Mechanisms of visceral pain and Mechanisms of visceral pain and hyperalgesia hyperalgesia Fernando Cervero Fernando Cervero Director, The Alan Edwards Centre for Research on Pain Director, The Alan Edwards Centre for Research on Pain McGill University, McGill University, Montreal, Canada Montreal, Canada President, IASP President, IASP
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Mechanisms of visceral pain and Mechanisms of visceral pain and hyperalgesiahyperalgesiaMechanisms of visceral pain and Mechanisms of visceral pain and hyperalgesiahyperalgesia
Fernando CerveroFernando Cervero
Director, The Alan Edwards Centre for Research on PainDirector, The Alan Edwards Centre for Research on Pain
CoCo--expression of CBexpression of CB11 and TRPVand TRPV11 receptorsreceptors• CB1 and TRPV1 are co-expressed in umbrella cells• Some nerve fibers of the sub-urothelial and muscular layers co-express CB1
and TRPV1 receptors
L L L
Musc
ula
r la
yer
Uro
theliu
m +
Suburo
thelia
l
layer
*
*
*
*L = lumenBar = 20µm
CBCB11 receptorreceptor Substance PSubstance P MergedMergedO
vera
ll
L L L
CoCo--expression of CBexpression of CB11 and Substance Pand Substance P• CB1 and Substance P are co-expressed in nerve fibers of the sub-urothelial layer.• Sparse co-localization of CB1 and Substance P in the muscular layer.
Sensitization reversal is mediated by CBSensitization reversal is mediated by CB11 receptorsreceptors
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30 35 40
CYP pre
AZ12646915 +
AM630CYP post
AZ12646915 +
AM630
Intravesical pressure (mm Hg)
No
rma
lize
d a
ctiv
ity (
%)
(ve
rsu
s p
re-d
rug
ma
xim
al
act
ivit
y)
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20
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60
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120
140
0 5 10 15 20 25 30 35 40
CYP pre
AZ12646915 +
AM251
CYP post
AZ12646915 +
AM251
•• Cannabinoid receptor CBCannabinoid receptor CB11 mRNA is present in the urinary bladder mRNA is present in the urinary bladder
(urothelium, and nerve fibers). CB1, TRPV1 and P2X3 (urothelium, and nerve fibers). CB1, TRPV1 and P2X3 receptors are receptors are coco--expressed.expressed.
•• Intravesical administration of a cannabinoid receptor agonist reduces the Intravesical administration of a cannabinoid receptor agonist reduces the mechanicallymechanically--evoked activity of bladder afferents. This effect is evoked activity of bladder afferents. This effect is abolished by the previous administration of a CB1 antagonist.abolished by the previous administration of a CB1 antagonist.
• Afferent activity in inflamed bladders is increased for intravesical pressures
Cannabinoids and visceral nociceptorsCannabinoids and visceral nociceptors
• Afferent activity in inflamed bladders is increased for intravesical pressures between 10 and 40 mmHg. Local treatment with a CB1/CB2
cannabinoid agonist significantly reduces afferent activity at intravesical pressures above 20 mmHg. This effect is mediated by CB1
receptors.
•• Cannabinoid CBCannabinoid CB11 receptors are implicated in the peripheral modulation of receptors are implicated in the peripheral modulation of bladder sensory information by a bladder sensory information by a direct action of cannabinoids on nociceptive afferents
Mechanistic features of visceral Pain
• CNS / central organization:
– Evidence against brief/short lived nociceptive pain (no visceral “tail flick” equivalent)
– Alarm system with widespread motor and autonomic reactions (“trip-wire” arrangement)
– fMRI data: some (relatively minor) differences in activated brain areas (mostly concerned with non-sensory aspects: emotional, affective)
Viscero-somatic convergence in the spinal cord
Pain and spinal cord Pain and spinal cord hyperexcitabilityhyperexcitability
““the irritable focusthe irritable focus””
From: J. MacKenzie (1909)
…..this portion of the spinal …..this portion of the spinal cord may be looked upon as cord may be looked upon as cord may be looked upon as cord may be looked upon as being rendered abnormally being rendered abnormally excitable in consequence of a excitable in consequence of a violent stimulation from the violent stimulation from the organ V…..organ V…..
CNS
How visceral pain worksHow visceral pain works
P
Aδδδδ / CPrimaryPrimaryHyperalgesiaHyperalgesia
Aββββ
Nociceptor
sensitization
1
Synaptic
strengthening by
incoming
afferent volleys
(sensitization)2
AllodyniaReferredReferredHyperalgesiaHyperalgesia Aδδδδ / C
T
Aββββ
P
Aδδδδ / CActivation of
nociceptive
neurons by LT
afferents3
Synaptic strengthening by incoming afferent volleys (sensitization)
Visceral Hyperalgesia and CNS hypersensitivity:
Role of glutamate receptor trafficking
A. Contractor, S.F.Heinemann Sci. STKE 2002, RE14 (2002)
Visceral painful stimuli recruit GluR1 AMPA receptor subunits to the membrane
GluR1
B 10 45 90 180
GluR2/3
MEMBRANE
2
3
4
5
*** **
** GluR1
CYTOSOL
GluR1
B 10 45 90 180
GluR2/3
Capsaicin (min)
B 10 45 90 180
Capsaicin (min)
Galan, Laird and Cervero, 2004
10 45 90 1800
1
Time after capsaicin instillation (min)
GluR2/3
Mobilization by exocytosis?
Inhibition of the exocytosis pathway blocks recruitment of
GluR1 to the membrane and reduces referred hyperalgesia
MEMBRANE
B Vh BFA
Brefeldin A given i.t. 10 min before intracolonic capsaicin
45 min
80
100 Baseline
Vh + CapsaicinCaps + 15 nmoles BFA
Capsaicin
Galan et al , 2004
1 4 8 16 320
20
40
60
****
****
Force (mN)
0.0
0.5
1.0
1.5
2.0
Capsaicin
**
#
AMPA trafficking and visceral painAMPA trafficking and visceral pain
• Acute painful stimuli induce trafficking (membrane delivery) of GluR1 AMPA receptors in vivoGluR1 AMPA receptors in vivo
• Inhibition of AMPA trafficking reduces secondary hyperalgesia induced by acute stimuli
Functional Pain
Spontaneous and persistent pain in the
absence of an apparent cause
• Frequent form of chronic pain (Irritable Bowel Syndrome, Interstitial Cystitis, (Irritable Bowel Syndrome, Interstitial Cystitis, Chronic Pelvic Pain, Fibromyalgia….)
>30% all chronic pain
• More prevalent in women (> 65%)
• Unknown mechanisms (a role for estrogen?)
Functional Pain and HyperalgesiaFunctional Pain and Hyperalgesia