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The perception of pain
From Ch. 24
“Principles of Neural Science”, 4th Ed.
Kandel et al
April 29, 2009
Somatic sensations
• Somatic sensation = bodily sensation
– Pain is a submodality of somatic sensation
– Pain and nociception (conscious vs. peripheral)
• Pain sensation is the most salient sensation
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Pricking
Burning
Aching
Stinging
Soreness
• Pain is a warning of actual or potential injury and damage
• Pain depends on the psychological state
– The same stimulus can result in different responses under similar
conditions and in different individuals (soldiers, athlete, etc.)
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Nociceptors
Mechanical nociceptor
• Information about stimuli that can
damage tissue are conveyed by
nociceptors
• Chemicals are released from
traumatized tissue
– E.g. Substance P, histamine, and
bradykinin
• 3 classes of nociceptors
– Mechnical: pinch, punctate, squeeze
– Thermal: above 45 deg or below 5 deg
Polymodal: mechanical, thermal,
chemical
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Somatic receptor types
1
2
3
4
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Afferent fibers
Different size and conduction velocity of axons
Compound AP =
sum of all activated
nerves
Spike amplitude is
proportional to fiber
diameter
-Large fibers conduct faster than small/ thin fibers
because the internal resistance to current flow is low
and nodes of Ranvier are spaced further apart
- Myelination sheets increase conduction velocity
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Nociceptive afferents
Compound Action Potential
DRG
Spinal dorsal horn
First pain: Sharp and pricking, faster A-delta fibers
Second pain, burning and dull, slower C-fibers
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Blocking each nerve blocks the sensation
Spinal dorsal horn neurons
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2 overall types of interneurons:
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Lamina I and II
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Direct input from A-beta and A-delta. Direct/ indirect from C-fibers. Convergence of visceral
afferents. WDR interneurons projecting to brain stem and thalamus.
Lamina VI
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Direct input from A-beta. Nonnoxious input. Topographically organised receptive field
Lamina V
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Direct input from mainly A-delta and C fibers.
NS and WDR interneurons
Lamina III and IV
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Nociceptive specific: responds exclusively to noxious stimuli
Wide dynamic range neurons: graded response to non-noxious and noxious stimuli
Direct input from A-alpha (nonnoxious) from joints and muscle
Lamina VII and VIII
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Respond to noxious input. Polysynaptic. Bilateral response
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Neurotransmitters
• Fast synaptic potentials
– Glutamate (amino acid)
– Efficient reuptake of amino acids
– Range: postsynaptic neurons in vicinity
• Slow synaptic potentials
– Neuropeptides e.g. Substance P
– No reuptake mechanisms
– Range: diffusion, many neurons, unlocalized nature of pain
• Neuropeptides
– Released and increased in persistent pain conditions
– Enhances and prolong the actions of glutamate
– Application of substance P produces signs of inflammation e.g. heat,
redness, and swelling
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Peripheral activation and
sensitization
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Chronic pain
• Chronic pain appears to serve no useful purpose
– Abnormal pain states
– Nociceptive and neuropathic
• Nociceptive pain
– Direct activation of nociceptors
– Tissue damage or inflammation
• Neuropathic pain
– Direct injury to the nerves
– Peripheral or central
– Burning or electrical sensation
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Chronic pain
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Spontaneous ongoing pain
– Pain of variable intensity and duration
– Spontaneous discharges in periphery and centrally
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Referred pain
– Pain in a location distant from the source. Could be explained by viscero-somatic
convergence in lamina V
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Hyperalgesia
– Increased pain sensitivity
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Allodynia
– Non-painful input becomes painful e.g. touch on sun burned skin
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Allodynia and hyperalgesia only exist during stimulation
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Alterations in biochemical properties and excitability of dorsal horn neurons
can induce spontaneous pain, hyperalgesia and allodynia
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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
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Hyperalgesia
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Peripheral sensitization:
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Central sensitization:
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Increased spontaneous activity
Hyperexcitability of spinal dorsal horn neurons
Wind-up: progressive increased response = amplification (depends on glutamate acting on
NMDA receptors)
Prolonged after-discharges to afferent input
Expansion of peripheral receptive fields of central neurons
Can be induced by repetitive firing of nociceptive afferents
Primary hyperalgesia
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Increased nociceptor sensitivity
Increased spontaneous activity
Hyperalgesia in damaged area (within 5-10mm)
Peripheral sensitization
Secondary hyperalgesia:
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Hyperalgesia in surrounding undamaged tissue (10-20mm).
Peripheral and central sensitization
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Clinical hyperalgesia
Myofascial pain patients (PTS) vs. normal controls (CTR)
Myofascial trigger points are hyperalgesic contractures in the muscle
Pressure pain thresholds
P<0.001
800
600
400
200
IMES stimulus-response curves
6
Pain Intensity
Pressure [kPa]
1000
PTS
5
CTR
4
P<0.001
3
2
0
CTR
PTS
6
10
14
Stimulus Intensity [mA]
Niddam et al. 2008
April 29, 2009
Pain and the brain
• Pain is a subjective conscious experience. Pain does not
exist without the brain
• CNS inhibitory or facilitatory mechanisms are remarkable
efficient in decreasing or amplifying the pain experience
• Changes in CNS contributes to chronic pain
(reorganization: biochemical, atrophy, functions)
• A better understanding of endogenous pain modulatory
systems may lead to new mechanism-based therapies
and drug targets
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Pain and the brain: modulation
• Factors that can influence the pain experience
– Top-down brain processes
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Memories (previous experience)
Emotion
Cognition (attention/ distraction)
Mood (depression, anxiety)
Context (stress, anticipation/ expectation, placebo)
– Endogenous pain control systems
– Other factors
• Genes
• Pathological factors (structure, transmitters, receptors, transporters
etc.)
• Age, gender
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Acute vs. chronic pain
• Acute pain characteristics
– Activation of peripheral receptors under normal conditions
– Sensation of pain closely related to the duration of the stimulus
• Chronic pain characteristics
– Spontaneous ongoing pain
• Peripheral sensitization (spontaneous resting activity and hyperexcitable receptors)
• Central sensitization (prolonged peripheral input)
– Lowered pain threshold (Hyperalgesia)
– Non-nociceptive input becomes painful (allodynia)
– Functional and structural changes in PNS and CNS
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Segmental expansion of receptive fields
De novo synthesis of membrane proteins
Spouting of spinal terminals of afferent fibers
Formation of new synaptic contacts
Altered balance in descending influences
Acute vs. chronic pain
• It is important to differentiate between:
– Acute and chronic pain states
• Different time horizons engage different emotional coping strategies
• Chronic pain becomes maladaptive and is highly co-morbid with
mood and anxiety disorders
• Chronic pain induces CNS changes
– Ongoing spontaneous chronic pain vs. perturbations
of chronic pain (allodynia/ hyperalgesia)
• Passive vs. active coping => medial vs. lateral brain regions?
April 29, 2009
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
April 29, 2009
Lin et al. (preliminary)
Vermis
Lu et al., 2004
Niddam et al., 2002
Distinct ascending pathways
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Dorsal column-medial lemniscal
system
– Touch and proprioception from limbs
and trunk
– Somtatotopically organized from spinal
to cortical level
– Ascends ipsilateral side
– Cross over to contralateral side in
medulla
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Contralateral
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Spinothalamic pathway
– Spinal lamina I, V-VII
– Pain and temperature from limbs and
trunks
– Cross over to contralateral side in
spinal cord
– Somtatotopically organized from spinal
to cortical level
Ascending pathways
• 5 major ascending pathways
– Spinothalamic: axons of nociceptive specific and WDR neurons from laminae I
and V-VII; contralateral projection, ascends in anterolateral white matter
– Spinoreticular: neurons in laminae VII and VIII; anterolateral ascend
– Spinomesencephalic: neurons in laminae I and V; anterolateral ascend to PAG,
and spinoparabrachial tract to PB, amygdala; pain affect
– Cervicothalamic: arises from lateral cervical nucleus; laminae III and IV; some
projects via the dorsal column to cuneate and gracile nuclei (large fiber pathway)
– Spinohypothalamic; laminae I, V, VIII; autonomic control
• Thalamic nuclei
– Lateral nuclear group: spinothalamic tract, NS and WDR, laminae I and V, small
receptive fields, encoding location of injury
– Medial nuclear group: spinoreticulothalamic tract, laminae VII and VIII
April 29, 2009
Ascending pathways
April 29, 2009
Pain pathways in the brain
Ascending pathways and cortical/ sub-cortical
connectivity
Spino-bulbo-spinal loop
(pain facilitation)
Apkarian et al. 2005
Pain components (variable expression):
Sensory-discriminative, affective-motivational
Cognitive, Motor
April 29, 2009
Millan 2002
Pain and the brain: pathways
• Stress and the reward/ motivation system
Hypothalamus
Amygdala
Dopamine based mesolimbic
system modulates mainly
tonic pain
Hippocampus
Ventral
tegmental area
Dopoaminergic
nucleus
April 29, 2009
Ventral striatum/
Nucleus accumbens
Ventral pallidum
MDm thalamus
Pain
modulation
Anterior cingulate
Motivation and emotions
April 29, 2009
Borsook 2007, EJP
Pain modulation: large fibers
The gate control hypothesis
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The balance of activity in small- and largediameter fibers is important in pain
transmission/ determines the pain intensity
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The gate control theory involves 4 types of
neurons in the dorsal horn of the spinal cord
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Large-diameter fibers
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Inhibits interneuron and increases pain
transmission/ Opens the pain-gate
Observation: in absence of conduction in A-ά/
A-β fibers pain perception is abnormal
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Excites interneuron and decrease pain
transmission/ Closes the pain-gate
Small-diameter fibers
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Large-diameter afferent (non-nociceptive)
Small-diameter afferent (nociceptive)
Inhibitory interneurons (spontaneously active)
Projection neurons
Pin prick, pinch, ice cold produces burning pain
Pain modulation: opiods
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Direct stimulation of PAG produces analgesia
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Moprhine (an opioid) induced analgesia via endogenous
opioid receptors in descending pathway
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Opioid receptors
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Types: -, δ-, κ-, nociceptin
Transmitters: enkephalins, β-endorphin, dynorphin
Location (mainly): PAG, ventral medulla, superficial dorsal horn
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Stress-induced analgesia of escapable pain is mediated
via the endogenous opioid system
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Side effects
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April 29, 2009
Inhibits firing of nociceptive neurons in lamina I and V
Descending pathway recruited: PAG excites rostroventral medulla/
nucleus raphe magnus (5HT)
Other regions not involved in pain also contains opioid
receptor
Minimize diffusion by local administration can avoid side
effects e.g. in cerebrospinal fluid