L. Buéno Unité de Neurogastroentérologie INRA Toulouse, France Symposium Mayoly sur le Syndrome...
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Transcript of L. Buéno Unité de Neurogastroentérologie INRA Toulouse, France Symposium Mayoly sur le Syndrome...
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