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