotrophic factor, artemin, and estrogens. Bladder sensory neurons of adult female Sprague-Dawley rats were identified with retrograde tracer. Diverse groups of neurons express these receptors, and some neurons express receptors for both neurotrophic factors and estrogens. Lumbar and sacral sensory neurons showed some distinct differences in their expression profile. We also distinguished the chemical profile of myelinated and unmyelinated bladder sensory neurons. Our second aim was to identify bladder sensory neurons likely to be undergoing structural remodeling during inflammation. Following systemic administration of cyclophosphamide (CYP), its renal metabolite acrolein causes transient urothelial loss, exposing local afferent terminals to a toxic environment. CYP induced expression of the injury-related immediate-early gene product, activating transcription factor-3 (ATF-3), in a small population of sacral nitrergic bladder sensory neurons. In conclusion, we have defined the bladder sensory neurons that express receptors for GDNF, artemin and estrogens. Our study has also identified a sub-population of sacral sensory neurons that are likely to be undergoing structural remodeling during acute inflammation of the bladder. Together these results contribute to increased understanding of the neurons that are known to be involved in pain modulation and hyperreflexia during inflammation.

Highlights

Visceral pain is one of the most frequent types of pain seen in the clinical setting
TRPV1 is a marker of polymodal nociceptor neurons that is expressed by the majority of bladder afferent neurons (Bennett et al, 2003)
Previous studies of dorsal root ganglia (DRG) at other spinal levels have shown that the majority of calcitonin gene-related peptide (CGRP)-IR neurons express TRPV1 (Kiasalari et al, 2010) and that GFRα3-IR is expressed in a sub-population of CGRP-IR neurons (Orozco et al, 2001; Kalous et al, 2009)

Summary

Introduction

Visceral pain is one of the most frequent types of pain seen in the clinical setting. Development of appropriate animal models of visceral pain is challenging, but bladder inflammation models in rodents have revealed many changes in bladder afferent pathways and their targets in the lumbosacral spinal cord that underpin nociceptor sensitization [reviewed in De Groat and Yoshimura (2009); Daly et al (2011); Kanai (2011)]. This sensitization is critically linked to the initiation of pain and altered reflex behaviors, including increased voiding frequency and a reduction in micturition threshold, characteristics of clinical bladder inflammation. Defining which particular afferent neurons undergo these changes is critical to understanding the overall mechanism underlying pain and bladder dysfunction

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