Sympathetic nervous system and visceral pain: the case of the bladder pain syndrome

2013/2014 André Ferreira Canelas Sympathetic nervous system and visceral pain: the case of the bladder pain syndrome março, 2014 Mestrado Integrado em Medicina Área: Urologia Trabalho efetuado sob a Orientação de: Doutora Célia da Conceição Duarte Cruz E sob a Coorientação de: Doutor Francisco José Miranda Rodrigues da Cruz Trabalho organizado de acordo com as normas da revista: Neurourology and Urodynamics André Ferreira Canelas Sympathetic nervous system and visceral pain: the case of the bladder pain syndrome março, 2014 ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Aos!meus!pais,! ! ! À!Bia,! ! ! À!Raquel,! ! ! Os!verdadeiros!mestres!da!minha!vida.! ! ! ! ! ! ! ! Sympathetic+nervous+system+and+visceral+pain:+the+case+of+the+bladder+pain+syndrome.+ By# André#Canelas1;#Ana#Charrua1,2,3,4;#Francisco#Cruz2,3,4;#Célia#Duarte#Cruz1,2# # 1Department*of*Experimental*Biology,*Faculty*of*Medicine*of*Porto,*University*of*Porto,*Portugal;# 2IBMC*B*Instituto*de*Biologia*Molecular*e*Celular,*University*of*Porto,*Porto,*Portugal;* 3Department*of*Renal,*Urologic*and*Infectious*Disease,*Faculty*of*Medicine,*University*of*Porto,*Porto,*Portugal;* 4Department*of*Urology,*S.*João*Hospital,*Porto,*Portugal.* # # ##Corresponding#author:#Célia#Duarte#Cruz# Address:#Department#of#Experimental#Biology,#FMUP,#Alameda#Hernâni#Monteiro# Tel:#+351#22#0426767# Fax:#+351#22#551#36#55# Email:#[email protected]# # # Short#title:#Sympathetic#hyperactivity#in#BPS/IC.# # # # Word#count:#2243# Tables#and#figures:#3# + + # ! ! 2! Abstract.+ Aim:+ To# review# and# summarize# available# data# on# the# possible# influence# of# sympathetic# nervous#system#in#Bladder#Pain#syndrome/Interstitial#Cystitis#(BPS/IC)#pathogenesis.# Methods:#A#search#for#relevant#articles#was#performed#in#the#Medline,#EMBASE,#Web#of# Science#and#Cochrane#Library#electronic#databases.#Only#English#language#publications#since# 1900#to#January#2014#were#selected.+ Results:+ The# true# causes# of# BPS/IC# remain# elusive.# However,# several# causes# have# been# recently# proposed,# including# epithelial# dysfunction,# deregulation# of# the# immune# response# and# neurogenic# inflammation.# The# contribution# of# the# of# sympathetic# nervous# system# to# BPS/IC# has# been# traditionally# disregarded# but# there# is# strong# evidence# for# a# sympathetic# role.# Indeed,# published# reports# show# that# rat# models# of# chronic# adrenergic# stimulation# reproduced#many#of#clinical#aspects#and#typical#histological#findings#of#BPS/IC#patients.# Conclusion:+The# reports# found# and# analyzed# in# the# present# review# indicate# that# several# factors# may# contribute# to# the# etiology# of# BPS/IC.# Particularly,# the# sympathetic# nervous# system#emerges#as#one#of#the#main#contributors#to#BPS/IC#pathogenesis.#Its#influence#may# underlie#at#least#some#of#the#multiple#problems#reported#by#BPS/IC#patients.## + + Key=words:+Interstitial# Cystitis,# Bladder# Pain# Syndrome,# Painful# Bladder# Syndrome,# Sympathetic# Nervous# System,# Adrenergic# Fibers,# Autonomic# Nervous# System,# Neurotrophins;#Mast#cells;#Urothelium.# + + + # ! ! 3! Introduction+ Bladder# pain# syndrome/interstitial# cystitis# (BPS/IC)# is# a# poorly# defined# clinical# condition.# The# prevalence# in# USA# was# suggested# to# reach# 100/100# 000# women# (1).# More# recent# European#epidemiological#surveys#reported#a#prevalence#of#about#200`300/100#000#women# (2).# No# cure# exists# yet# for# this# disease# and# the# etiology# is# unknown.# The# initial# diagnostic# criteria# were# proposed# in# 1987# by# the# National# Institute# of# Diabetes# and# Kidney# Disease# (NIDDK)#(3).#These#criteria#are#now#obsolete#as#they#miss#more#than#60%#of#cases.#A#more# accurate#definition#of#BPS/IC#was#recently#proposed#by#the#American#Urological#Association# (AUA)#for#diagnosis#and# treatment.#According#to#the# AUA,#BPS/IC#is#characterized# by:# “An# unpleasant# sensation# (pain,# pressure,# discomfort)# perceived# to# be# related# to# the# urinary# bladder,#associated#with#lower#urinary#tract#symptom(s)#of#more#than#6#weeks#duration,#in# the#absence#of#infection#or#other#identifiable#causes’’#(4).# BPS/IC# may# be# accompanied# by# other# pathological# conditions,# not# necessarily# bladder# – related.# The# most# common# comorbidities# associated# to# BPS/IC# include# irritable# bowel# syndrome#(IBS),#fibromyalgia,#chronic#fatigue#syndrome,#Sjogren’s#syndrome,#chronic#pelvic# pain,#anxiety#disorders,#migraine,#allergies,#asthma,#sleep#disorders#and#other#syndromes#not# related# to# the# bladder# (5).# Epidemiologic# studies# suggest# that# only# 7%# of# BPS/IC# patients# have#none#of#those#co`morbid#syndromes#(6).#Conversely,#patients#with#these#non`bladder# syndromes#have#an#higher#probability#of#developing#BPS/IC#in#the#future,#and#this#probability# is#proportional#to#the#number#of#associated#syndromes#(7).#Interestingly,#these#non`bladder# syndromes#shares#many#of#the#characteristically#findings#of#BPS/IC,#such#as,#the#worsening# during#stressful#situations#and#the#possible#involvement#of#urothelial#and#mast#cells#as#well# as#the#neurotrophins#in#their#pathogenesis.#These#common#features#may#suggest#there#is#a# common#factor#in#their#pathophysiology.# # ! ! 4! The#true#causes#of#BPS/IC#remain#elusive,#with#a#variety#of#possibilities#being#indicated#by# several#clinical#and#experimental#studies.#Therefore,#the#aim#of#this#study#was#to#review#and# summarize#available#data#on#this#matter.### # Methods+ A#search#for#relevant#articles#was#performed#in#the#Medline,#EMBASE,#Web#of#Science#and# Cochrane# Library# electronic# databases# with# different# combinations# of# the# following# key` terms:# “Interstitial# Cystitis”,# “Bladder# Pain# Syndrome”,# “Painful# Bladder# Syndrome”,# “Sympathetic# Nervous# System”,# “Adrenergic# Fibers”,# “Autonomic# Nervous# System”,# “Neurotrophins”# and# “Mast# cells”.# Only# English# language# publications# since# 1900# to# 2014# January#were#included.#Additionally,#references#of#retrieved#articles#were#scanned#for#any# potentially#relevant#article.! # Results+ The# pathophysiologic# mechanisms# underlying# BPS/IC# remain# unclear.# However,# several# causing# agents# have# been# proposed# in# recent# years.# These# include# epithelial# dysfunction,# deregulation#of#the#immune#response#and#neurogenic#inflammation#(8).#A#number#of#animal# models#have#been#used#for#the#study#of#BPS/IC,#which#include#administration#of#an#irritant#or# immune# stimulant# (e.g.# hydrochloric# acid,# turpentine,# protamine# sulfate,# mustard# oil,# lipopolysaccharide# and# cyclophosphamide).# In# addition,# cats# with# with# feline# interstitial# cystitis#and#an#experimental#autoimmune#cystitis#(EAC)#murine#model#have#also#been#used.# These# animal# models# exhibit# a# number# of# functional# and# histological# alterations# of# the# bladder,#comparable#to#those#observed#in#in#human#BPS/IC#(9,#10),#and#have#been#widely# used#to#identify#the#putative#cause#of#this#syndrome.#Available#results#point#towards#damage# # ! ! 11! from#sympathetic#hyperactivity.#In#fact,#patients#with#irritable#colon#also#present#increased# sympathetic#innervation#and#urinary#noradrenaline#(49).## # Conclusion# BPS/IC#is#considered#a#multifactorial#disease.#The#role#of#the#sympathetic#nervous#system# has# been# poorly# investigated# but# its# hyperactivity# may# be# a# crucial# event# for# the# pathophysiology# of# BPS/IC.# This# may# have# important# clinical# implications# as# different# experimental#and#clinical#approaches#may#be#used#with#BPS/IC#patients.#Further#research#is# necessary#not#only#to#identify#the#triggering#event#leading#to#sympathetic#activation#but#also# to#design#more#efficient#therapeutic#strategies.## # # Acknowledgments+ The# authors# thank# S.# Barros,# V.# Nunes,# J.# Freita,# and# A.# Wolf# Johnston# for# technical# assistance.# Ana# Charrua# is# supported# by# SFRH/BPD/68716/2010.# This# work# was# partially# supported# by# InComb# FP7# HEALTH# project# no# 223234,# and# NIH# R37# DK54824# and# R01# DK57284.#Francisco#Cruz#is#a#consultant#for#Allergan,#Astellas,#and#Recordati.# # # References+ 1.!Hanno!P,! 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Anxiety,! depression,! and! catecholamine! levels! after! self2management! intervention! in! irritable! bowel! syndrome.! Gastroenterology! nursing! :! the! official! journal! of! the! Society! of! Gastroenterology! Nurses! and! Associates.! 2014! Jan;37(1):24232.! PubMed! PMID:! 24476829.!Epub!2014/01/31.!eng.! ! ! # ! ! 16! ! Tables'and'Figures' ! ! ! # # # # # + Control+ BPS/IC+ ΔSDPP+ 57.2#±723.0# 24.2#±#18.2*# rMSSD+ 6.3#±2.8# 5.6#±#8.4# BRS+ 7.1#±3.8# 7.7#±#8.2# 24+hr+urinary+NA+(mg/day)+ 47.8#±17.8# 102.1#±#43.7*# Plasmatic+NA+(supine)+(μg/ml)+ 204.3#±46.6# 397.0#±#36.4***# Plasmatic+NA+(upright)+(μg/ml)+ 578.3#±69.0# 596.3#±#30.4# Table'I.'Sympathetic'overactivity'in'IC/BPS'patients.' Standard# deviation# of# the# P# wave# intervals# (Δ SDPP);# Root# mean# square# successive# differences# (rMSSD);# Baroreflex# sensitivy# (BRS);# Noradrenaline# (NA).# Mean# values# of# observations# obtained# during# TILT# test,# and# noradrenaline# quantification#in#24#hr#urine#samples#and#plasma.# Δ SDPP#was#used#to#record#the#increment#in#sympathetic#activity.#rMSSD#and# BRS#were#used#to#evaluate#the#parasympathetic#system.# *P<0.05.# ***P<0.001# Adapted#from#Charrua#et#al.#(2013)# ! # ! ! 17! !#(a) !# # #(b) !!!! # !# 0! 10! 20! 30! 40! 50! 60! 70! Basal! 4!dias! 7!dias! 11!dias! 14!dias! Mechanical'threshold'(g)' Saline! Phenylphrine! 0! 10! 20! 30! 40! 50! 60! 70! Basal! 4!dias! 7!dias! 11!dias! 14!dias! Mechanical'threshold'(g)' Saline! Phenylphrine! Fig.'1.'Mechanical'sensitivity'of'the'lower'abdomen'(a)'and'hindpaw'(b)' after' chronic' phenylephrine' treatment.!The! group! treated! with! phenylephrine!(PHE)!had!a!significantly!lower!threshold!both!in!the!abdomen! (a)!and.in!hindpaw!(b).!The!increase!in!the!mechanical!sensitivity!was!evident! from! the! 1st!week! of! treatment! onwards! (p<0.05! versus! non2treated! rats).!! This!indicates!the!presence!of!visceral!pain.!! *P<0.01!vs!saline!treatment;!repeated!measures!ANOVA!followed!by!Student2 Neumman2Keuls.! Adapted!from!Charrua!et!al.!(2013)! ! * * * * * * * # ! ! 18! # ## # # Fig.' 2.' Urothelial' changes' following' chronic' administration' of' phenylephrine.'A:!Haemotoxilin/eosing!staining!showed!that!compared!with! controls,! PHE! treated! rat! bladder! shows! a! reduced! thickness! of! urothelium.! B/C:Cytokeratin! 202positive! umbrella! cells! (in! red)! that! are! decreased! or! absent! in! areas! of! PHE! treated! group! bladders! (nuclei! are! stained! in! blue).! D/E:' Staining! of! Caspase! 3! and! BAX! pro2apoptotic! proteins! was! strongly! increased!in!PHE2treated!rats.!!Adapted!from!Charrua!et!al.!(2013)! Agradecimentos. . Apesar' de' o' espaço' destinado' aos' agradecimentos' ser' curto' face' à' todas' as' pessoas' que' tornaram' possível' a' realização' deste' trabalho,' não' podia' deixar' de' manifestar'o'meu'agradecimento:' ' À' Professora' Doutora' Célia' Cruz,' minha' orientadora,' mas' que' nunca' se' deixou' restringir' somente' a' esse' papel,' sempre' motivandoDme' a' olhar' mais' à' frente,' à' encarar' o' “e' agora?”' e' especialmente' sempre' me' ajudando' a' crescer' como' investigador' e' como' pessoa.' Obrigado' pelos' extensos' conhecimentos' que' me' transmitiu'e'que'levo'comigo'para'a'vida.' ' Ao' Professor' Doutor' Francisco' Cruz,' meu' coorientador,' pela' competência' científica,'apoio'e'disponibilidade''demonstradas'ao'longo'destes'anos.''' ' À' Professora' Doutora' Ana' Charrua,' pela' simpatia,' amabilidade' e' carinho' que' sempre'demonstrou'por'mim,'oferecendoDme'a'possibilidade'de'voar'mais'alto.' ' À' todas' as' pessoas' do' departamento' de' Biologia' Experimental,' por' sempre' se' demonstrarem'disponíveis'a'ajudar,'muitos'deles'amigos'que'nunca'vou'esquecer.' ' Aos'meus'amigos,'por'serem'a'família'que'eu'escolhi'ter.' ' À'Raquel,'pela'companhia'nos'momentos'menos'bons,'e'pela'inspiração'e'força' para'alcançar'os'momentos'extraordinários.'' ' Aos' meus' tios,' por' serem' os' meus' segundos' pais,' pelo' apoio' inigualável' e' reconforto'diário.' ' Aos'meus'pais'e'irmã','os'alicerces'da'minha'vida.' ' À'todo'o'resto'da'minha'família,'sem'a'qual'nada'disto'tinha'valido'a'pena.' ' Este'trabalho'é'de'todos'nós.'Muito'obrigado'a'todos.' Anexos'