PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...

 
PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
PAIN MODULATION BY NEGATIVE
          AFFECTIVE STATE:
ROLE OF THE ENDOCANNABINOID SYSTEM

               David P. Finn

     National University of Ireland Galway
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
PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
Tracey and Mantyh 2007 Neuron
PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
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)
PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
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)
PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
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
PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
Fear-conditioned analgesia is mediated by activation
     of the descending inhibitory pain pathway

                 Butler and Finn (2009) Prog Neurobiol
PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
Opioid receptors
               GABA

       -             +        -

                  Fear-
               conditioned
?   Pain        analgesia
                              Fear    ?

           -           ?          -
       Cannabinoid receptors
        Endocannabinoids
PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
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
PAIN MODULATION BY NEGATIVE AFFECTIVE STATE: ROLE OF THE ENDOCANNABINOID SYSTEM - David P. Finn National University of Ireland Galway ...
Components of the endocannabinoid system are
expressed throughout the descending inhibitory pain pathway

                                            CB receptors
                                            (and TRPV1, PPARs,
                                            GPR55)
                                            EndoCs
                                            Enzymes
Pharmacological 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

                                            *P
Pharmacological 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

                                               *P
Pharmacological 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

                                               *P
Does 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

* P
Which 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) Pain
Hohmann, 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

                                                    *P
Fear-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

                                                +P
Differential 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
                                                  +P
Summary 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
                               **
                                                                *p
Pharmacological 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)

                                                                           *p
Pharmacological 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)

      *p
Pharmacological 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)

        **p
Pharmacological 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
**p
GPR55 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

                                       **p
Summary 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 pain
Impact 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 Pschiatry
Exacerbation of pain by anxiety is associated with
   increased activity in the entorhinal cortex

                           Ploghaus et al. (2001) J Neurosci
Sites and mechanisms mediating
   stress-induced hyperalgesia

              Jennings et al. (2014) Prog Neurobiol
Animal 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) Neuroscience
Higher 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

  **P
Intra-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., Unpublished
Intra-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., Unpublished
Intra-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., Unpublished
Intra-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

                                             *p
Summary 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 affect
Role 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. Unpublished
Conclusions
 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-morbid
Postdocs                      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’Halloran
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