Pain:

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Pain the most dynamic of senses Lessons in
neural plasticity
Erin.milligan_at_colorado.edu
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Goals for Today

• I. The classic view of pain
• A. Functions
• B. Pathway (spinothalamic tract)
• II. Updating the classic view of pain
• A. Molecular biology of pain receptorsB.
  Organization/neurochemistry of pain in spinal
  cord dorsal hornC. Central pathways in addition
  to the spinothalamic tract
• III. Pain (algesia) is dynamically modulated1.
  Pain suppression (analgesia)2. Pain enhancement
  (hyperalgesia)

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PART I
Pain Classics
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Pain as a Concept

• HISTORICAL PERSPECTIVE
• A. Plato Aristotle - passion of the soulB.
  Descartes (1600s) - mechanisticC. Mueller -
  over stimulation of touch (mid-1800s)D. Von
  Frey - separate system from touch (late 1800s)
• E. Sherrington - proposed existence of
  nociceptors 60 yr before their discovery (1900)
• F. Willis Wall - Electrophysiological study of
  pain responsive peripheral nerves (1960s)
• G. Melzack Wall (late 1960s) - pain is not
  just a sensation (sensory modality)
• more properly pain experience

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Pain as a Sensation

• HISTORICAL PERSPECTIVE
• A. Plato Aristotle - passion of the soul
• B. Descartes (1600s) - mechanisticC. Mueller -
  overstimulation of touch (mid-1800s)D. Von Frey
  - separate system from touch (late 1800s)
• E. Sherrington - proposed existence of
  nociceptors (pain receptors) 60 yr before their
  discovery (1900)
• F. Willis Wall Electrophysiological study of
  pain responsive peripheral nerves (1960s)
• Large numbers of sensory nerves uniquely
  responsive to damaging/potentially damaging
  stimuli
• However, what pain is continued to be debated

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Pain as an Experience

• HISTORICAL PERSPECTIVE
• A. Plato Aristotle - passion of the soul
• B. Descartes (1600s) - mechanisticC. Mueller -
  over stimulation of touch (mid-1800s)D. Von
  Frey - separate system from touch (late 1800s)
• E. Sherrington - proposed existence of
  nociceptors (pain receptors) 60 yr before their
  discovery (1900)
• F. Willis Wall - Electrophysiological study of
  pain responsive peripheral nerves (1960s)
• G. Melzack Wall (late 1960s) - pain is not
  just a sensation (sensory modality)
• more properly pain experience (sensation,
  interpretation emotion)

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The Pain Experience Dimensions of Pain
Sensory-Discriminative location, quality,
intensity and temporal characteristics Cognitive-
Evaluative ongoing perception and appraisal of
the meanings of what is taking place, what
might take place in future, in relation to this
sensation Affective-Motivational felt sense of
these meanings in relationship to ones desire to
avoid harm and/or expectations of avoiding harm
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Dimensions of Pain
Sensory-Discriminative location, quality,
intensity and temporal characteristics
DESCRIPTORS Temporal flickering, quivering,
pulsing, throbbing beating, pounding Spatial
jumping, flashing, shooting spreading,
radiating, piercing Pressure pricking, boring,
drilling, stabbing, lancinating Incisive sharp,
cutting, lacerating Constrictive pinching,
pressing, gnawing, cramping, crushing Traction
tugging, pulling wrenching Thermal hot, burning,
scalding, stinging cool, cold,
freezing Brightness tingling, itchy, smarting,
stinging Dullness dull, sore, hurting, aching,
heavy Miscellaneous tender, taut, rasping,
splitting tight, numb, drawing, squeezing,
tearing

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Dimensions of Pain
Cognitive-Evaluative ongoing perception and
appraisal of the meanings of what is taking
place, what might take place in the future, in
relation to this sensation
DESCRIPTORS Evaluation annoying, troublesome,
miserable, intense, unbearable
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Dimensions of Pain
Affective-Motivational felt sense of these
meanings in relationship to ones desire to avoid
harm and/or expectations of avoiding harm
DESCRIPTORS Tension tiring, exhausting Autonomic
nauseating, sickening, suffocating Fear
fearful, frightful, terrifying Victim punishing,
gruelling, cruel, vicious, killing Miscellaneous
wretched, blinding nagging, agonizing,
dreadful, torturing
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Dimensions of Pain
Sensory-Discriminative Cognitive-Evaluative Affe
ctive-Motivational This 3 component explanation
of pain recognizes that all of these exist
simultaneously and moment-by-moment asan
integrated experience
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Currently Formal Definition of Pain (International
Assoc. Study of Pain)
An unpleasant sensory and emotional experience
associatedwith actual or potential tissue
damage, or described in termsof such
damage. but many strange things happen with
pain
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BIOLOGICAL FUNCTIONS OF PAIN

• Pain as a Warning DeviceA. Pain spinal
  reflexes triggered at 45C (113F) Both protective
  reflexes threshold occur
• B. Maintenance of 45C ? for prolonged periods
  is damaging
• Nociceptive -pain responses- kick in long
  before
• 2. Pain as a Recuperative Healing
  MechanismTrauma can be followed by 3 behavioral
  phases
• A. Immediate phase 40-50- high stress? no pain
• Fight or flight has powerful effects survival
• B. Acute phase pain returns coping/preparing
  for recovery
• C. Chronic phase inactivity, sickness
  symptoms
• May persist far longer than necessary - failure
  to regain a normal life
• Lessons Learned from Congenital Pain
  Insensitivity

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Congenital Insensitivity to Pain
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Congenital Insensitivity to Pain
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Congenital Insensitivity to Pain
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Congenital Insensitivity to Pain

• The Human Pincushion
• At the age of 7, dull pick edge under the right
  malar bone. Separately, right parietal bone cut
  with a hatchet.
• At 10 years, knee severely injured with a
  hatchet. At a different time, he shot his fingers
  with a .22
• At 16, he was able to play the clarinet with a
  severely ulcerated tooth.
• At 26, he unwittingly placed his fingers on a hot
  gas stove, but moved his hand only upon smelling
  the odor of his burning flesh.
• No pain at any time!

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Pain Pathways Classical

• Spinothalamic tract Afferent pathway
• Pain, temperature, crude touch hard pressure
• Sensory afferents A. Ad Cs ? PAIN Abs ?
  no pain
• Ad 10 C 70
• B. Cell bodies in dorsal root ganglia (DRG)
  pairs each side of each vertebral bone
• C. Dermatomes skin slices, area of
  body innervated by a set of DRGs
• D. Neurotransmitters/neuromodulators

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Cross Section of Peripheral Nerve Ad and C
Fibers Ab
A fibers Alphas biggest and fastest. 200
yd/sec Motorneurons Betas touch, vibration,
light pressure Deltas pain fibers, slowest
smallest myelinated, 20 yd/sec C fibers One class
unmyelinated, 1 yd/sec
A myelinated C unmyelinated
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Pain Pathways Classical
Peripheral nerves - long axons carrying pain to
spinal cord I. A-delta fibers (10) First pain
sharp A. A myelinated d smallest (a, b
g are bigger) conduct 20 yd/sec B. Bright,
well localized painC. Epicritic pain (ltL
perceived upon) - external world attacking
you D. Sets off protective reflexes II. C fibers
(70) Second pain, glows spreads A.
Unmyelinated smaller than A-d conduct 1
yd/sec B. Wooooonnnng pain dull, aching, poorly
localized C. Protopathic pain (ltL ancient
suffering) - arising within the body D.
Triggers disuse of the injured site protection
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Pain Pathways Classical

• Spinothalamic tract
• Pain, temperature, crude touch temperature
• Sensory afferents A. Ad Cs (PAIN) Abs
  (NONpain)
• B. Cell bodies dorsal root ganglia (DRG)
• pairs on each side of spinal cord just
  prior to reaching the spinal cord
• C. Dermatomes skin slices, area of
  body innervated by a set of DRGs
• D. Neurotransmitters/neuromodulators

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Dorsal Root Ganglia Receive incoming information
from the body. Left/Right Pairs for each
vertebral segment
Look for the circular cluster of nerve cells
(ganglia) They look like lumpswhere each
peripheralnerve approachesthe spinal cord
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Pain Pathways Classical

• Spinothalamic tract
• Pain, temperature, crude touch temperature
• Sensory afferents A. Ad Cs (PAIN) Abs
  (NONpain)
• B. Cell bodies in dorsal root ganglia (DRG)
• pairs each side of each vertebral bone
• C. Dermatomes skin slices area innervated
  by a set of DRGs
• D. Neurotransmitters/neuromodulators

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Dorsal Root Ganglia organization leads to
Dermatomes (sensory skin slices) DRGs lower
down pick up lower body pain
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Pain Pathways Classical

• Spinothalamic tract
• Pain, temperature, crude touch temperature
• Sensory afferents A. Ad Cs (PAIN) Abs
  (NONpain)
• B. Cell bodies in dorsal root ganglia (DRG)
• pairs each side of each vertebral bone
• C. Dermatomes skin slices, area of
  body innervated by a set of DRGs
• D. Neurotransmitters/neuromodulators

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Sensory Neuron
Pain message to the brain
Schematic Diagram Cross Section of Spinal Cord
Painful stimulus
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Pain Pathways Classical
Spinothalamic tract II. Sensory afferents D.
Neurotransmitters/neuromodulators 1. Pain
transmitters ( their receptors cell signaling
where known) a. Neuropeptides i. Substance
P (NK1 activates PLC) ii.Neurokinin A (NK2
activates PLC) iii. Calcitonin Gene Related
Peptide (CGRP-R1 activates Adenylate
Cyclase)
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Pain Pathways Classical
Spinothalamic tract II. Sensory afferents D.
Neurotransmitters/neuromodulators 1. Pain
transmitters ( their receptors) b. Excitatory
Amino Acids, e.g. glutamate aspartate
(AMPA/Kainateionotropic, mGlu G-proteins
activate PLC inhibit Adenylate Cyclase)
NMDA-ionotropic, NOTE NONFUNCTIONAL during
normal pain c. Extracellular ATP (P2X3)
ionotropic and metabotropic purinoceptors d.
Brain Derived Neurotrophic Factor ??
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Muir, JAVMA, 2001
NMDA receptor is nonfunctional under normal
circumstances
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INFO FOR PRIOR SLIDE Schematic diagram of
structures processes involved in physiologic
(normal) pain.VR1vallinoid (heat)receptor
mDG/BNaCdegenerin/epithelial (mechanical) sodium
channel P2X3purine (ATP) receptor
TTXrtetrodotoxin resistantsodium channel umu
opioid receptor ddelta opioid receptor
a2alpha2 receptor GABAbetaits receptor
TrkBtyrosine kinasereceptor VGCCvoltage gated
calcium cahnnel NMDAyouvegone over before
AMPA/KAI alpha amino 3 hydroxy-5-methyl-4-isoxaz
oleproprionic acid and kainate excitatory amino
acid receptorsmGluRmetabotropic glutamate
receptor NSCnonspecific cationchannels
NK1neurokinin receptor (binds Substance
P) NOTE under normal day-to-day pain
situations, the NMDA receptor isplugged by
Mg (thus the dotted line through the NMDA
receptoron the figure to denote that the channel
may open but is nonfunctionalunder normal
conditions. This changes under conditions of
inflammation damage, causing the NMDA channel
to become operative, leading toamplification of
the pain message
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Pain Pathways Classical

• Spinothalamic tract
• Pain, temperature, crude touch temperature
• Sensory afferents
• Spinal cord dorsal horn neurons

Synaptic relay to neurons
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SPINAL CORD DORSAL HORN Receives sensory
information from the body 6 rostrocaudal layers
(laminae) of cells based on function Each slice
of spinal cord is somatotopically organized -
tiny homunculus based on the dermatome it
receives information from
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LAMINA I1. Nociceptive specific neurons
Receive info from A-delta C fibers2.
Projection neurons relay pain up to the
brain via the spinothalamic tract
Pathological Pain hot, cold hard pressure
pains - amplified
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Pain Pathways Classical
III. Spinal cord dorsal horn neurons A.
Nociceptive specific ( lamina I) 1. Receive
information from Ads Cs 2. Projection
neurons - send pain to brain 3. Key to
pathological pain pain is amplified B. Pain
modulatory neurons (lamina II) -interneurons 1.
Are wide dynamic - received both pain and
non- pain information 2. Upon activation,
inhibits Laminae I V and presynaptically
inhibits Ad C fibers C. Wide dynamic range
(lamina V) 1.Receive information from Ads
Cs plus Abs 2. Projection neurons - send
pain to brain 3. Key to pathological pain
clothing hurts
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LAMINA II Wide dynamic range neurons pain,
light touch, cool, warm Interneurons for pain
modulation Work locally to shut off pain
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Pain Pathways Classical
III. Dorsal spinal cord neurons A. Nociceptive
specific ( lamina I) 1. Receive information from
Ads Cs 2. Projection neurons - send pain
to brain 3. Key to pathological pain pain is
amplified B. Pain modulatory neurons (lamina
II) -interneurons 1. Are wide dynamic -
received both pain and non- pain information
2. Upon activation, inhibits Laminae I V and
presynaptically inhibits Ad C fibers C.
Wide dynamic range (lamina V) 1.Receive
information from Ads Cs plus Abs 2.
Projection neurons - send pain to brain 3. Key
to pathological pain clothing hurts
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LAMINA V Wide dynamic range neurons Receive
info from A-beta, A-delta C fibers Touch,
vibration, pain Projection neurons
Pathological Pain warm, cool light touch -
painful A-beta information is now coded as pain
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Pain Pathways Classical
III. Dorsal spinal cord neurons A. Nociceptive
specific ( lamina I) 1. Receive information from
Ads Cs 2. Projection neurons - send pain
to brain 3. Key to pathological pain pain is
amplified B. Pain modulatory neurons (lamina
II) -interneurons 1. Are wide dynamic -
received both pain and non- pain information
2. Upon activation, inhibits Laminae I V and
presynaptically inhibits Ad C fibers C.
Wide dynamic range (lamina V) 1. Receive
information from Ads Cs plus Abs 2.
Projection neurons - send pain to brain 3. Key
to pathological pain clothing hurts
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Pain Pathways Classical
IV. Higher centers 4. Spinothalamic fibers
cross to the opposite side of cord 5. Fibers
ascend via the ventrolateral spinal cord 6.
Midbrain fibers join other head neck fibers
7. Second synapse when fibers arrive at the
ventrobasal posterior lateral thalamus 8.
Cerebral cortex - Somatosensory Cortex areas SI
SII (a third neuron projects to these
sites) Exact terminology of thalamic nuclei
involved varies between authors, species, etc
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Spinothalamic Tract
Cerebral Cortex (SI SII)
Thalamus (ventrobasalposterior)
Caudal Medulla
Cervical Enlargement (C5-T1 Neurons inLaminae
I, V)
Lumbar Enlargement (L1-S2 Neurons in Laminae
I,V)
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SENSORY HOMUNCULUS of SI LOCATION OF SII
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PART 2
Pain Non-Classical
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Pain Pathways NON-Classical
I. Pain receptors A. Unique aspects 1.
Individual pain fibers detect a wide range of
pain types (modalities) - hard
pressure, cuts burns, cold - require diverse
receptors 2. Receptors/transduction highly
modulated - normal pain responses become
exaggerated after exposure to inflammatory
soup (acid, arachidonic acid serotonin,
bradykinin, etc) Silent or Sleeping pain
receptors 3. Neurogenic inflammation - occurs
when pain fibers are strongly activated
release Substance P, CGRP, ATP etc into the skin
from terminals the released stuff sensitizes
pain nerves creates inflammation (leaky
capillaries, attracts/activates immune cells)
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HOT CHILI PEPPER RECEPTOR / HEAT RECEPTOR
Molecular Thermometer for Moderate Heat Pain
(110-126F 43-52C)
Capsaicin Bound to Vanilloid Receptor subtype
1? VR1. Is likely to form a tetramer with the
cation-conducting pore in the center. Capsaicin
(red) interacts with a cystolic aromatic residue
linking TM2 and TM3. Non-selective cation
permeability with outwardly rectifying
current-voltage relationship. Shows high Ca
permeability, which is one why Ca imaging
strategy resulted in successful cloning of the
receptor
Capsaicin binding to receptor
Jordt and Julius, Cell, 2002, 108 421-430
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QUESTION How can you protect your bird feeder
from squirrels?Species differences in 8
aminoacids near TM3
Jordt and Julius, Cell, 2002, 108 421-430
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- Capsaicin (or -Heat)
Capsaicin (or Heat)
Calcium Imaging in Cell Culture
Expression cloning of a VR1 receptor using
calcium imaging. HEK293 cells transiently
transfected with pools of clones from rat DRG
cDNA library were subjected to microscopic
fluorescent calcium imaging before (left) and
during (right) treatment with 3 uM capsaicin.
(a) No response in cells transfected just with
the vector. (b) 1-5of pooled DRG respond to one
clone ( pool 11). (c ) Iterative subdivision
yields isolation of a single positive clone (VR1).
a
b
c
Caterina et al., Nature, 1997, 389 816-824
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This Channel Receptor Can Now be Studied
Electrophysiologically!
VR1 Responses to Capsaicin pepperextracts.
Membranecurrents measured from Xenopus oocytes
expressingVR1. VR1 responseparallels
hotnessof the peppers. Pungencies forpeppers
(Scoville units)Habanero (H) 200K Thai
Green (T) 75K Wax (W)
8K Poblano verde(P) 3K
Caterina et al., Nature, 1997, 389 816-824
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PAIN RECEPTORS IN SKIN AS OF 2001
Heat (40-50C) capsaicin Modified by acid
products of tissue damage (High Heat found in
2002)
Pressure
Cold found in 2002
Acid
Julius Basbaum, Nature 2001, 413 203-210
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Vanilloid ReceptorLike (VRL-1)
Cold-Menthol Receptor (CMR-1)
Discovery of COLD andHIGH HEAT Receptors
in2002.
STIMULI TESTED BLUECold REDHeat GREENMenthol
BLACKCapsaicin
CMR-1
VRL-1
Coexpressing CMR-1 VRL-1
McKemy et al., Nature,2002,416 52-58
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Pain Pathways NON-Classical
I. Pain receptors A. Unique aspects 1.
Individual pain fibers detect a wide range of
pain types (modalities) require
diverse receptors 2. Receptors/transduction
highly modulated - normal pain responses
become exaggerated after exposure to
inflammatory soup (acid, arachidonic acid
serotonin, bradykinin, etc) Silent or
Sleeping pain receptors. Interact with
receptors on nerve endings. 3. Neurogenic
inflammation - occurs when pain fibers are
strongly activated release Substance P, CGRP,
ATP etc into the skin from terminals the
released stuff sensitizes pain nerves
creates inflammation (leaky capillaries,
attracts/activates immune cells)
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Exaggerated Responses
ISCHEMIA INFLAMATION
NORMAL
Proposed Model for VR1 Integration of Pain in
Normal and Ischemic or Inflamed Tissues. Heat
(flame) or capsaicin (pepper) evoke pain by
activating VR1 in pain fiber terminals. In
ischemic or inflamed tissue, VR1 is activated at
room temp (22C) by H associated with ischemia
inflammation. H also enhances responses to heat
capsaicin.
VR1
Room temp 71 F
Acid 71 F
Tominaga et al, Neuron 1998. 21 531-543
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Amplification of Pain in Silent (Sleeping) Pain
Receptors

• Prevalent in internal (visceral) organs
  joints C-fibers
• Under healthy conditions, not excitable
• Under infection/inflammation conditions,
  inflammatory soup - easily excitable
• even spontaneously activate
• Immune-derived/inflammation-derived Arthritis,
  lung urinary bladder infections

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Pain Pathways NON-Classical
I. Pain receptors A. Unique aspects 1.
Individual pain fibers detect a wide range of
pain types (modalities) require
diverse receptors 2. Receptors/transduction
highly modulated - normal pain responses
become exaggerated after exposure to
inflammatory soup (acid, arachidonic acid
serotonin, bradykinin, etc) Silent or
Sleeping pain receptors 3. Neurogenic
inflammation - occurs when pain fibers are
strongly activated release Substance P, CGRP,
ATP etc into the skin from terminals the
released stuff sensitizes pain nerves
creates inflammation (leaky capillaries,
attracts/activates immune cells)
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NEUROGENIC INFLAMMATION
Adaptive because Damage ? Infection ? Immune
activation
Pain fibers strongly activated ? Release factors
to attract immune cells ? Increased plasma
extravasation ? Production of more pain relevant
factors ? Behavioral change to protect
wound ? Recovery
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Pain Pathways NON-Classical
II. Pain from areas other than skin
Visceral (internal organ) pain little is
understood Handled, squeezed, torn and burned
no pain Distention (gas, kidney stone), spasms
(cramps), ischemia (angina) infection
(bladder) pain Angina (heart pain),
appendicitis, bladder infection, giving
birth Often accompanied by autonomic (sweating,
change in heart rate, etc) somatic
reflexes (flinching, bracing against
pain) Internal organs sensitive to more than
only pain (Boring 1915) Pressure, warmth, cold
chemical stimuli Sensations of viscera are
poorly localized Referred sensation acute pain
from the heart is localized to the chest wall
and radiates outward to the underside of the left
arms Muscle pain dull aching /or cramp-like
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Pain Pathways NON-Classical
II. Pain pathways other than the spinothalamic

• Pain patients say they must exist -
• failure of cutting the classical pathway to
  control pain (peripheral nerve all the way to
  prefrontal cortex) ventrolateral
• spinal cord, ventrobasal posterior thalamus
• Search for Pathways other than the classical
• Spinothalamic tract to conscious awareness of
  pain
• Point Once the dorsal horn neurons get excited
  by pain, pain goes EVERYWHERE

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ASCENDING PATHWAYS USED FOR TRANSMITTING
PAIN-TO-BRAIN (to name just a few)
Pain pathway
Type of Pain Message
Spinothalamic Sensory Affective Spinoreticular Af
fective Spinomesencephalic Affective
Autonomic Spinoparabrachioamygdaloid Affective
Autonomic Spinohypothalamic Autonomic Spinocervica
l Sensory Affective Postsynaptic dorsal
column Sensory Affective
Theres a lot more than just the classic
pathway.pain can make its way to the brain
through virtually all parts of the spinal cord
Millan, Prog. Neurobiol. 1999, 57 1-164
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Pain Pathways NON-Classical
III. Role of the thalamus in pain A.
Encodes type, temporal pattern, intensity,
(for skin) topographic localization B.
Inter-links with cortical limbic
structures responsible for sensory/discriminative
affective/motivational aspects of pain
Millan, Prog. Neurobiol. 1999, 57 1-164
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PART 3-A
Dynamic regulation of pain An-algesic (without
pain) Aspirin/Tylenol/Motrin Novocaine/Lidocaine C
odeine/Morphine
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Drugstore Analgesics (Pain relievers)
Aspirin Known for centuries originally isolated
from spiria ulmaris (from which Aspirin comes
from) Bayer figured out how tomake in the
mid-1800s action Prostaglandin synthesis
inhibitor Prostaglandins made after cell damage
directly stimulate nocicpetors at sites of
injury, over-worked muscles, etc 10-20 TONS in
the US alone!
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Other drugstore pain relievers, such as the
proprionic acid derivatives, also act by
blocking prostaglandin synthesis. They differ
mainly in half-life, biodistribution,
degradation pathways, etc
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Local Anesthetics
Cocaine The first local anesthetic
discovered Search for synthetic substitutes began
from 1890 Procaine first (1905) synthetic
cocaine substitute lidocaine, novacaine etc
followed. The -caine ending refers to their
similarity to cocaine. Mechanism of Action Block
nerve conduction by binding to a specific
receptor site within the sodium channel, thereby
physically blocking it The sodium channels are
blocked - they can still depolarize, but cannot
conduct an action potential. Affect every kind of
nerve, but small nerves far more susceptible
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Morphine
Opium (juice) gt4,000 yr old 20 pain
suppressive compounds including
morphine Morphine named for Greek god of
dreams synthesized in 1805 legal in the US
until early 1900s (major constituent of
patent medicine in old wild west
times) Addiction liabilitysearch for
non-addicting alternatives - found Heroin
Methadone but no non-addictive
agonist. Naloxone- good for overdose
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The search for non-addicting opiates
Heroin developed by Bayer-- still addictive. The
search for compounds led to methadone and
antagonists like naloxone - competitively blocks
opiates from acting at the opiate receptors
but one has not been found yet
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First discovered in the early 1970s
Major Groups of Endogenous Opioid Peptides
Leucine-enkephalin Methionine-enkephalin B-Endor
phin Dynorphin A-Neoendorphin
Opiates - exogenous compounds that bind opioid
receptors in the CNS i.e. Morphine Heroin
mimic opioid compounds
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How can one activate the brains morphine- like
transmitter system without giving morphine?
Peri-Aqueductal Gray (PAG) First site of
electrical stimulation induced analgesia
(Reynolds, 1968) Comparable to very high
doses of morphine.
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Human with Brain Stimulator for Chronic Pain
Wire inside
Eyes
Outside ? external Device for self stimulation
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Electrical Brain Stimulation Produces Analgesia
How? By activating specific neural circuits Many
brain-to-spinal cord circuits that are able to
produce analgesia
Opioids inhibit the activity of
inhibitory interneurons in the PAG. This
increases the activity of neurons whose axons
descend to the raphe nucleus.
The activity of axons that Descend from the PAG
excites Raphe nucleus neurons Whose axons descend
in the dorsal lateral funiculus (DLF) of the
spinal cord
The activity of descending spinal cord DLF
excites Spinal interneurons that Block incoming
pain signals
Logically, where would Pain be inhibited?
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Excite by Electrical Brain Stimulation or Stress
()
Periaqueductal Gray
()
()
Excitation
Raphe Nuclei(Ventral Medial Medulla)
( )
Inhibition
( )
( )
()
Laminae II Pain Suppressive Interneurons
Ad C Pain Sensory Fibers
Laminae I V Pain Projection Neurons
( )
( )
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Morphine Activates
Or endogenous morphine-like compounds
Activating brain-to-spinal cord pathway
Periaqueductal Gray
()
Excitation
()
Morphine Activates
( )
Inhibition
Raphe Nuclei(Ventral Medial Medulla)
Morphine Activates
Morphine Inhibits
Morphine Inhibits
( )
( )
()
Laminae II Pain Suppressive Interneurons
Ad C Pain Sensory Fibers
Laminae I V Pain Projection Neurons
( )
( )
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Translations of Abbreviations in Prior
Slide ACH acetylcholine AND adenosine bEND
beta endorphin CART cocaine amphetamine
related transcript CCK cholecystokinin CGRP
calcitonin gene related peptide DA dopamine DYN
dynorphin ENK enkephalin GABA gamma amino
butyric acid GAL galanin GLU glutamate MC
melanocortin NO nitric oxide NPFF neuropeptide
FF OFQ orphanain FQ OT oxytocin Subs P
substance P VP vasopressin
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Acupuncture can work through these same pathways
to release endogenous opioids.
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PART 3-B
Dynamic regulation of pain Hyperalgesia(pain
facilitation)

• Pain is dynamic not always suppressive
• Peripheral nerves (a) transmit sensory signals to
  CNS, (b) modify their own activation via
  neurogenic inflammation
• Hyperalgesia can be due to (a) sensitization of
  peripheral nerves, and (b) sensitization of pain
  in the spinal cord
• think of a sunburn. or when you have the flu

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Hyperalgesia From injury/infection/inflammation
of Body tissues Peripheral nerves Spinal
cord Brain Characterized by Decreased pain
threshold Enhanced pain from supra-threshold
stimuli Spontaneous pain
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Hyperalgesia Neurogenic inflammation
release of substance P, CGRP, ATP
from peripheral nerve terminals of pain
fibers induces signs of inflammation
swelling, redness, heat, pain and loss of
function attracts/activates immune cells,
release of histamine, serotonin,
proinflammatory cytokines, etc Example
rheumatoid arthritis....but we will not discuss
this further.
77
General Mechanisms of Pathological Pain
PERIPHERAL MECHANISMS 1. Direct excitation of
pain peripheral nerve terminals in skin,
muscle, etc (e.g. inflammatory mediators) 2.
Neurogenic inflammation (e.g. peripheral nerves
release pain-enhancing substances into the skin)
3. Spontaneous activity of peripheral nerves 4.
Phenotypic shift (e.g.non-pain Ab?fibers
begin making Substance P pain transmitter) 5.
Damaged nerves begin expressing adrenergic
receptorsnow excited by sympathetic
activation 6. Peripheral nerve sprouting into
denervated tissues 7. Direct excitation of nerve
trunks by inflammatory mediators
78
FOR PRIOR SLIDE Schematic of structures and
processes involvedin peripheral sensitization.
Inflammation and tissue damage induceproduction
of a variety of sensitizing substances,
includingprostaglandins, norepinephrine,
proinflammatory cytokines (such as tumor
necrosis factor TNF), and nerve growth factor.
Theseincrease intracellular calcium
concentration and activate a varietyof
intracellular signaling cascades, which change
high-thresholdpain receptors (nociceptors
pain receptors) to low-thresholdnociceptors and
activate silent nociceptors, resulting in
exaggeratedpain responses. Rreceptor
PKCprotein kinase C PKAproteinkinase A
Hhydrogen ion (acid) Kpotassium ion
NasodiumionCa2calcium ion TNFatumor
necrosis factor alpha See prior Muir figure for
other abbreviations.
79
General Mechanisms of Pathological Pain

• PERIPHERAL MECHANISMS
• 1. Direct excitation of pain peripheral nerve
  terminals in
• skin, muscle, etc (e.g. inflammatory mediators)
• 2. Neurogenic inflammation (e.g. peripheral
  nerves release pain-enhancing substances into
  the skin)
• 3. Spontaneous activity of peripheral nerves
• 4. Phenotypic shift (e.g.non-pain Ab?fibers
  begin making
• Substance P pain transmitter)
• 5. Damaged nerves begin expressing adrenergic
  receptorsnow excited by sympathetic activation
• 6. Peripheral nerve sprouting into denervated
  tissues
• Direct excitation of nerve trunks by inflammatory
  soupActing on the nerve bundles, and not the
  receptors in the
• skin or joint.

80
How Do Proinflammatory Cytokines Increase
Excitability?
AXON
2. Increase axonal cation channel
conductance
TNF
TNFtumor necrosisfactor, a proinflammatorycytok
ine in inflammatorysoup
Cation (Na, Ca)
Wilkenson et al.96 van der Goot et al.99
81
PAIN NMDA receptor becomes functional after
strong/prolongedLaminae I V neuronal membrane
depolarization by Substance P CGRP Plus
Excitatory Amino Acid (AMPA/kainate receptors)
82
NMDA Variety of 2nd messenger cascades
Plus Nitric Oxide Production that facilitates
pain!
83
General Mechanisms of Pathological Pain
CENTRAL MECHANISMS 1. Sensitization of pain
neurons in dorsal horn A wide array of other
mechanism proposed 2. Decrease in
brain-to-spinal cord pain suppression activity 3.
Decrease in dorsal horn inhibitory interneuron
activity 4. Increased in brain-to-spinal cord
pain enhancing activity 5. Increased activity of
pain enhancing interneurons in dorsal horn 6.
Nonpain fibers sprout into pain parts of
dorsal horn, sowhen they become activated they
stimulate pain neurons
Millan, Prog. Neurobiol. 1999, 57 1-164
84
Beyond Neurons Glia are involved too !

• Views of pathological pain are dramatically
  changing
• Glia (microglia astrocytes) actively communicate
  with neurons
• Spinal cord glia are implicated in diverse
  pathological pain states
• Implications for drug developmentThe current
  definition of a good drug forclinical pain is
  that it leaves 4/5 patientswith no pain relief
  at all!