L. BuénoL. BuénoUnité de Neurogastroentérologie INRAUnité de Neurogastroentérologie INRA

Toulouse, FranceToulouse, France

Symposium Mayoly sur le Syndrome de l'Intestin Irritable.Symposium Mayoly sur le Syndrome de l'Intestin Irritable.Organisateur: Pr. Boucekkine Organisateur: Pr. Boucekkine

Alger, 25 Avril 2010 Alger, 25 Avril 2010

VOIE DE SIGNALISATION ET D'INTEGRATIONVOIE DE SIGNALISATION ET D'INTEGRATIONDE LA DOULEUR VISCERALEDE LA DOULEUR VISCERALE

AbdominalViscus

AbdominalViscus

Dorsal RootDorsal Root

Brain StemBrain Stem

Spinoreticular tractSpinoreticular tract

Lat. spinothalamic tractLat. spinothalamic tractSpinal CordSpinal Cord

Dorsal column nociceptive pathway

Dorsal column nociceptive pathway

Processing of Sensory Signals in Spinal Cord, Brain Stem, and Brain

Processing of Sensory Signals in Spinal Cord, Brain Stem, and Brain

Gracilis and CuneatusGracilis and Cuneatus

IBS - Ascending Visceral Pain PathwayIBS - Ascending Visceral Pain PathwayAscending Pain PathwaysAscending Pain Pathways

ACCACC

RectosigmoidRectosigmoid

NoradrenergicNoradrenergic

ThalamusThalamus

PAGPAGLocus coeruleusLocus coeruleus

Caudal raphe nucleusCaudal raphe nucleus

OpioidOpioid

Rostral ventral

medulla

Rostral ventral

medulla

AmygdalaAmygdala

Descending Pain ModulationDescending Pain Modulation

SerotonergicSerotonergicTest

balloonTest

balloon

Spinal cordSpinal cordSpinal afferentSpinal afferent

IBSIBS

pACCpACC

MCCMCC

ThalamusPf, Re, Cl, LiThalamus

Pf, Re, Cl, Li

Prefrontal CortexCing Cx included

Prefrontal CortexCing Cx included

Brain Activation with Noxious Visceral StimulationBrain Activation with Noxious Visceral Stimulation

Locus coeruleusLocus coeruleus

Subnucleus reticularis dorsalis

Subnucleus reticularis dorsalis

Spinal cordLamina 1Spinal cordLamina 1

BrainBrain

Visceral afferentVisceral afferent

Spinothalamic tract

Spinothalamic tract

GallbladderGallbladder

Somatic afferentSomatic afferent

Dorsal root ganglion

Dorsal root ganglion

Convergence of Somatic and Visceral Afferents in the Spinal Cord

Convergence of Somatic and Visceral Afferents in the Spinal Cord

Divergence of Somatic and Visceral Afferents in the Spinal Cord

Divergence of Somatic and Visceral Afferents in the Spinal Cord

(Wolf et al. 1965)(Wolf et al. 1965)(Wolf et al. 1965)(Wolf et al. 1965)

Colonic Referred PainColonic Referred Pain(mechanosensitivity)(mechanosensitivity)

Colonic Referred PainColonic Referred Pain(mechanosensitivity)(mechanosensitivity)

Increased pain intensityIncreased pain intensity

Mechanoreceptors of the Digestive tract - Mechanoreceptors of the Digestive tract - localisationlocalisation

Mechanoreceptors of the Digestive tract - Mechanoreceptors of the Digestive tract - localisationlocalisation

Serosal (1/3 low threshold)

Serosal (1/3 low threshold)

Vascular(8/10 high threshold)

Vascular(8/10 high threshold)

Mucosal(8/10 low threshold)

Mucosal(8/10 low threshold)

Tonic Tonic DistensionDistension

(act in series)(act in series)

Tonic Tonic DistensionDistension

(act in series)(act in series)

PhasicPhasicDistension (act in parallel)Distension (act in parallel) PhasicPhasicDistension (act in parallel)Distension (act in parallel)

Tonic & Tonic & PhasicPhasic

distensionsdistensions

Tonic & Tonic & PhasicPhasic

distensionsdistensions

---

CortexLimbicsystem

Thalamus

Raphe Raphe NucleiNuclei

Brain Brain

5-HT 5-HT

-

+

PNPN ++

SPEAA

Gut Gut Wall Wall

SPINALSPINALCORD - DH CORD - DH

NociceptiveNociceptivestimulusstimulus

+-

+-

Dorsal root Dorsal root Ganglia Ganglia

Possible sites of alterations in gut sensitivityPossible sites of alterations in gut sensitivity

1122

33

4 4

11

22

33

44

Afferent nerve terminalsAfferent nerve terminals

Dorsal hornDorsal horn

Brain integrative nucleiBrain integrative nuclei

Diffuse noxious inhibitory systemDiffuse noxious inhibitory system

Spinal Gating for Three Classes of Visceral Nociceptors (Low, High and Silent) Account for

Normal Regulatory Functions, Acute and Chronic Pain

Spinal Gating for Three Classes of Visceral Nociceptors (Low, High and Silent) Account for

Normal Regulatory Functions, Acute and Chronic Pain

HighHighThresholdThreshold

SilentSilent

Normal sensationNormal sensation(No pain)(No pain)

Normal sensationNormal sensation(No pain)(No pain)

LowLow HighHighThresholdThreshold

SilentSilent

High intensityHigh intensity(Acute pain)(Acute pain)

High intensityHigh intensity(Acute pain)(Acute pain)

LowLow HighHighThresholdThreshold

SilentSilent

InflammationInflammation(Chronic pain)(Chronic pain)InflammationInflammation

(Chronic pain)(Chronic pain)

LowLow

Synaptic terminal, second order, active neuron

Synaptic terminal, second order, active neuron

Synaptic terminal, spinal and inactive neuron

Synaptic terminal, spinal and inactive neuron

Mediators contained in visceralMediators contained in visceral primary afferents :primary afferents :- glutamate, aspartate- glutamate, aspartate- SP, NKA, NKB- SP, NKA, NKB- CGRP- CGRP- somatostatin- somatostatin- VIP, galanin- VIP, galanin

Postsynaptic receptors atPostsynaptic receptors atdorsal horn level:dorsal horn level:- NMDA, AMPA- NMDA, AMPA- NK- NK11, NK, NK22, NK, NK33

- CGRP- CGRP11, SST, SST33

- 5-HT- 5-HT11, 5-HT, 5-HT33

- opioid (µ,- opioid (µ,2 2 adrenergicadrenergic

- GABA- GABAAA

Presynaptic receptors atPresynaptic receptors atdorsal horn level:dorsal horn level: - CCK- CCK - GABA- GABAAA

- 5-HT- 5-HT33

- µ,- µ,2 2 adrenergicadrenergic

(Bueno et al. 1996)(Bueno et al. 1996)

IL6IL6

TNFTNF

LIFLIF

NGFATPH+ IL-1ß PGE2

Nociceptive terminal

Sub.P

Mastcell

5-HTHist. Tryp.

PressurePressure

Tissuedamage

BradykininHeatHeat

Receptors at nerve terminals of nociceptive fibers as putativeReceptors at nerve terminals of nociceptive fibers as putativetargets to reduce inflammation-induced hyperalgesia targets to reduce inflammation-induced hyperalgesia

Other putative targetsOther putative targets(spinal cord level)(spinal cord level)

TRPVTRPV1….51….5mGluRmGluR11,,55

CBCB11, CB, CB22

22opioidopioid

NKNK1,2,31,2,3

CCKCCK11

and….. othersand….. others

Other putative targetsOther putative targets(periphery)(periphery)

CRF-RCRF-R11, CRF-R, CRF-R2 2 TrkA, p75TrkA, p75 PARPAR11, PAR, PAR2 2

CRFCRF ProteasesProteasesNGFNGF

MastMastcellcell

StressStress

AllergyAllergy

InflammationInflammation

InfectionInfection

SympatheticSympathetic activationactivation

CRFCRF

IgE, SP,5-HTIgE, SP,5-HT

NGF

NG

F, NPY

, NPY

DegranulationDegranulation

SecretionSecretion

minutesminutes

hourshours

GM-CSF, IL-1

GM-CSF, IL-1

PAF, ATPPAF, ATP

HistamineHistamineLeukotrienesLeukotrienesCytokinesCytokines**proteasesproteasesNGFNGF

CytokinesCytokines**ChemokinesChemokines

** Cytokines: TNFCytokines: TNF, IL-3, IL-5, IL-4, IL-13, IL-10, GM-CSF, IL-3, IL-5, IL-4, IL-13, IL-10, GM-CSF

(adapted from Shakoory et al,2004, Penicci et al.2003)(adapted from Shakoory et al,2004, Penicci et al.2003)

Role of Mast cell in mucosal inflammation-induced visceral hyperalgesia

BIDIRECTIONAL REGULATION OF MAST-CELL-EOSINOPHIL FUNCTIONBIDIRECTIONAL REGULATION OF MAST-CELL-EOSINOPHIL FUNCTION

tryptasetryptase

PARPAR22

SCFSCF

SCFSCF

CytokinesCytokinesGM-CSFGM-CSFChemokinesChemokinesIL-1 / TNF-IL-1 / TNF-

MastMastcellcell

Eosinophil/Eosinophil/neutrophilsneutrophils

CytokinesCytokineschymasechymase

Adapted from Shakoory et al. 2004Adapted from Shakoory et al. 2004

Endothelium/Endothelium/EpitheliumEpithelium

IL-4IL-4

EotaxinEotaxin

CCR3CCR3

PARPAR22

PARPAR22

SPSP

ROLE OF MAST CELLS IN VISCERAL PAIN:ROLE OF MAST CELLS IN VISCERAL PAIN:(degranulation in response to mechanical stimuli)(degranulation in response to mechanical stimuli)

Post-infectionPost-infection

MC degranulationMC degranulation

PP

PainPain

Normal barosensitivityNormal barosensitivity

PP PP

MC degranulationMC degranulation

PP

Normal barosensitivityNormal barosensitivity

Post-stressPost-stress PainPain

DensityDensity SensitizationSensitization

T-lymphocyteT-lymphocyteNeutrophilsNeutrophils

IFN IFN

TJ OPENINGTJ OPENING

MastMast cellcellactivationactivation

CytokinesCytokinesChemokinesChemokines

activationactivation

sensitizationsensitization

sensory nervesensory nerve terminalterminal

5-HT, tryptase5-HT, tryptaseNGFNGF

InflammatoryInflammatorymediatorsmediators

VisceralVisceralhyperalgesiahyperalgesia

STRESSSTRESS

Role of mast cell in favorising increase in colonic gut permeabilityRole of mast cell in favorising increase in colonic gut permeability and subsequent increase in visceral sensitivity to distensionand subsequent increase in visceral sensitivity to distension

(Ait-Belgnaoui et al. Pain 2005)(Ait-Belgnaoui et al. Pain 2005)

MLC

MLCP

MLCK

CRFCRF

Dorsal root ganglionDorsal root ganglion

Mechanosensitive afferentMechanosensitive afferent

Sensitized spinal circuits

Sensitized spinal circuitsRepeated

balloon distention

Repeated balloon

distention

Repetitive Stimulation Sensitizes the Spinal Cord

Repetitive Stimulation Sensitizes the Spinal Cord

Wind-upWind-up

(from Svensson et al. 2010)(from Svensson et al. 2010)

MODULATION OF NEURONAL NOCICEPTIVE TRANSMISSIONMODULATION OF NEURONAL NOCICEPTIVE TRANSMISSION AT SPINAL CORD LEVEL BY GLIAL CELLSAT SPINAL CORD LEVEL BY GLIAL CELLS

(from Svensson et al. 2010)(from Svensson et al. 2010)

GLIAL CELL NEUROMEDIATORS INVOLVED IN GLIAL CELL NEUROMEDIATORS INVOLVED IN NOCICEPTIVE TRANSMISSION AT SPINAL CORD LEVELNOCICEPTIVE TRANSMISSION AT SPINAL CORD LEVEL

?

?

SPINAL MICROGLIA ACTIVATION IN STRESS -INDUCED SPINAL MICROGLIA ACTIVATION IN STRESS -INDUCED VISCERAL HYPERALGESIAVISCERAL HYPERALGESIA

Bradesi et al. 2009 Bradesi et al. 2009

SPINAL MICROGLIA ACTIVATION IN “NARCOTIC BOWEL SYNDROME”SPINAL MICROGLIA ACTIVATION IN “NARCOTIC BOWEL SYNDROME”

Agostini et al. 2010 (in press)Agostini et al. 2010 (in press)

CONCLUSIONS CONCLUSIONS

La douleur d'origine digestive est le plus souvent associée à une La douleur d'origine digestive est le plus souvent associée à une sensibilisation des mécano-récepteurs pariétaux principalement par sensibilisation des mécano-récepteurs pariétaux principalement par les produits de dégranulation des mastocytes.les produits de dégranulation des mastocytes.

La présence d'une micro-inflammation associée à une redistribution La présence d'une micro-inflammation associée à une redistribution des terminaisons est un facteur majeur de l'hypersensibilité viscéraledes terminaisons est un facteur majeur de l'hypersensibilité viscéraleobservée dans le SII.observée dans le SII.

La douleur viscérale chronique est déclenchée par à une La douleur viscérale chronique est déclenchée par à une hypersensibilité locale mais facilité et entretenue par une facilitation et hypersensibilité locale mais facilité et entretenue par une facilitation et amplification spinale des messages nociceptifs amplification spinale des messages nociceptifs

Outre les facteurs locaux, les cellules gliales et en particulier la Outre les facteurs locaux, les cellules gliales et en particulier la microglie participent à la facilitation spinale de cette transmission microglie participent à la facilitation spinale de cette transmission nociceptivenociceptive