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