L. BuénoUnité de Neurogastroentérologie INRA
Toulouse, France
JARCA 2013
Bordeaux, 14 Novembre 2013
LES DOULEURS VISCERALES:Actualités physiopathologiques et perspectives thérapeutiques
DOULEURS D’ORIGINE DIGESTIVE
Organiques et/ou inflammatoires:
Fonctionnelles et/ou non-inflammatoires
- Pathologies cancéreuses (foie, pancréas, intestins…etc)
- Pathologies ischémiques ( intestins…etc)
- MICI (Crohn, RCH )
- Obstructions, accident,
- RGO
- Dyspepsie
- TFI - SII
- FAPS
Algorithm for pre-diagnostic analgesia of acute abdominal pain in general adult population
Manterola et al. Cochrane rev. 2011
AbdominalViscus
AbdominalViscus
Dorsal RootDorsal Root
Brain StemBrain Stem
Spinoreticular tractSpinoreticular tractLat. spinothalamic tractLat. spinothalamic tract
Spinal 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
BrainBrain
Visceral afferentVisceral afferent
Spinothalamictract
Spinothalamictract
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)
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
Colonic Referred Pain(mechanosensitivity)
Colonic Referred Pain(mechanosensitivity)
Increased pain intensityIncreased pain intensity
PATHOLOGIES INTESTINALES DOULOUREUSES
MICI: maladie de Crohn, RCH
Gastroentérites infectieuses
Troubles fonctionnels intestinaux (TFI)Dyspepsie
Syndrome de l'Intestin Irritable (SII-IBS)Douleurs fonctionnelles abdominales (FAPS)
Cancer
Reflux gastro-esophagien (EBO +/-)
Dans les TFI: la douleur viscérale est-elle associée à une hypersensibilité de la paroi en particulier à celle des mécano-récepteurs?
Mechanoreceptors of the Digestive tract -localisation
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)
Tonic Distension
(act in series)
Tonic Distension
(act in series)
PhasicDistension (act in parallel)
PhasicDistension (act in parallel)
Tonic & Phasic
distensions
Tonic & Phasic
distensions
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 sensation(No pain)
Normal sensation(No pain)
LowLow HighHighThresholdThreshold
SilentSilent
High intensity(Acute pain)
High intensity(Acute pain)
LowLow HighHighThresholdThreshold
SilentSilent
Inflammation(Chronic pain)Inflammation(Chronic pain)
LowLow
Synaptic terminal, second order, active neuron
Synaptic terminal, second order, active neuronSynaptic terminal, spinal and inactive neuron
Synaptic terminal, spinal and inactive neuron
Trimble et al.1995
1995-2013: Evidence (27 articles) of allodynia in 60-70% of IBS patients Trimble et al.1995
Munakata J, Gastroenterology 1997; 112:55 Munakata J, Gastroenterology 1997; 112:55
Rectal Pain Threshold
(mm Hg)
Rectal Pain Threshold
(mm Hg)
Post sigmoidstimulationPost sigmoidstimulation
BaselineBaseline4545
4040
3535
3030
2525
2020
00IBSIBS ControlsControls
HYPERALGESIA IN IRRITABLE BOWEL SYNDROME(Use of “barostatic” distensions)
HYPERALGESIA IN IRRITABLE BOWEL SYNDROME(Use of “barostatic” distensions)
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
IL6TNF
LIF
NGFATPH+ IL-1ß PGE2
Nociceptive terminal
Sub.P
Mastcell
5-HTHist. Tryp.Pressure
Tissuedamage
BradykininHeat
Receptors at nerve terminals of nociceptive fibers as putativetargets to reduce inflammation-induced hyperalgesia
Other putative targets(spinal cord level)
TRPV1….5mGluR1,5CB1, CB22opioidNK1,2,3CCK1and….. others
Other putative targets(periphery)
CRF-R1, CRF-R2 TrkA, p75 PAR1, PAR2
CRF ProteasesNGF
(Bueno et al. 2005)
TRILOGY OF IBS PERIPHERAL PATHOPHYSIOLOGY
Altered gut sensitivity to Distension
Colonic mucosal micro-inflammation
Increased paracellular permeability
• Increased number of mast cells, immune cells (Weston et al.1993 and 10-12 ref.)• Presence of pro-inflammatory cytokines (Gwee et al. 2003)• Release of pro-inflammatory (eicosanoïds)(Jones et al.1982) and pronociceptive agents (Barbara et al. 2005)
• colonic or intestinal level in PI-IBS (Dunlop,2000), • intestinal in all Rome I (Marschall et al.2004)• colonic in IBS-D patients (Gesce et al. 2008)
• Lower threshold of sensitivity (pain) to distension evidenced in 60-70% of IBS patients• Increased perception of pain for a given visceral stimulus (Whitehead et al.1998, 20-25 ref.)
Epithelial cells
IS INCREASED GUT PERMEABILITY ABLE TO INITIATE MUCOSALIMMUNE RESPONSE AND VISCERAL HYPERSENSITIVITY?
Increased paracellular permeability=
Entry of pathogens, toxins, antigens, bacteria
- activation of immunocytes- cytokines release- inflammatory mediators
Nociceptivehypersensitivity PAIN
Motilitydisorders
ENSdisorders
T-cell
B-cell
Mastcell
GranulocyteSensory nerves(nociceptive fibers)In
test
inal
or c
olon
ic m
ucos
a
Epithelialcells
Tight junction Pathogens Allergens
( from Perdue et al. 2000 )
(LPS, DNA,peptidoglycans,…etc.)
Distribution of nerve terminals close to mast cellin IBS patients.
MCMC
Red: nerve terminals (enolase labeling)Blue: mast cells (alcian blue)
( Wang et al. Gut 2004 )
Mast cell number (mm2)(ileal mucosa)
(X1000)
PI-IBS……… 11.2 ± 2.8*(n=27)
Non PI-IBS…..10.8 ±1.2*(n=29)
Control………..6.1±0.5(n=12)
*: from control at p<0.01
PI-IBS CTRL
MastocyteStress
Allergie
Inflammation
Infection
activationSystème
Degranulation
Secretion
HistamineLeukotrienesCytokines*proteasesNGF
Cytokines*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)
Facteurs principaux produisant la dégranulation ou l’activationdes mastocytes muqueux du tube digestif
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
0 5 10 15 200
1
2
3
4
0 5 10 15 200
1
2
3
4
(Barbara et al. Gastro. 2004)
RELATIONSHIP BETWEEN MAST CELL-NERVESCONNECTION AND PAIN IN IBS PATIENTS
Number of mast cells at a distance < 5µm from nerves
enzymesBiliary salts bacteria (proteases?)
Allergens, parasites
stress sepsis
Bacterial secetion or lysis (acetaldehyde, LPS…etc)
Inflammation(gastroenteritis)
Factors able to alter gut permeability/sensitivity in FGID
Piche et al. Gut 2009
IN VITRO MEASUREMENT OF PARACELLULAR PERMEABILITY OF COLONIC BIOPSIES (Ussing chambers)
The degree of porosity of biopsies from IBS patients is higher than that of healthy subjects independently of bowel habit alterations.
This altered permeability is associated with a decrease in the expression of ZO-1, a protein linking the actinomyosin apical ring to the proteins of the TJs
EFFECTS OF COLONIC BIOPSY SUPERNATANT ON CaCo2 CELL PERMEABILITY AND CORRELATIONS WITH SYMPTOM SCORES
Increase of permeability of CaCo2 cells, 48h after mucosal exposure with supernatant of biopsies from IBS paients
Changes in permeability of CaCo2 cells is correlated with the pain score of explored IBS patients
Piche et al. Gut 2009
Normal IBS
10.0
7.5
5.0
2.5
0.0VA
S sc
ore
(vis
cera
l)
VISCERAL PAIN*
Zhou et al. Pain 2009
0.30
0.25
0.20
0.15
0.10
0.05
0.00
Lact
ulos
e/ M
anni
tol
Normal IBS
INTESTINAL PERMEABILITY
RELATIONSHIPS BETWEEN GUT PERMEABILITY AND PAINFUL SENSATIONSTO DISTENSION MEASURED IN VIVO
Pain measurement after repeated (2) 35mm Hg rectal distension performed during 30 sec. at 2 min. interval.
*
Zhou et al. Pain 2009
120
100
80
60
40
20
0
FBD
SI s
core
CONTROL IBS
RELATIONSHIPS BETWEEN GUT PERMEABILITY AND SOMATIC* SENSITIVITYIN IBS PATIENTS
Patients with altered
permeability
skin thermal stimulus (Pelletier probe 3x3 cms) at 47°C applied to the left hand during 10 sec.*
SPINAL MICROGLIA ACTIVATION IN STRESS -INDUCED VISCERAL HYPERALGESIA
Bradesi et al. 2009
SPINAL MICROGLIA ACTIVATION IN “NARCOTIC BOWEL SYNDROME”
Agostini et al. 2010
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 viscéraleobservée dans le SII.
Des altérations de la perméabilité intercellulaire de l'épithélium intestinal sont en partie responsables de cet état micro-inflammatoire, ces altérations pouvant être générées par des facteurs locaux et systémiques
Outre les facteurs locaux, des altérations non sélectives de la transmission spinale associée à un activation de la microglie sont à prendre en considération dans les douleurs viscérales chroniques comme le SII.
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