Tony Dickenson,

Neuroscience, Physiology and Pharmacology

University College London

PAIN - WHAT DOES IT DO TO US,

AND WHAT CAN WE DO ABOUT IT?

Cortex - where and how much pain

Peripheral events

Tissue and nerve

damage

Spinal events

Brain stem descending controls

Limbic areas - unpleasantness Central reward

and co-morbidities

Peripheral channel and sensors

Peripheral sensitization

Wind-up

Impact of the brain

Central sensitization

Key types of pain

Nociceptive painPain caused by

an inflammatory or

non-inflammatory

response to a

noxious stimulus

Tissue damage

Chemical activation

Osteoarthritis

Neuropathic painPain initiated or caused

by a primary lesion or

disease in the

peripheral or central

nervous system

Nerve damage

Ion channel changes

Both types

of pain

can co-exist

Post-surgical pains

Low back pain,

cancer pain etcNociplastic

Thakur M, Dickenson AH, Baron R, Nature Reviews Rheumatology 2014;10:374-380

The patients with pain

after joint replacement?

Inflammation and Neuropathy in Cancer Induced Bone Pain

Tissue Damage

Tumor pro-pain chemicals

Immune cells

Nerve Damage

Hyperinnervation

Denervation

Invasion

Stretch

Translating from spinal neurones to humans

sensitize, activate

NSAIDS

COX 1/2

capsaicin

heat

H+

PGs 5HTATP Na+, K+,

Ca2+

channels

C-fibre

Inflammation – ongoing activation

of pain sensors

NGF

cytokines

Direct peripheral, direct gene effects and indirect…

Xian CJ and Zhou X-F et al. (2009) Treating skeletal pain: limitations of conventional anti-inflammatory drugs, and anti-neurotrophic factor as a possible alternative

Nat Clin Pract Rheumatol doi:10.1038/ncprheum0982

NGF - nerve growth factor

Tanezumab - humanized

Monoclonal Antibody

10pM >100 hr stable binding

Prevents TrkA action

Excess of NGF in states of

inflammation

But……….premature joint

replacement

A -beta fibres

Non-noxious

A -delta fibres

Some noxious

C- fibres

Noxious

Disordered

conduction

Accumulations

of channels

Ectopic and

ephatic activity

De-novo channels

DRG

Neuropathy - nerves tend not to heal…

Calcium Potassium Sodium

A-beta fibres - tactile sensations

C and A-delta fibres - nociceptors - heat, mechanical and

chemicals

All types of fibres can be damaged

Disconnection - numbness

Ectopic activity - ongoing pain

Still connected - evoked pains

Allodynia -

central sensitization

Calcium channels Potassium channels Sodium channels

Release of transmitter Brakes Accelerator - action potentials

Problem of driving

with faulty brakes and

transmission

lidocaine

carbamazepine

gabapentin

pregabalin

opioids

Calcium channels Potassium channels Sodium channels

Release of transmitter Brakes Accelerator - action potentials

lidocaine

Inherited mutations – gain of function can be loss

of inactivation, gain of activation – but can alter lidocaine

actions……

Channelopathic pain

syndromes

Inherited

erythromyalgiaNav 1.7

Lower threshold,

enhanced responses

Attacks of burning pain

and redness in

extremities

Paroxysmal extreme

pain disorderNav 1.7

Impaired inactivation

Enhanced response

Episodic lower body

visceral, ocular, jaw pain

Channelopathy

associated

insensitivity to pain

Nav 1.7 Loss of function Inability to sense pain

Familial episodic

pain syndromeTRPA1 Enhanced response

Episodic upper body

pain, triggered by

fasting, cold, fatigue

C-fibreAd-fibreAb-fibre

Nav1.8

Nav1.7

•Nav1.8 and Nav1.7

Transduction, propagation and …….transmission. Peripheral restriction may be an

error.

Major spinal increases in excitability

Carbamazepine

Lidocaine

Damaged Zone

Electrical activity

Release of

transmitters

s

s

a1

a2

d

b

i

a2d ligands

Channels are key to neuropathic pain

Bauer CS et al. J Neurosci 2009;29:4076-88

Pregabalin at effective doses prevents

function of the subunit

Upregulated alpha-2 delta subunits in the

spinal cord on the side of nerve injury

The Search for the Holy Grail?

NSAIDs

Lido

GBP

Nociceptive pain

Chemical activationNeuropathic

pain

Electrical events

Pain and molecular gastronomy - the fine line….

A gain-of-function mutation in TRPA1

causes familial episodic pain syndrome

Upper body pain

Triggered by

– cold

– hunger

– fatigue

– exertion

–emotions

Irritant sensor

Prodermal……pain 1.5 hrs…..sleep

Normal acute painKremeyer B et al.

Neuron 2010;66(5):671-80

PERIPHERAL

ACTIVITYCENTRAL

SENSITIZATION

Decreased

threshold to

peripheral

stimuli

Increased

spontaneous

activityExpansion of

receptive

field

HyperalgesiaAllodynia

Tissue damage

Primary hyperalgesia

Nerve damage

Spontaneous

pain

Secondary hyperalgesia

FMS

OIH

0

10

20

30

40

Stimulus number

Neuro

nal re

sponse

NMDA-R mediated amplification & prolongation of response

NMDA receptors and wind-up

Decay dependent on peripheral input

secs - hours -weeks

(intensity and frequency of

stimulus)

ketamine

D’Mello RD, Dickenson AH. Br J Anaesthesia 2008;101:8-16

Stimulus no.1 6 12 16

Increased excitability

Wind-up - temporal summationLong-term potentiation

Peripheral and descending pathways converge …

Spinal mechanisms -

central hypersensitivity

++++++Early C-fibre inputs

Subsequent inputs

Altered pain states

Tactile, cold

Ketamine

NMDA - Receptor

For glutamate

Powerful analgesic but cognitive

and other side-effects

Loss of spinal GABA and chloride controls after nerve injury

III

Ad

C

Peripheral nerve

Spinal cord

Ad

Aa/bIII

IV

V

+

Glycine inhibitions

Brain

Withdrawal

reflex

Descending

inhibitions

+

++

-Human hyperekplexia

Glycine R mutation Cl

On-Cell

Off-CellLimbic System

Amygdala

Hypothalamus

Periaqueductal grey PAG

Rostroventral medial medulla RVM

Locus coeruleus

Inhibitory controls

Noradrenaline

PAIN

Alpha-2 adrenoceptor

Adapted from: Bannister K, Bee LA, Dickenson AH. Neurotherapeutics. 2009.

5-HT 2 and 3R

Excitatory controlsExcitatory controlsInhibitory controls

Sub reticularis

dorsalis

Parabrachial

Anterior

cingulate

cortex

…..

DNIC/CPM

5-HT7R

Neutral Cell

What is the Pharmacology of Descending Controls?

NA and 5-HT are Key Transmitters

Anxiety

Pain related changes

Goncalves & Dickenson, Eur J Neurosci 2012

Neuropathy - ongoing and evoked asymmetrical neuronal changes

…..with time

Pain changes our brain functions

18

27

33

36

39

55

60

0 10 20 30 40 50 60 70

Poor appetite

Anxiety

Depression

Concentration difficulties

Drowsiness

Lack of energy

Difficulty sleeping

% patients with moderate to very severe

discomfort due to symptoms (n=126)

Meyer-Rosberg K et al. Eur J Pain 2001;5:379–89

Psychology is part of neurobiology

Beliefs, distraction, anxiety……

Limbic System

Amygdala

Hypothalamus

Periaqueductal grey PAG

Rostroventral medial medulla RVM

Mood, fear, anxiety, rage

panic, sleep-wake….

Locus coeruleus

On-CellOff-Cell

Neutral Cell

Inhibitory controls excitatory controls

Noradrenaline 5HT

Noradrenaline and 5-HT AND THE CONTROL OF PAIN

PAIN

Alpha-2 adrenoceptor

Same circuits

imaged in humans

Brain noradrenaline pathways - ascend and descend…

Descending inhibitions Descending excitations

CHANGED IN PERSISTENT PAINS

Protects Promotes

NA

Noradrenaline 5-HT

Alpha2 AR 5HT2/3R

Punctate mechanical hypersensitivity

Could there be time-related events in neuropathic pain?

0

25

50

75

100

0 5 10 15

Resp

on

se F

req

uen

cy (

%)

Post-operative Day

vF 8g

Bee LA, Dickenson AH. Pain 2008;140:209-23

Maintained hypersensitivity

after peripheral neuropathy

Ablation of RVM descending

facilitations

and abnormal cold…

Control values

Altered functional magnetic resonance imaging resting-state

connectivity in periaqueductal

gray networks in migraine.Caterina Mainero MD, PhD1,

Jasmine Boshyan BS1, Nouchine Hadjikhani MD, PhD1,2,*

Psychophysical and Functional

Imaging Evidence Supporting

Presence of Central

Sensitisation in a Cohort of

Osteoarthritis Patients

Translation to patients…..

Gwilym SE et al. Arthritis Rheum 2009; 61(9):1226-34

2.0

1.5

1.0

0.5

0.00 5 10 15 20 25

Pain DETECT score

% c

hange o

f B

OLD

sig

nal

(vm

ax)

within

PA

G m

ask

Patients > Controls

High PainDETECT > Low PainDETECT

PAG activation

Noradrenaline

5HT

promotes pain

NA

protects

Descending inhibitions - via brainAltered by gender, age….

Relate to chronic post-op pain

Reduced in fibromyalgia, osteoarthritis, after

peripheral neuropathy and in opioid hyperalgesia

Peripheral and central pain states have a common

loss of inhibition - compounded by depression and

sleep issues

Failure of descending inhibitions in patients

Diffuse Noxious Inhibitory Controls (DNIC)

Conditioned Pain Modulation

Peripheral neuropathy

Fibromyalgia, Irritable Bowel Syndrome,

Migraine, Tension-type headache,

Temporomandibular joint (TMJ) disorders,

Osteoarthritis and muscle pain,

Interstitial cystitis,

Patients at risk of developing chronic post-surgical pain

Cancer pain patients with

greater opioid-induced hyperalgesia.

Reduced CPM in many pain conditions

Yarnitsky D, Curr Opin Anaesth 2010; 23:611–615

0

100%

DNIC

normal

DNIC

nerve

injury

DNIC

nerve

injury

+ 5HT3

blockDNIC

normal

DNIC

With

NA a2R

block

DNIC uses descending NA systems - lost after nerve injury

Overcome by facilitations

Probing the pharmacology of DNIC

Pain. 2012 Jun;153(6):1193-8.

Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.

Yarnitsky D1, Granot M, Nahman-Averbuch H, Khamaisi M, Granovsky Y.

Br J Anaesth. 2014 Jul;113(1):148-56. doi: 10.1093/bja/aeu056.

Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy.

Niesters M1, Proto PL2, Aarts L2, Sarton EY2, Drewes AM3, Dahan A

LOSS OF CPM IN PATIENTS - RELATES TO ACTIONS OF DULOXETINE

AND TAPENTADOL - both have NA actions……

What targets for chronic pain

prevention?Ø Altered peripheral transduction, altered nerve

function

Ø Consequent shift in spinal cord to hypersensitive state – gain of excitation…..

Ø Enhanced drive into brain areas responsible for sensory and affective aspects of pain

Ø Shifts towards lower effective stimuli for pain

Ø Comorbidities - anxiety, sleep problems etc

Ø Impaired descending inhibitions, enhanced facilitations

A struggle between the outer and inner worlds….when

and which?

Symptom/sign

Ongoing/ evoked

Mechanism

Mechanism

Mechanism

Three subgroups of patients – aetiology is unimportant

Subgrouping patients with peripheral neuropathic pain

based on sensory signs

Colloca, L. et al. (2017) Neuropathic pain

Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.2

Reproduced with permission from Baron, R. et al., Peripheral neuropathic pain: a

mechanism-related organizing principle based on sensory profiles, Pain, 158, 2, 261–272,

http://journals.lww.com/pain/ Fulltext/2017/02000/Peripheral_neuropathic_pain___a_mechanism_ related.10.aspx

It is likely that brexpiprazole affects

individual patients in a different way, as the

effects of antipsychotics in general depend

a lot on the specific symptoms, which show

especially high variability in schizophrenia.

The same drug can be beneficial for one

patient, while not improving symptoms in

another patient.

Sensory inputs

Life

Internal processes

Pain intensity

Abnormal

touch, cold etc

Anxiety

A struggle between the

outer and inner worlds

Cortex - where and how much pain

Peripheral events

Tissue and nerve

damage

Spinal events

Brain stem descending controls

Limbic areas - unpleasantness

Risk factors

Failure of descending inhibition

Presence of central sensitisation

Restore normal modulation

When we can’t fixed the source - we can modulate the pain

The peripheral and central changes induced by nerve injury or peripheral neuropathy

Colloca, L. et al. (2017) Neuropathic pain

Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.2

Adapted with permission from Tesfaye, S., Boulton, A. J. & Dickenson, A. H. Mechanisms and management

of diabetic painful distal symmetrical polyneuropathy. Diabetes Care 36, 2456–2465 (2013), American Diabetes Association,

2013. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association

Thank you!