dolor crónico: por que unos sí y otros...

Dolor crónico: por que unos sí y otros no

Fernando Cerveró

Director del Centro de Investigación sobre el Dolor

Universidad McGill, Montreal, Canadá

Presidente de la IASP

La cronificación del Dolor

1. 30-35% neuropatía diabética dolorosa

2. 5-10% lesión traumática nervios CRPS-II

3. 5-8% lesiones menores periféricas CRPS-I

4. 10% herpes zóster neuralgia post-herpética

5. 5-15% cirugía mayor dolor neuropático crónico

6. 3-7% hernia inguinal dolor crónico

7. 4-8% amputaciones miembro fantasma doloroso

1. …………..

La cronificación del Dolor

Entre el 80 y el 95% del dolor agudo NO se cronifica

(solo un porcentaje pequeño de dolor agudo se cronifica)

?

pain

sensa

tion

100

50

0

75

25

normal pain allodynia

hyperalgesia

injury

The dynamics of pain sensation (Cervero & Laird, 1996)

innocuous noxious

stimulus intensity

pain threshold

pain threshold

La cronificación del Dolor

1. El inicio: sensibilización: reversible

2. El mantenimiento: des-inhibición: reversible

3. La cronificación: alteraciones estructurales: reversibles?

4. El futuro: alterationes genéticas?: reversibles?

La cronificación del Dolor

INICIO

Sensibilización periférica y central

Fullness

Pain

Bladder reflexes

ATP P2X3

LUMEN BLADDER

TRPV1

vanilloids

distension

TRPV1

?

? Primary afferent neuron

Urothelial cell

Role of the urothelium in the signalling of sensory events in the bladder

Wind-up of Nociceptive Reflexes

(de Felipe et al, 1998)

CNS

Allodynia Secondary Hyperalgesia

Three key processes in sensitization

P

A / C Primary Hyperalgesia

T

A

P

Nociceptor sensitization

1

Synaptic strengthening by incoming afferent volleys (sensitization) 2

Activation of nociceptive neurons by LT afferents 3

La cronificación del Dolor

MANTENIMIENTO

Des-inhibición

1 4 8 16 320

25

50

75

100

OVX

Control

Sham

mN

Resp

on

se f

req

uen

cy (

%)

1 4 8 16 320

25

50

75

100

*

* ** *

mN

Resp

on

se f

req

uen

cy (

%)

OVX induces a long lasting abdominal mechanical hyperalgesic state

Week 1 Week 5

• Neuronal switch from pain inhibition to excitation

• Reversal of the postsynaptic actions of GABA

• Enhancement of the presynaptic actions of GABA

Hyperalgesic states:

inflammatory, neuropathic…

Activation of nociceptive neurons by A afferents

Des-inhibition of nociceptive neurons

Nociceptors

•Nociceptive specificity

•Intensity of painful stimulus

CNS neuron

Touch-evoked pain

Low Threshold receptors

Normal

Inflammation, neuropathy

0

5

10 BRUSH TOUCH BRUSH TOUCH

10

5

0

10

0

5

BRUSH TOUCH

PINCH

0

100

200

100

200

0

PINCH

0

200

100

PINCH

mustard

oil

0.3 μg

bicuculline

recording site site of mustard

oil application

ALLODYNIA AND GABA

Nociceptor-specific neurone s

pik

es

\s

sp

ike

s\s

(Garcia-Nicas, Laird & Cervero, 2003)

Net Cl- movement

(GABA-induced depolarization)

Chloride movements in adult DRGs

[Cl-]i = 30mM

[Cl-]o = 100mM

Vm= -60 mV

[Cl-]

NKCC1

K+ Na+ 2Cl-

Painful stimuli induce in vivo phosphorylation of mouse spinal cord NKCC1 co-transporter

B 10 45 90 180

Capsaicin (min)

Phospho-NKCC1

β-tubulin

Galan & Cervero, 2005

NKCC1 null mice: Reduced tactile hyperalgesia

Touch-evoked

Laird et al, 2004

**

**

Punctate

La cronificación del Dolor

CRONIFICACION

Alteraciones estructurales del cerebro

• Chronic pain patients have changes in brain grey matter that reflect changes in pain modulation

• Gray matter decreased first shown in back pain patients

• Chronic back pain is associated with decreased prefrontal and thalamic gray matter density (Apkarian et al 2004)

Anatomical and functional brain changes in Chronic Back Pain patients

• Similar findings with multiple chronic pain conditions: chronic tension-type headache, fibromyalgia, IBS

• Chronic back pain patients are impaired on emotional decision- making task

• FM patients have impaired working memory

When pain persists brain gray matter density decreases. Connectivity of nucleus accumbens with prefrontal cortex predicts pain persistence. Corticostriatal circuitry is involved in the transition from acute to chronic pain.

Baliki et al. Nature Neurosci. 2012

Corticostriatal functional connectivity predicts

transition to chronic back pain

Pain-related neuroanatomical and functional changes are reversible with effective treatment

Can gray matter changes be reversed with

treatment of pain?

Seminowicz et al. J. Neurosci. 2011;31:7540-7550

La cronificación del Dolor

FUTURO

Alteraciones genéticas?

Variability of neuropathic pain among 12 inbred mouse strains

Mogil et al, PAIN, 1999

Nissenbaum, Clinical Genetics, 2012

1. Quantitative trait locus mapping

2. Fine-mapping strategies (recombinant

progeny testing and recombinant inbred

segregation test)

3. Sequence-based analysis and mRNA

profiling

4. Selection of the most promising

candidate gene

5. Role in pain confirmed by behavior and

functional analyses in mutated mice

6. Association testing in human cohorts

(breast cancer patients) establishing the

connection of the gene to neuropathic

pain susceptibility.

Trabajando juntos para aliviar el dolor en todo el mundo

www.IASP-pain.org