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L. Buéno Unité de Neurogastroentérologie INRA Toulouse, France Symposium Mayoly sur le Syndrome de l'Intestin Irritable. Organisateur: Pr. Boucekkine Alger,

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Presentation on theme: "L. Buéno Unité de Neurogastroentérologie INRA Toulouse, France Symposium Mayoly sur le Syndrome de l'Intestin Irritable. Organisateur: Pr. Boucekkine Alger,"— Presentation transcript:

1 L. Buéno Unité de Neurogastroentérologie INRA Toulouse, France Symposium Mayoly sur le Syndrome de l'Intestin Irritable. Organisateur: Pr. Boucekkine Alger, 25 Avril 2010 VOIE DE SIGNALISATION ET D'INTEGRATION DE LA DOULEUR VISCERALE

2 Abdominal Viscus Abdominal Viscus Dorsal Root Brain Stem Spinoreticular tract Lat. spinothalamic tract Spinal Cord Dorsal column nociceptive pathway Processing of Sensory Signals in Spinal Cord, Brain Stem, and Brain Gracilis and Cuneatus

3 IBS - Ascending Visceral Pain Pathway Ascending Pain Pathways

4 ACC Rectosigmoid Noradrenergic Thalamus PAG Locus coeruleus Caudal raphe nucleus Opioid Rostral ventral medulla Amygdala Descending Pain Modulation Serotonergic Test balloon Spinal cord Spinal afferent

5 IBS pACC MCC Thalamus Pf, Re, Cl, Li Thalamus Pf, Re, Cl, Li Prefrontal Cortex Cing Cx included Prefrontal Cortex Cing Cx included Brain Activation with Noxious Visceral Stimulation Locus coeruleus Subnucleus reticularis dorsalis Spinal cord Lamina 1 Spinal cord Lamina 1

6 Brain Visceral afferent Spinothalamic tract Gallbladder Somatic afferent Dorsal root ganglion Convergence of Somatic and Visceral Afferents in the Spinal Cord

7 Divergence of Somatic and Visceral Afferents in the Spinal Cord (Wolf et al. 1965)

8 Colonic Referred Pain (mechanosensitivity) (mechanosensitivity) Increased pain intensity

9 Mechanoreceptors of the Digestive tract - localisation 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) TonicDistension (act in series) TonicDistension Phasic Phasic Distension (act in parallel) Phasic Phasic Distension (act in parallel) Tonic & Phasic distensions distensions

10 Cortex Limbic system Thalamus Raphe Nuclei Brain 5-HT - +PN + + SP EAA GutWall SPINAL CORD - DH Nociceptivestimulus Dorsal root Ganglia Possible sites of alterations in gut sensitivity Afferent nerve terminals Dorsal horn Brain integrative nuclei Diffuse noxious inhibitory system

11 Spinal Gating for Three Classes of Visceral Nociceptors (Low, High and Silent) Account for Normal Regulatory Functions, Acute and Chronic Pain High Threshold Silent Normal sensation (No pain) Normal sensation (No pain) Low High Threshold Silent High intensity (Acute pain) High intensity (Acute pain) Low High Threshold Silent Inflammation (Chronic pain) Inflammation Low Synaptic terminal, second order, active neuron Synaptic terminal, spinal and inactive neuron

12 Mediators contained in visceral primary afferents : primary afferents : - glutamate, aspartate - SP, NKA, NKB - CGRP - somatostatin - VIP, galanin Postsynaptic receptors at dorsal horn level: - NMDA, AMPA - NK 1, NK 2, NK 3 - CGRP 1, SST HT 1, 5-HT 3 - opioid (µ, - opioid (µ, 2 adrenergic 2 adrenergic - GABA A Presynaptic receptors at dorsal horn level: - CCK - CCK - GABA A - GABA A - 5-HT HT 3 - µ, - µ, 2 adrenergic 2 adrenergic (Bueno et al. 1996)

13 IL6 TNF TNF LIF NGFATP H+H+ IL-1ß PGE2 Nociceptive terminal Sub.P Mast cell 5-HT Hist.Tryp. Pressure Tissue damage Bradykinin Heat Receptors at nerve terminals of nociceptive fibers as putative targets to reduce inflammation-induced hyperalgesia Other putative targets (spinal cord level) TRPV 1….5 mGluR 1, 5 CB 1, CB opioid opioid NK 1,2,3 CCK 1 and….. others Other putative targets (periphery) CRF-R 1, CRF-R 2 TrkA, p75 PAR 1, PAR 2 CRF Proteases NGF

14 Mastcell Stress Allergy Inflammation Infection Sympathetic activation activation CRF IgE, SP,5-HT NGF, NPY Degranulation Secretion minutes hours GM-CSF, IL-1 PAF, ATP HistamineLeukotrienes Cytokines* proteasesNGF Chemokines * Cytokines: TNF, IL-3, IL-5, IL-4, IL-13, IL-10, GM-CSF (adapted from Shakoory et al,2004, Penicci et al.2003) Role of Mast cell in mucosal inflammation-induced visceral hyperalgesia

15 BIDIRECTIONAL REGULATION OF MAST-CELL-EOSINOPHIL FUNCTION tryptase PAR 2 SCF SCF CytokinesGM-CSFChemokines IL-1 / TNF- IL-1 / TNF- Mastcell Eosinophil/neutrophils Cytokineschymase Adapted from Shakoory et al Endothelium/Epithelium IL-4 Eotaxin CCR3 PAR 2 SP

16 ROLE OF MAST CELLS IN VISCERAL PAIN: (degranulation in response to mechanical stimuli) Post-infection MC degranulation P Pain Normal barosensitivity P P MC degranulation P Normal barosensitivity Post-stress Pain Density Sensitization Sensitization

17 T-lymphocyteNeutrophils IFN IFN TJ OPENING Mast cell activation CytokinesChemokines activation sensitization sensory nerve terminal terminal 5-HT, tryptase NGF Inflammatorymediators Visceralhyperalgesia STRESS Role of mast cell in favorising increase in colonic gut permeability and subsequent increase in visceral sensitivity to distension and subsequent increase in visceral sensitivity to distension (Ait-Belgnaoui et al. Pain 2005) MLC MLCP MLCK CRF

18 Dorsal root ganglion Mechanosensitive afferent Sensitized spinal circuits Repeated balloon distention Repetitive Stimulation Sensitizes the Spinal Cord Wind-up

19 (from Svensson et al. 2010) MODULATION OF NEURONAL NOCICEPTIVE TRANSMISSION AT SPINAL CORD LEVEL BY GLIAL CELLS AT SPINAL CORD LEVEL BY GLIAL CELLS

20 (from Svensson et al. 2010) GLIAL CELL NEUROMEDIATORS INVOLVED IN NOCICEPTIVE TRANSMISSION AT SPINAL CORD LEVEL ? ?

21 SPINAL MICROGLIA ACTIVATION IN STRESS -INDUCED VISCERAL HYPERALGESIA Bradesi et al. 2009

22 SPINAL MICROGLIA ACTIVATION IN NARCOTIC BOWEL SYNDROME Agostini et al (in press)

23 CONCLUSIONS La douleur d'origine digestive est le plus souvent associée à une sensibilisation des mécano-récepteurs pariétaux principalement par les produits de dégranulation des mastocytes. La présence d'une micro-inflammation associée à une redistribution des terminaisons est un facteur majeur de l'hypersensibilité viscérale observée dans le SII. La douleur viscérale chronique est déclenchée par à une hypersensibilité locale mais facilité et entretenue par une facilitation et amplification spinale des messages nociceptifs Outre les facteurs locaux, les cellules gliales et en particulier la microglie participent à la facilitation spinale de cette transmission nociceptive


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