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.