PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
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PAIN MODULATION BY NEGATIVE
AFFECTIVE STATE:
ROLE OF THE ENDOCANNABINOID SYSTEM
David P. Finn
National University of Ireland Galway
Talk Overview
• Relationship between negative affect/stress and
pain
• Fear-induced analgesia
&
• Anxiety/depression-related hyperalgesia
– Role of endocannabinoid system (CB1, TRPV1, PPARs, GPR55)
• Key brain regions
• Neurochemical and molecular mechanisms
Tracey and Mantyh 2007 Neuron
Impact of Stress on Pain
Chance et al. (1978)
Rosecrans et al. (1986)
Flor and Grusser (1999)
Intense Butler and Finn (2009)
acute
Analgesia stress/fear
Genetic
Pain background Stress
Hyperalgesia
Moderate chronic
stress/anxiety
Vidal and Jacob. (1986)
Rhudy and Meagher. (2000)
Suarez Roca et al. (2008)
Jennings et al. (2014)
Olango and Finn (2014)
Fear-Conditioned Analgesia (FCA)
• Analgesia expressed during or following exposure to
conditioned stress
• Potent form of endogenous analgesia
– Can be profound, reducing pain in rodents by > 90% at its peak
(Chance et al., 1978; Fanselow, 1984; Harris & Westbrook, 1995; Finn et al., 2004)
• Expressed in rodents and humans (e.g. Janssen and Arntz, 1996; Flor
and Grusser 1999)
Fear-conditioned analgesia represents a useful model for: • Understanding the physiology and neural substrates of endogenous analgesia • Elucidating mechanisms underpinning altered pain processing during stress/fear • Understanding how anticipation and/or memory of pain modulates subsequent responses to noxious stimuli • Identification of new therapeutic targets for pain- and fear-related disorders
Fear-conditioned analgesia is mediated by activation
of the descending inhibitory pain pathway
Butler and Finn (2009) Prog Neurobiol
Opioid receptors
GABA
- + -
Fear-
conditioned
? Pain analgesia
Fear ?
- ? -
Cannabinoid receptors
Endocannabinoids
The Endocannabinoid System
CB receptors
CB1
CB2
Endocannabinoids MAGL
Anandamide
(AEA)
2-AG
Enzymes Anandamide
2-Arachidonyl glycerol
FAAH
(AEA, OEA, PEA)
MAGL FAAH
(2-AG)
Related targets
PPARs
TRPV1
GPR55
V. Di Marzo
www.endocannabinoid.net
Components of the endocannabinoid system are
expressed throughout the descending inhibitory pain pathway
CB receptors
(and TRPV1, PPARs,
GPR55)
EndoCs
EnzymesPharmacological blockade of CB1 receptor prevents
fear-conditioned analgesia
1.4
Composite pain score
Veh
1.2
1.0
0.8
0.6 *
0.4
0.2
0.0
No FC FC
*PPharmacological blockade of CB1 receptor prevents
fear-conditioned analgesia
1.4
Composite pain score
Veh
1.2
+ Rim
1.0
0.8
0.6 *
0.4
0.2
0.0
No FC FC
*PPharmacological blockade of CB1 receptor prevents
fear-conditioned analgesia and attenuates the suppression of
dorsal horn Zif268 associated with fear-conditioned analgesia
1.4
Composite pain score
Veh
zif268 mRNA expression
1.2 150
+ Rim Veh
1.0 + AM251
(% NFC-Veh)
0.8 100
0.6 * *
0.4 50
0.2
0.0 0
No FC FC NFC FC
*PDoes blockade of endocannabinoid
degradation enhance fear-
conditioned analgesia?FAAH inhibitor enhances fear-
conditioned analgesia
1.5
Vehicle
Composite Pain Score
URB597
1.0
*
0.5
+
0.0
No FC FC
* PWhich brain region(s) are involved in endocannabinoid-
mediated fear-conditioned analgesia?The endocannabinoid system in the dlPAG
mediates fear-conditioned analgesia
1.5
AEA Veh
Composite pain score
Rim
10 *
AEA (pmol/g)
1.0 +
8
6
4 0.5
**
2
0
NoFC FC 0.0
NoFC FC
Olango et al. (2012) Br J Pharmacol
The endocannabinoid system in the basolateral amygdala
mediates fear-conditioned analgesia
1.5 Vehicle
Composite pain score
AM251
1.0
+
0.5
*
0.0
NoFC FC
Rea et al. (2013) PainHohmann, Piomelli & colleagues
Role of the mPFC in Pain and Fear
• Affective/cognitive components of pain and fear
(Tolle et al. ,2001; Singer et al. 2004; Xie et al., 2009; ACC
Etkin et al. 2011; O’Hara et al. 2005; Wiech et al. 2008)
• Top-down modulation of the descending PrL
inhibitory pain pathway (Millan 2002; Butler and
Finn 2009) IL
• Expression of conditioned fear to a noxious
stimulus (Corcoran & Quirk, 2007; Sierra-Mercado et
al. 2011)
• Opposing Influences of PrL and IL on
conditioned fear (Sierra-Mercado et al. 2011; Vidal- PFC: Bregma +3.20mm
Gonzalez et al. 2006) and formalin-induced
conditioned place avoidance (jiang et al. 2014)
• Role for the endocannabinoid system in the
mPFC in stress, emotionality (McLaughlin et al.
2014), fear (Draycott et al. 2014; Lin et al. 2009)
and pain (Ji and Neugebauer 2014)
• CB1 receptor antagonism in the PrL attenuates
fear-induced analgesia elicited by GABAA
receptor blockade in the ventromedial
hypothalamus (de Freitas et al. 2013)
Vidal-Gonzalez et al. (2006)Fear-conditioned analgesia expressed
Prelimbic Cortex Infralimbic Cortex
1.5 VEH
1.5
Composite Pain Score
Composite Pain Score
1.0 1.0
0.5 * 0.5 *
0.0 0.0
NFC FC NFC FC
*PFear-conditioned analgesia attenuated by microinjection of
CB1 receptor antagonist into the PrL or IL cortex
Prelimbic Cortex Infralimbic Cortex
VEH
AM251
1.5 1.5
Composite Pain Score
Composite Pain Score
+ +
1.0 1.0
0.5 0.5
0.0 0.0
NFC FC NFC FC
+PDifferential effects of FAAH inhibition in PrL vs IL cortex
Prelimbic Cortex Infralimbic Cortex
VEH
URB597
1.5 1.5
Composite Pain Score
Composite Pain Score
+
1.0 1.0
0.5 0.5
0.0 0.0
NFC FC NFC FC
+PSummary I: supraspinal regulation of
fear-conditioned analgesia
– Mediated by the endocannabinoid system in:
– Dorsolateral PAG
– BLA
– Ventral hippocampus
And
– mPFC
– Similar role for CB1 in PrL vs IL
– AEA/2-AG
– Differential effects of FAAH inhibition in PrL vs IL
– PrL: AEA?
– IL: PEA, OEA? PPARs?
– ACC (see poster no. 92, Louise Corcoran)Pain-related alterations in the PPARα
signalling system in the rat ACC
PEA PPAR-α
saline
0.15
formalin
150
saline
nmol/g tissue
(%saline )
0.10 formalin
100
mRNA
*
0.05 50
**
0.00
0
OEA
0.15
nmol/g tissue
0.10
**
*pPharmacological blockade of PPARα in the ACC delays the onset of
second phase formalin-evoked nociceptive behaviour
1.5
Vehicle
Composite pain 10µgGW6471 (PPARα antagonist)
1.0
*
score
*
0.5
0.0
0 1 2 3 4 5 6 7 8 9 101112131415161718
Time bins (5 min)
*pPharmacological blockade of PPARγ in the ACC
reduces formalin-evoked nociceptive behaviour
Composite pain score
1.5 * Veh
1.2 GW9662
(PPARγ antagonist)
0.9
0.6
0.3
0.0
10 0
5
15 5
20 0
25 5
30 0
35 5
40 0
45 5
50 0
55 5
0
0-
-1
-2
-2
-3
-3
-4
-4
-5
-5
-6
1
5-
Time bins (5 min)
*pPharmacological blockade of TRPV1 in the ACC
reduces formalin-evoked nociceptive behaviour
Vehicle
5'-IRTX (TRPV1 antagonist)
1.5
Composite pain score
**
1.2
*
0.9
0.6
0.3
0.0
5
15 5
20 0
25 5
30 0
35 5
40 0
45 5
50 0
55 5
0
10 0
0-
1
-1
-2
-2
-3
-3
-4
-4
-5
-5
-6
5-
Time bins (5 min)
**pPharmacological blockade of GPR55 in the ACC
reduces formalin-evoked nociceptive behaviour
1.0 Vehicle
** **
Composite pain score
0.8 CID16020046
* (GPR55 antagonist)
0.6
0.4
0.2
0.0
5
10 0
15 5
20 0
25 5
30 0
35 5
40 0
45 5
50 0
55 5
0
0-
1
-1
-2
-2
-3
-3
-4
-4
-5
-5
-6
5-
Time bins (5 mins)
rat brain ACC
**pGPR55 receptor blockade reduces levels of
Phospho-ERK in the ACC
Phospho ERK (42/44kDa)
150 Total ERK (42/44kDa)
Phospho/Total ERK 44
expressed as a %
100
of vehicle
**
50
0
ID
e
cl
C
hi
Ve
**pSummary II
• Pharmacological blockade of PPARα,
PPARγ, TRPV1 and GPR55 in the ACC
reduces formalin-evoked nociceptive
behaviour
– Facilitatory/permissive role for these receptors
in the ACC in painImpact of Stress on Pain
Intense
acute
Analgesia stress/fear
Genetic
Pain background Stress
Hyperalgesia
Moderate chronic
stress/anxiety% of primary care patients with pain
disorder and co-existent mood disorder
Von Korff and Simon (1996) Br J PschiatryExacerbation of pain by anxiety is associated with
increased activity in the entorhinal cortex
Ploghaus et al. (2001) J NeurosciSites and mechanisms mediating
stress-induced hyperalgesia
Jennings et al. (2014) Prog NeurobiolAnimal models of SIH: Role of endoC system
Is there a role for the
endocannabinoid system in pain
hyper-responsivity in negative
affective states?
(Anxiety/depression-related hyperalgesia)The Wistar-Kyoto rat as a model of
anxiety/depression-related hyperalgesia
Duration in centre zone (s)
Open-field
25 Forced swim test
20
15
10
5
**
0
SD WKY
1.5 Formalin test
Hot plate test
Composite Pain Score
**
Latency to paw lick (s)
25
1.0
20
15 **
10 0.5
5
0 0.0
SD WKY SD WKY
Burke et al. (2010) NeuroscienceHigher 2-AG levels and lower CB1 receptor mRNA expression
in the LPAG of WKY rats compared with SD rats
2-AG in LPAG Saline CB1 in LPAG
15 Formalin
++
2-AG (nmol/g tissue)
1.5
Saline
** Formalin
(% SD-saline )
10
1.0
**
mRNA
5 0.5
0 0.0
SD WKY SD WKY
**PIntra-LPAG administration of the CB1 receptor agonist
ACEA reduces formalin-evoked nociceptive behaviour
in SD rats but not in WKY rats
SD
**
1.2 Vehicle
Composite Pain Score
1.0 ACEA
0.8
0.6
0.4
0.2
0.0
0 2 4 6 8 10 12 14 16 18
5 min Time bins
Jennings et al., UnpublishedIntra-LPAG administration of the CB1 receptor agonist
ACEA reduces formalin-evoked nociceptive behaviour
in SD rats but not in WKY rats
SD
**
1.2
++ Vehicle
Composite Pain Score
ACEA
1.0
ACEA + AM251
0.8
0.6
0.4
0.2
0.0
0 2 4 6 8 10 12 14 16 18
5 min Time bins
Jennings et al., UnpublishedIntra-LPAG administration of the CB1 receptor agonist
ACEA reduces formalin-evoked nociceptive behaviour
in SD rats but not in WKY rats
Vehicle
SD ACEA
ACEA+AM251
WKY
**
1.2
++
Composite Pain Score
1.2
Composite Pain Score
1.0
1.0
0.8
0.8
0.6
0.6
0.4 0.4
0.2 0.2
0.0 0.0
0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18
5 min Time bins 5 min Time bins
Jennings et al., UnpublishedIntra-lPAG administration of ACEA increases c-Fos
expression in the RVM and decreases c-Fos expression
in the spinal cord of SD, but not WKY, rats
RVM Superficial Layers of the Ipsilateral
Dorsal Horn
200 50
Vehicle Vehicle
150
* ACEA 40 ACEA
c-Fos Count
c-Fos count
30 *
100
20
50 10
0 0
SD WKY WKY
SD
*pSummary III
• WKY rats:
– High anxiety/depression-related behaviour
– Hyperalgesia
• Reduced CB1R and increased 2-AG levels in the LPAG
• Differential responsivity to intra-LPAG admin of CB1R agonist
– Nociceptive behaviour
– C-Fos expression in RVM and DH
– Role for TRPV1 (see poster no. 13, Manish Madasu)
– Dysfunction of the endocannabinoid system in
PAG/RVM circuitry may contribute to exacerbated
nociceptive responding in a genotype associated with
negative affectRole of supraspinal endocannabinoid system in postoperative pain
following inguinal hernia repair surgery?
Sham Surgery saline
Surgery *
Surgery morph 3mgkg
light compartment
100 *
*
Surgery carp 5mg/kg
80
# +
% time in
100
60
+
80 #
% time in light
40
compartment
20 60
0 40
5 10 15 20 25 30
20
Time (min)
0
5 10 15 20 25 30
Bree et al. 2015 J Pain
Bree, Moriarty et al. UnpublishedConclusions
Endocannabinoids may play a pivotal role in regulating the
balance between fear, anxiety/depression and pain
Fear
Anxiety
EndoCs
Pain
Depression
• The precise nature of this regulation may depend on:
– Levels and types of endocannabinoids/related lipids
– Receptors activated (e.g. CB1, PPARs, TRPV1, GPR55…)
– Brain region and neural circuitry (e.g. GABA vs glutamate)
• Other models? (Post-op pain following inguinal hernia repair,
Neuropathic pain in WKY, IFN-α - induced hyperalgesia – Marie
Fitzgibbon, Poster no. 94)
• These data may be relevant to the development of endoC-based
therapeutics where anxiety/depression and pain are co-morbidPostdocs Acknowledgements
– Dr Kieran Rea Collaborators
– Dr Bright Okine National University of Ireland Galway
– Dr Cliona O’Mahony
– Dr Michelle Roche
– Dr Gemma Ford
University College London
Postgrad students
– Ryan Butler
– Prof Stephen Hunt
– Weredeselam Olango – Dr Sandrine Geranton
– Fiona McGowan
– Elaine Jennings
– Nikita Burke Funding sources
– Manish Madasu
– Orla Moriarty
– Dara Bree
– Louise Corcoran
– Karen Smith
– Yvonne Lang
– Daniel Kerr
– Jacqueline O’Connor
– Rebecca Henry
– Marie Fitzgibbon
– Lisa Flannery
– Ruth Concannon
Technical support
– Brendan Harhen
– Ambrose O’HalloranYou can also read
