Transcript The perception of pain

The perception of pain
Ching-Liang Lu
What is pain?
• Pain is an unpleasant sensory and emotional
experience associated with actual or
potential tissue damage, or described in
terms of such damage
IASP – International Association for the Study of Pain 2009
What is pain?
• Pain is
– subjective
• not a stimulus, but an experience
– protective (acute)
– modified by developmental, behavioural, personality
and cultural factors
• Associated signs are crying, sweating, increased
heart rate, blood pressure, behavioural changes etc
Pain
• Dimensions of the ‘PAIN”
– Sensory-discriminative
– Affective-motivate
– Cognitive
Nociceptive vs Neuropathic Pain
Nociceptive
Pain
Caused by activity in
response to potentially
tissue-damaging stimuli
Neuropathic
Pain
Initiated or caused by
primary lesion or
dysfunction in the
nervous system
Phantom
pain
Postherpetic
Arthritisneuralgia
Pos
postoperative
pain
Sickle cell
toperative
Mechanical
crisis
lowpain
arthritis, back pain
Neuropathic
low back pain
Sports/e sports or exercise injuries xercise
injuries
*Complex regional pain syndrome
Trigeminal
neuralgia
Central poststroke pain
Distal
polyneuropathy
(eg, diabetic, HIV)
Nociceptive pain: Tissue
injury/inflammation
Postherpetic neuralgia
Acute vs Chronic Pain
Characteristic
Acute Pain
Chronic Pain
Cause
Generally known
Often unknown
Duration of pain
Short,
well-characterized
Persists after healing,
3 months
Treatment
approach
Resolution of
underlying cause,
usually self-limited
Underlying cause and pain
disorder; outcome is often
pain control, not cure
What is Acute Pain?
•
•
•
•
•
•
Physiologic response to tissue damage
Warning signals damage/danger
Helps locate problem source
Has biologic value as a symptom
Responds to traditional medical model
Life temporarily disrupted (self limiting)
Acute pain is not that bad.
What is Chronic Pain?
• Chronic pain is persistent or recurrent pain,
lasting beyond the usual course of acute
illness or injury, or more than 3 - 6 months,
and adversely affecting the patient’s wellbeing
• Pain that continues when it should not
Domains of Chronic Pain
Quality of Life
Physical functioning
Ability to perform
activities of daily
living
Work
Recreation
Social Consequences
• Marital/family
relations
• Intimacy/sexual activity
• Social isolation
Psychological Morbidity
Depression
Anxiety, anger
Sleep disturbances
Loss of self-esteem
Socioeconomic
Consequences
• Healthcare costs
• Disability
• Lost workdays
Pain measurement
Nociceptors
• 3 classes of nociceptors
–Mechanical: pinch, punctate, squeeze
–Thermal: above 45C or below 5C
–Polymodal: mechanical, thermal,
chemical
Somatic receptor types
Thermosensation
Heat
DRG
• 45% small- to medium-diameter neurons:
threshold of ∼42°C  heat-sensitive C and
type II Aδ fibres TRPV-1 receptor
• 5-10% medium- to large-diameter cells:
threshold of ∼51°C  type I Aδ TRPV-2
receptor
• TRPV-3 TRPV -4: warm range 31∼39°C
Thermosensation
Cold
•TPRVM8 receptor: ∼26°C ; (cool to cold) express
in 10-20 % of small-diameter neuron
• TRPA1: ∼17°C painful cold ?
TRP channel family
Mechanosensation
Mechanoreceptor:
•? Yet to be identified in mammalian
• non-mammalian
• Bacteria: MscL, MscS, DEG/EnaC ion
channel,
• Yeast, flies, worms: TRP channel
• Fly, Zebra fish: NOMPC (TRP channel)
AFFERENT (SENSORY) NEURON
Nociceptive afferents
First pain: Sharp, faster A-delta fibers
Compound Action Potential
Second pain: Dull, slower C-fibers
Blocking each nerve blocks the sensation
SPINAL CORD LAMINAE
LAMINA
PREDOMINANT
FUNCTION
INPUT
NAME
I
SOMATIC NOCICEPTION
THERMORECEPTION
Aδ, C
MARGINAL LAYER
II
SOMATIC NOCICEPTION
THERMORECEPTION
C, Aδ
SUBSTANTIA
GELATINOSA
III
SOMATIC NOCICEPTION
MECHANORECEPTION
Aβ, Aδ
NUCLEUS PROPRIUS
IV
MECHANORECEPTION
Aβ, Aδ,
NUCLEUS PROPRIUS
V
VISCERAL & SOMATIC
NOCICEPTION &
MECHANORECEPTION
Aβ, Aδ, C
NUCLEUS PROPRIUS
WDR NEURONS
VI
MECHANORECEPTION
Aβ
NUCLEUS PROPRIUS
VII
SYMPATHETIC
VIII
IX
X
MOTOR
INTERMEDIOLATERAL
COLUMNS
Aβ
MOTOR HORN
Aβ
MOTOR HORN
Aβ
CENTRAL CANAL
Dorsal
horn
Lamina of spinal cord
Referred pain
• Signals from muscles and viscera can
be felt as pain elsewhere
• Example: myocardial infarction and
angina can be felt in chest and left
arm
• Mechanism: convergence of afferents
muscle/ viscera afferents and somatic
afferents.
• Convergence on the same projection
neurons in the dorsal horn
• The brain cannot tell the difference
Neurotransmitters
• Fast synaptic potentials
– Glutamate (amino acid, excitatory)
– Efficient reuptake of amino acids
– Range: postsynaptic neurons in vicinity
• Slow synaptic potentials
– Neuropeptides e.g. Substance P(excitatory), GABA (inhibitory)
– No reuptake mechanisms
– Range: diffusion, many neurons, unlocalized nature of pain
• Other Neuropeptides
– Released and increased in persistent pain conditions
– Enhances and prolong the actions of glutamate
Substance P in dorsal horn
Pain modulation
below spinal level
1. PERIPHERAL
2. CENTRAL
1.
Peripheral (Sensitization)
TISSUE INJURY
RELEASE OF SUBBSTANCE-P
AND GLUTAMATE
CHEMICAL MEDIATORS OF
INFLAMMATION
STIMULATE NOCICEPTORS IN
THE PERIPHERY
Peripheral Sensitization
NSAID
Peripheral sensitization
53C 30 sec at site A&D
Central sensitization for chronic pain:
wind-up
• “Wind-up”
– Response to second stimulus is stronger than the
response to the first one in C fiber
• Change in temporal integration
"Wind-up" is NMDA mediated.
Response with and without an NMDA antagonist.
Control
NMDA antagonist
40
30
20
10
0
0
10
Stimulus number
20
Spinal microglia activation in the
chronic visceral pain (chronic pancreatitis)
Liu PY, Lu CL. Gastroenterology 2012; 142: 165-73.
Spinal microglia in visceral pain
TNBS
I.T. tetracycline
(microglia inhibitor)
Liu PY, Lu CL. Gastroenterology 2012; 142: 165-73.
Ascending pathways
Spinal cord ThalamusCortex
Ascending pathways
Spinal cord ThalamusCortex
• Thalamic nuclei
– Lateral nuclear group: spinothalamic tract,
NS and WDR, laminae I and V, small
receptive fields, encoding location of injury
–  Infarction  Thalamic syndrome
(spontaneous burning pain, allodynia)
– Medial nuclear group: spinoreticulothalamic
tract, laminae VII and VIII
New pathway for
visceral pain:
 Dorsal
column pathway
Lateral system: S1/2
Discrimitive component
Thalamus
Medial system:
Affective component
Neuroimaging of acute pain
Cutaneous pain
Muscle pain
Visceral pain
PFC
PFC
ACC
PFC
ACC
PCC
PPC
PPC
Insula
PCC
PCC
Chen et al.
Tooth pain
Insula
Thalamus
Insula
Vermis
Amygdala
Vermis
Lin et al. (preliminary)
Lu et al., 2004
Niddam et al., 2002
Somatosensory area
Cortical neuronal correlates upon
balloon distension in GI tract (volunteers)
Esophagus
Rectum
Antrum
Fundus
Mertz H.
Gastroenerology
2000; 118:8342
Ladabaum U.
Gastroenerology
2001; 120:369
Aziz Q. Gastroenerology
1997; 113:50
Lu CL
Neurogastroenterol 2004;16:575
Gastroenerology 2005; 128:1529
Brain  Pain perception
No Brain, No Pain
Rene Descartes (1596-1650)
Pain modulation
(Central)
• Gate control theory
• Descending inhibition
Gate control theory
• P.D. Wall & Melzack (1965)
• “There is an interaction between pain fibres and
touch fibre input at the spinal cord level in the form
of a ‘gating mechanism’
Gate control theory
pain is felt
+
pain
gate is
opened
When pain fibre is stimulated, gate will be opened & pain is felt
Gate control theory
pain is
not felt
touch
+
pain
gate is
closed
When pain and touch fibres are stimulated together, gate will be
closed & pain is not felt
Gate control theory
• This theory provided basis for various
methods of pain relief
– Massaging a painful area
– Applying irritable substances to a painful
area (counter-irritation)
– Transcutaneous Electrical Nerve
Stimulation (TENS)
– Acupuncture ?
Descending inhibition
• Direct stimulation of PAG produces analgesia
– Inhibits firing of nociceptive neurons in
lamina I and V
– Descending pathway recruited: PAG excites
rostroventral medulla/ nucleus raphe
magnus (5HT); LC(NE); VTA (DA)
• Role of Opioid receptor
– Opioid-induced analgesia via endogenous
opioid receptors (-, δ-, κ-) in descending
pathway ( PAG, ventral medulla, superficial
dorsal horn)
– Endogenous opioid peptide :enkephalins, βendorphin, dynorphin
– Stress-Induced Analgesia (SIA)
“Pain is a more terrible lord
of mankind than even death
itself”
“疼痛比死亡更可怕”
Dr. Albert Schweitzer (1875-1965)