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

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

IBS - Ascending Visceral Pain Pathway

Ascending Pain Pathways

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

IBS

pACC

MCC

Thalamus Pf, Re, Cl, Li

Prefrontal Cortex Cing Cx included

Brain Activation with Noxious Visceral Stimulation

Locus coeruleus

Subnucleus reticularis dorsalis

Spinal cord Lamina 1

Brain

Visceral afferent

Spinothalamic tract

Gallbladder

Somatic afferent

Dorsal root ganglion

Convergence of Somatic and Visceral Afferents in the Spinal Cord

Divergence of Somatic and Visceral Afferents in the Spinal Cord

(Wolf et al. 1965)

Colonic Referred Pain (mechanosensitivity)

Increased pain intensity

Mechanoreceptors of the Digestive tract - localisation

Serosal (1/3 low threshold)

Vascular (8/10 high threshold)

Mucosal (8/10 low threshold)

Tonic Distension

(act in series)

Phasic Distension (act in parallel)

Tonic & Phasic

distensions

-

-

-

Cortex

Limbic

system

Thalamus

Raphe

Nuclei

Brain

5-HT 5-HT

-

+

PN +

+

SP

EAA

Gut

Wall

SPINAL

CORD - DH

Nociceptive

stimulus

+ -

+ -

Dorsal root

Ganglia

Possible sites of alterations in gut sensitivity

1 2

3

4

1

2

3

4

Afferent nerve terminals

Dorsal horn

Brain integrative nuclei

Diffuse noxious inhibitory system

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)

Low High

Threshold

Silent

High intensity (Acute pain)

Low High

Threshold

Silent

Inflammation (Chronic pain)

Low

Synaptic terminal, second order, active neuron

Synaptic terminal, spinal and inactive neuron

Mediators contained in visceral

primary afferents :

- glutamate, aspartate

- SP, NKA, NKB

- CGRP

- somatostatin

- VIP, galanin

Postsynaptic receptors at

dorsal horn level:

- NMDA, AMPA

- NK1, NK2, NK3

- CGRP1, SST3

- 5-HT1, 5-HT3

- opioid (µ,d,k)

- a2 adrenergic

- GABAA

Presynaptic receptors at

dorsal horn level:

- CCK

- GABAA

- 5-HT3

- µ,d,k

- a2 adrenergic

(Bueno et al. 1996)

IL6

TNFa

LIF

NGF ATP 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)

TRPV1….5 mGluR1,5 CB1, CB2

a2d k opioid

NK1,2,3

CCK1

and….. others

Other putative targets

(periphery)

CRF-R1, CRF-R2 TrkA, p75 PAR1, PAR2

CRF Proteases NGF

Mast

cell

Stress

Allergy

Inflammation

Infection

Sympathetic

activation

Degranulation

Secretion

Histamine

Leukotrienes

Cytokines*

proteases

NGF

Cytokines*

Chemokines

* Cytokines: TNFa, 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

BIDIRECTIONAL REGULATION OF MAST-CELL-EOSINOPHIL FUNCTION

tryptase

PAR2

SCF

SCF

Cytokines

GM-CSF

Chemokines

IL-1 / TNF-a

Mast

cell

Eosinophil/

neutrophils

Cytokines

chymase

Adapted from Shakoory et al. 2004

Endothelium/

Epithelium

IL-4

Eotaxin

CCR3

PAR2

PAR2

SP

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

T-lymphocyte

Neutrophils

IFN

TJ OPENING

Mast cell

activation

Cytokines

Chemokines

activation

sensitization

sensory nerve

terminal

5-HT, tryptase

NGF

Inflammatory

mediators

Visceral

hyperalgesia

STRESS

Role of mast cell in favorising increase in colonic gut permeability

and subsequent increase in visceral sensitivity to distension

(Ait-Belgnaoui et al. Pain 2005)

MLC

MLCP

MLCK

CRF

Dorsal root ganglion

Mechanosensitive afferent

Sensitized spinal circuits Repeated

balloon distention

Repetitive Stimulation Sensitizes the Spinal Cord

Wind-up

(from Svensson et al. 2010)

MODULATION OF NEURONAL NOCICEPTIVE TRANSMISSION

AT SPINAL CORD LEVEL BY GLIAL CELLS

(from Svensson et al. 2010)

GLIAL CELL NEUROMEDIATORS INVOLVED IN

NOCICEPTIVE TRANSMISSION AT SPINAL CORD LEVEL

?

?

SPINAL MICROGLIA ACTIVATION IN STRESS -INDUCED

VISCERAL HYPERALGESIA

Bradesi et al. 2009

SPINAL MICROGLIA ACTIVATION IN “NARCOTIC BOWEL SYNDROME”

Agostini et al. 2010 (in press)

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