Definition of Pain (IASP)

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Nociception and Pain
Definition of Pain (IASP) An unpleasant sensory
and emotional experience associated with actual
or potential tissue damage, or described in terms
of such damage.
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Nociception vs Pain

• Tranduction
• Conduction
• Spinal Processing
• Perception

Nociceptors are a specific subset of peripheral
sensory organs which respond to noxious stimuli.
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Categories of Pain
Physiological Clinical Persistent
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Physiological Pain

• Fast pain carried by Ad fibers
• Sharp
• Well-localized
• Slow pain carried by C fibers
• Aching
• Poorly localized

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Nociceptor Activation
Heat ? VR1
nucleus
Ca2
Glutamate
ATP ? P2X2
H ? ASIC
Na/Ca2
?
PKA/PKC
? Bradykinin
? Mechanical
VR1 vanilloid receptor ASICacid sensing ion
channels P2X2purinergic receptor
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Nociceptors in Teeth
1. A? fibers thermoreceptors mechanoreceptor 2.
C fibers polymodal (chemoreceptors)
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Hydrodynamic Mechanism of Dental Pain

1. Odontoblast
2. Predentin
3. Dentin
4. Odontoblastic Process
5. Subodontoblastic Nerve Plexus
6. A? Fiber
7. Axon Terminal in Tubule

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Spinal Processing

1. Nociceptive nerve endings synapse in the spinal
   cord (substantia gelatinosa) or medulla (nucleus
   of the spinal tract of CN V).
2. Information passed to thalamus through the
   activation of secondary (projection) neurons.

Spinal Nucleus (C.N. V)
Substantia Gelatinosa
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Referred Pain
Visceral Nociceptors

• Fibers usually run with autonomic fibers
• Large receptive fields
• Converge on neurons that receive somatic input

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Ascending CNS Pathways

1. Spino- and trigemino-thalamic tracts
2. Thalamus (sensory-discrimination)
3. Reticular/limbic systems (motivational-affective)
4. Cortex (cognitive-evaluative)

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Gate Control Theory of Pain (Melzack and Wall,
1965)
Ad C
Ab
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Descending CNS Pathways
Inhibition Facilitation
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Inhibition
Facilitation
5-HT, NA(a2) GABA, GLY ENK, DNY bEN, ACh
5-HT, NA(a1) GLUT, SP ACh (nic)
PAIN

EXIN
ININ


ACh(nic) CCK DNY (N)
bEN, GABA GLY, ENK DNY (k)
DRG
DRG
SP GLUT
SP GLUT
-

-

Nx
Nx


PN
PN
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Endogenous Opioids Stress-induced Analgesia

1. Enkephalins dorsal horn
2. Dynorphins hypothalamus, PAG, dorsal horn
3. ?-endorphins (involved in stress-induced
   analgesia) hypothalamus

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Clinical Pain (Inflammatory or Post-surgical Pain)
Hyperalgesia
Allodynia
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Primary Hyperalgesia Peripheral Sensitization
Na Channels TTx-S/?TTx-R
B Transcription
B
VR1, Na channels.
Heat ? VR1
Glutamate ? SP
H ? ASIC
A
ATP ? P2X2
? PGs
? Bradykinin
? NGF Cytokines
A Sensitization
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Secondary Hyperalgesia Central Sensitization
CNS
Periphery
Injury site
DRG/TG

• Injury and inflammatory response results in
  increased nociceptor activation

• Afferent barrage leads to
• Increased excitability
• Decreased inhibition

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NMDA Receptor (N-methyl-D-aspartate)

• Natural agonist is glutamate usually blocked by
  Mg2
• Depolarization opens channel by removing block
• Channel opening has a long duration (100 ms)
  permitting summation of inputs (wind-up)

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Analgesics
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The Pharmacological Approach
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Inhibition
Facilitation
5-HT, NA(a2) GABA, GLY ENK, DNY bEN, ACh
5-HT, NA(a1) GLUT, SP ACh (nic)
PAIN

EXIN
ININ


ACh(nic) CCK DNY (N)
bEN, GABA GLY, ENK DNY (k)
DRG
DRG
SP GLUT
SP GLUT
-

-

Nx
Nx


PN
PN
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The Problem of Persistent Pain

• Peripheral Processes
• Spontaneous activity
• Sympathetic activity
• Nociceptor sensitization

• Central Processes
• Central sensitization
• Spinal reorganization
• Cortical reorganization
• Loss of inhibitory pathways