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PATOPHYSIOLOGY of PAIN
A.M.Takdir Musba
Dept. of Anesthesiology, ICU & Pain Management.
Faculty of Medicine Hasanuddin University
Makassar
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Nociceptors. Primary afferent neuron
Dorsal horn Neurons
Ascending pathway Descending control of pain
Pathophysiology
Peripheral Sensitization Central Sensitization
Pain perception.
OBJECTIVES
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Pain can be defined as the conscious awarenessof actual or potential tissue injury.
Pain is involving:
1. Nociceptors activation by mediators released
from injured tissue and nerves'.2. Afferent transmission /conduction to the spinalcord and processing within the dorsal horn andsupra spinal center.
3. Pain perception is depend on the net result ofinteraction between ascendent input anddescendent control.
4. In general, pain is an alarm mechanism toprotect our body.
What is Pain.
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Anatomy
Primary afferent neurons1. Sensory afferent neurons have a unipolar
cell body located in DRG.
2. They are classified into 3 major groups
(A,B,C), according to the fiber size.3. Group A is further sub-classified into 3
subgroups (A, A, A).
4. Sensory afferent that respond to noxiousstimulation include myelinated A, or
unmyelinated C- fiber.5. Most Aand all C fiber originate as free nerve
endings which is calledNOCICEPTORS
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Classification
ofPeripheral
nerve
5
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1. NOCICEPTORS
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What is a nociceptor?
A number of receptors/channels thatsense damage
VR1 - vanilloid receptor family ASICs - respond to low pH
P2X receptors - respond to ATP
TRPs receptorsrespond temp.
Chemical sensors - prostaglandins,5HT etc
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TRPVs ASICs TRPs P2X
capsaicin
H+
PGs
EPs
coldwarm ATP
COX1/2
ATP
heat
Na+, K+,
Ca2+channels
DRG
C-fibre
Tissue damage and pain in the periphery
Mechanical?
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Nociceptors;is characterizedby their response;
1. A-delta Mechanothermal nociceptors Respond to mechanical and thermal stimuli.
display rapid conduction.
Produced first pain and well localized.
Ad fibers respond to this naciceptors.
2. C-fiber Polimodal nociceptors Respond to mechanical, thermal and chemical.
Slow conduction.
Produced second pain and diffuse.
C fibers respond to this receptor.
Exist in many tissues, skin, muscle, pariosteum, joints, and viscera, except brain.
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Characteristic of Aand C-fiber
PolimodalNociceptor
A FiberRapid Conduction
First
Pain
Secound Pain
C-Fiber
Slow Conduction
MechanoThermal
Nociceptors
Glu
First Pain
Secound
Pain
Glu
sP
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2. PERIPHERAL SENSORY
AFFERENT FIBERS
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Anatomy of peripheral sensory
nerve fibers
A
AC
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Dorsal Horn
Dorsal root
ganglion
Peripheral sensory
Nerve fibers
A
A
C
Large
fibers
Small
fibers
Two sensory afferent neurons1. Large myelinated Afibers, very fast conduction velocity.
Respond to innocuous stimuli2. Small myelinated A& C unmyelinated fibers, have slowconduction velocity. Respond to noxious stimuli
Modified by AHT
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Although in normal condition Afiber does notresponse to noxious stimuli, but it plays a bigrole in NORMAL SENSATION.
The Role of A fiber
Without Afiber, any noxious stimuli will perceive
as BURNING PAIN (TN, HZ)
A
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I
IIo
IIi
III
IV
V
VI
VII
VIII
IX
X
A
WDR
A
C
heavily
myelinated
fast conducting
thinly myelinated
intermediate
conducting
unmyelinated
slow conducting
peripheral
endingsdorsal root
ganlgia
high intensitynoxiousstimuli
lowintensity
non-noxiousstimuli
SP & CGRP
INPUTS
REFLEXES
SENSATIONS
NS
Peripheral fibre systems
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It is important to know that two
distinct responses to a noxious
stimulus FIRST PAIN andSECOND PAIN
First pain: sharp andpricking, well-localised
and brief. Responded bymechanoreceptors ,conveyed by Ad fiber.
Second pain: dull and
diffuse and prolonged .Responded by polimodalnociceptors , conveyed byC fiber
C Fiber
AFiberFirst Pain
Secound Pain
Modified by AHT
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1. TRANSDUCTION
2. CONDUCTION
Role of nociceptors
and primary afferentneurons are:
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TRANSDUCTION PROCESS
(NOCICEPTORS ACTIVATION)
Action Potential
Na+Ca++
TRPPeptides-
sP, CCK,
CGRP
Ca++TRP
Generator
Potential
Traumatic
Mediators-
K+, H+,
ATP,PGE
Neural
Mediators-
Epine,
Norepine
Local &
Vescular
Mediators-
Bradykinin,
Cytokines
Histamine,
5HT.
In CreasedSynthesis
Pro
Inflammatory
Cytocaines
-(IL) 1
-IL-6
Modified by AHTR. Sinatra 2007
Noxious Soup
Tissue
Injury
TRP (Transient Receptor Potential) Ion
Channel is a Transducer molecules.
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Pain pathway
Spinothalamictract
Peripheralnerve
Dorsal Horn
Dorsal rootganglion
Pain
Ascendinginput
Descending
modulation
Peripheralnociceptors
Trauma
Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Conduction
Modified by AHT
Transduction
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3. DORSAL HORN NEURONS
D l H f S i l d
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Lehmann, K. A.: From the first stimulus to pain memory. UN. Cologne, 2000
Dorsal Horn of Spinal cordPlays a big role in pain perception
Is the first gate to control pain
Nociception (Pain) is born in DHN
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Dorsal Horn Neurons
Is highly organized center of neurons
The place where afferent input is processed.
The place where terminal endings of primary
afferent ( first order neuron) and receivingneurons (second order neurons) synapse. Where interaction between excitatory and
inhibitory system.
Two types of second order nociceptive neuronsare found in DHN.1. NS (Nociceptive-Specific Neurons2. WDR (Wide-Dynamic Range Neuros)
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Targets of Primary Afferent Neurons in
the posterior gray (dorsal) horn
24Transmission at DH
NS
WDR
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NS : Respond exclusively to noxious stimulifrom A& C fiber.
WDR :
Respond to both noxious and innocuousstimuli.
May receive afferent input from skin, muscle,joint and visceral nociceptorsreferred pain.
Low frequency stimulation of C fiber lead togradually increase WDR discharge, until
continuous dischargewind up. These responsible by NMDA receptors, while
AMPA receptors responsible for short-lastingdepolarization (brief pain).
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Neurotransmitters and receptors
on Dorsal Horn
27Modulation at DH
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Primary afferent neurons may release one or moreexcitatory Amino acid (EAA) such as:
Glutamate Aspartate, or
Peptide such as Substance P Neurokinin A CGRP (Calcitonin Gene-Relate Peptide)
CCK (Cholecystokinin) Somatostatin
Bombezine etc. EAA mediated rapid short-duration depolarization of
second order neurons.
Peptides produce a delayed and long lastingdepolarization.
NEUROTRANSMITTERS
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4. ASCENDING PATHWAYS
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Ascending Pathways
5 ascending pathways have been recognized.
1. SPINOTHALAMIC TRACT
Discriminative pathway location of pain
2. SPINORETICULAR TRACT Emotional aspect of pain (suffering pathway)
3. DORSAL HORN COLUMN TRACT
Transmission of visceral pain
4. SPINOMESENCEPHALIC TRACT
Behavioral response
5. SPINOHYPOTHALAMIC TRACT
Sensational from the skin, lips & sex organs
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A-Alpha Motor
Efferent
SympatheticEfferent
Delta SensoryAfferent
C-Fiber SensoryAfferent
PeripheralNociceptor
Spinal Cord
NSTT
PSTT
NRMBrainstem
Midbrain
Hypothalamusand Pituitary
Cortex andThalamus
LC
PAG
MTVPL
SSC FLC
AscendingPathaways
DescendingPathaways
SympatheticOutflow
Hypothalamic-Pituitary Outflow
SPINOTHALAMIC TRACT Neo Spino Thalamic Tract direct to
Thalamus SSCLocalizing and
discriminative informationwithdrawal
reflex.
Pleo Spino Thalamic TractFLC (Frontal
Limbic Cortex)Affecting circulation,
respiration, endocrine, emotional,
behavioral responses (fear, anxiety,
helplessness, avoidance).
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Response Cortical
Response Suprasegmental
Response Segmental
Response Local
-anxiety-fear-apprehension
-neurohumoral response-catecholamines-cortisol
-dll.
-muclespasm-vasospasm
-bronchospasm
-decreased gastrointestinalmotility
-release pain substances-inflammation
RESPONSES TO NOXIOUS STIMULI INDUCED BY AN ABDOMINAL SURGERY
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5. DESCENDING MODULATING
PATHWAYS
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Descending Modulating
Pathways
CEREBRAL CORTEX
THALAMUS HYPOTHALAMUS
BRAINSTEM/ MIDBRAIN Periaqueductal gray (PAG)
Nuclei raphe magnus Locus ceruleus
Sub ceruleus
SPINAL CORD
Those ascending pathways is modulated by descendingmodulating pathways in several higher centers;
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A-Alpha Motor
Efferent
SympatheticEfferent
Delta SensoryAfferent
C-Fiber SensoryAfferent
PeripheralNociceptor
Spinal Cord
NSTT
PSTT
NRMBrainstem
Midbrain
Hypothalamusand Pituitary
Cortex andThalamus
LC
PAG
MTVPL
SSC FLC
AscendingPathaways
DescendingPathaways
SympatheticOutflow
Hypothalamic-Pituitary Outflow
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SEROTONINNEOREPINEPHRINE
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Modulation
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Postsynaptic
Opioid
Receptors
(-)
(+)
Glutamate
Receptors
Enkephalinergic
Interneuron
(Inhibitory)
Descending
EnkephalinergicFiber (Inhibitory)
Presynaptic Opioid
Receptors
(-)
Primary
Nociceptive
Fiber
Spinal Sensory
Neuron
ENKENK
ENK
ENK
SITES OF ENKEPHALIN BINDING IN SPINAL CORD.ROLED BY INTRNEURON INHIBITORY AND DESCENDING FIBER INHIBITORY
Modified by AHT
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Presynaptic & Post Synaptic Receptors
Dorsal Horn Neurons
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Descending Pain Control
CortexHypothalamusThalamus
PAG
NRM
DHN
Brain
Midbrain
Brain stem
Spinal cord
Releases
Endogenous opioidsGABANE
Releases
SerotoninNE
InhibitWDR neuronsNS neurons
Analgesia
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NO BRAIN, NO PAIN
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1. MODULATION
2. TRANSMISSION
Role of DHN, is the place
where interaction between
afferent ascendern input
and descedern modulation
pain control.
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Pain Perception
Spinothalamictract
Peripheralnerve
Dorsal Horn
Dorsal rootganglion
Pain
Medulation
Ascendinginput
Descending
modulation
Peripheralnociceptors
Trauma
Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Conduction
Modified by AHT
Transduction
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PAIN PERCEPTION
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PainPerception Brain
Noxious perception?
A number of theories:
1. Specificity theory byDescartes
(16 century)
2. Gate control theory by
Melzack and Wall (i965)
3. Sensitization theory by Woolfet al (1990 an)
PAIN PERCEPTIONHow pain perception is processed still obscured andWhere pain perceptions in the brain still unclear.
Limbic Cortex
Sensory Cortex
Thalamus
SS
SS
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Pain wasfaithfully
transmitted
fromperiphery to
brain
1. Specificity theory
Descartes(17thCentury)
Modified by AHT
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2.GATE CONTROL THEORY by MELZACK and Wall
Ascending Action
System
Large
fibers
Central
Control
Descending
Modulation
Small
fibersDorsal Horn Gate
The Gate control theory of pain processing. T = Second-order transmission cell; SG = substantia
gelatinosa cell.
Modified by AHT
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3.Sensitization theory by Woolf
After the injury sensitization in the peripheryand centrally is occurred. (Hyperalgesia andallodynia).
Pain perception is the net process starting
from: Nociceptor activation
Neural conduction
Spinal transmission Noxious modulation
Limbic & frontal cortical perception
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So, there are three
possibilities how dowe feel pain.
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Noxious stimulus with Pain
Pain
CNS
Nociception exp.no rmal si tuat ion
Nociception with Pain
Inhibi t ion
Exci tat ion
Modulat ion
i i l i h i
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Pain
CNS
Nociception
Nociception without pain
Inhibi t ion
Exci tat ion
Example:
Stress Induced Analgesia
X
Modulat ion
Noxious stimulus without Pain
i i h i i l
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Pain
CNS
Nociception
Pain without nociception
Inhibi t ion
Exci tat ion
Example: Phantom PainNeurophatic Pain
X
Modulat ion
Pain without noxious stimulus
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6. Peripheral Sensitization
Activation of neciceptor
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Activation of neciceptor
HT Hist.
PGE2
PGI2LTB4
BK NOR
Primary afferent nerve
Nociceptive stimulation
Axon reflex
vessel
PlateletTissuecell
Mastcell
Membranephospholopid
Tissue damage
Kininogen
Nociceptor
RednessSwellingPainFever
H+K+H+
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serotoin platelets ++ activate
histamine mast cell + activate
leukotrienes arachidonic acid-damaged cell sensitize
Chemical intermediaries in nociceptive transduction
Pain: Howard L. Fields
p.32
Primary Hyperalgesia
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Primary Hyperalgesia
Cell injuryKinins
H+
K
Prostaglandin
Bradikynin
NO
Kinins
Vasculature
NeuropeptidesPrimary Afferent Neurones
Nociceptors
Cannabioids
Opioids
Adenosine
Cytokines
Neurotrophins
Histamine
5HT
Immuno Cells
Prostaglandins
Sympathetic Efferent Neurones
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Primary hyperalgesia
Secondary hyperalgesia(allodynia)
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7. Central Sensitization
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NMDA RECEPTOR / CHANNEL
IS BLOCKED BY Mg ion
Gly NMDA AMPA
PCPZn
Mg
NaCa
K
Na
K
NKr
PKC
Dickenson, 1994
3 conditions are needed to release Mg blockade
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3 conditions are needed to release Mg blockade.
NMDA is binding by Glu, Gly and Long depolarisation
Gly NMDA AMPA
PCPZn
NaCa
K
Na
K
NKr
PKC
SP
DEPOLARIZATION
Mg
GluGlu
Dickenson, 1994
Wh NMDA h l i l f
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When NMDA channel is open large of
Ca and Na influx into the cell
Gly NMDA AMPA
PCPZn
NaCa
K
Na
K
NKr
PKC
SP
DEPOLARIZATION
MgGluGlu
Ca
Increased excitability
Long term changes
Cell death Dickenson, 1994
Central sensitization Processing in Spinal Cord
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Central sensitization Processing in Spinal Cord
Inhibitory
Interneuron
Nociceptor
Terminal ending
NMDA Receptor: Requires voltage
dependent priming for activation -mRNA synthesis, and
upregulation of inducible
enzymes/ protein
Second Messenger
Formation, (cAMP, PKA)
Post Synaptic Membrane of
the Spinal Sensory Neuron
NE
MU
Glu SP
Glu
Glu
MU
Glu
Na+
AMPA
ReceptorKainate
Receptor
Fast Prime Slow Prime
NK-1
Receptor
NMDA
Receptor
Glu
Mg++
SP
SP
SP
Ca++
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S KI NTERIMA KASIH BANYAK
SEMOGA ADA MANFAATNYA
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REVIEW
What PAIN is?
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What the textbookswould have you believe
about pain
Noxious (painfull)
stimulus to the body
What PAIN is?
Descending
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Dorsal homsOpioids
NRM LC
PAG
Cortex
Opioids
Descending
Modulatory Systems
5-HT - - Enkephalin - Norepinephrine
Modified by AHT
Two distinct sensations
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Injury
C fiber=second pain
Afiber=first pain
Pain intensity
Time
Two distinct sensations(dual pain sensation)
early sharp, relatively briefpricking sensation
later dull, somewhatprolonged sensation
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Limbic Cortex
Sensory Cortex
Thalamus
Central Grey
Mid Brain
Ascending
Pathways
Spinal CordMotor Efferent
Noxious Fiber
Nociceptor
Trauma
DescendingPathway
DorsalHorn
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Adapted from Julius & Basbaum.
Nature 2001;413(6852):203
P i P i i S i l C d
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Pain Processing in Spinal Cord
Inhibitory
Interneuron
Nociceptor
Terminal ending
NMDA Receptor: Requires voltage
dependent priming for activation -mRNA synthesis, and
upregulation of inducible
enzymes/ protein
Second Messenger
Formation, (cAMP, PKA)
Post Synaptic Membrane of
the Spinal Sensory Neuron +
-
NE
MU
Glu SP SP
SP
SPGlu
Glu
MU
Na+ GluMg++
Na+
-Glu
Na+
AMPA
ReceptorKainate
ReceptorFast Prime Slow Prime
NK-1
Receptor
NMDA
Receptor
Modified by AHT
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NOCICEPTIVE TRANSMISSION
C-fiber Dorsal Horn Neuron
Glu
( SP )
NOAA
NMDA r
(CGRP)
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Cortical structures
It has been long to divide higher neural centerin pain processing into 2 parts:
Somatosensory cortex sensory discriminative
pain
Cingulate cortex affective pain
However, this is maybe an oversimplification,
the role of cortex in PAIN PERCEPTIONremains unclear.
( Philip Siddal )
PAG
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PAG( Periaqueductal gray )
Play a big role in pain control modulation,it may releases:
Endogenous opioids
Enkephalin
Endorphine
Dynorphine
GABA (gamma amino butiric acid)
Norepinephrine
Noxious afferent fibers
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A myelinated fiberC unmyelinated fiber
Responds to noxious stimuli
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A nociception has at least 4 components
1. TRANSDUCTION2. CONDUCTION
TRANSMISSION
3. MODULATION4. PERCEPTION
ACUTE (NOCICEPTIVE)
PAIN PATHWAYS
PersepsionNeuron III
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Mechanical
Thermal
Chemical
Transduction
Conduction/Transmission
Modulation
Transmission
Persepsion
Neuron I
Neuron II
Neuron III
Modified by AHT
1 TRANSDUCTION (NOCICEPTOR ACTIVATION)
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1.TRANSDUCTION (NOCICEPTOR ACTIVATION)
Defines as noxious stimuli are converted into acalcium ion-(Ca2+) mediated electricaldepolarization within the distal nociceptorendings.
Note!
Ca++ion channels is a Generator Potential (gear)
Na+ ion channels is like accelerator (gas) Ka+ ion channels is like breaker (rem) in
automobile.
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Transduction and Conduction Process
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K+K+
Ca2+
Na+
1. Transduction
4. Transmission2. Spike Initiation
3. Propagation (conduction)
Modified Meliala, 2006
S SS O ( i l t i i )
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TRANSMISSION (spinal transmission)
Refers to the transfer of noxious impulsesfrom primary nociceptors cells in the dorsalhorn neurons.
Ad and C fibers are the axons of unipolarneurons that have distal projections known asnociceptive field.
Two nociceptive fields in dorsal horn neurons;1. Nociceptive-specific neurons (NS)
2. Wide dynamic range (WDR)
( )
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MODULATION (noxious modulation)
Refers to pain- suppressive mechanism within thespinal cord dorsal horn neurons and at higher levelsof the brainstemand midbrain.
In the spinal cord, this intrinsic breakingmechanism inhibits oxious transmission at thefirst synapse between the primary noxious afferentand second order WDR and NS neurons.
Thereby reducing spinothalamic relay of noxiousimpulses.
Spinal modulation is mediated by spinal-interneurons and terminal descending inhibitory.
Pharmacologic Modalities of
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g
acute pain management
Cyclo-oxygenase inhibitors Non-specific COX inhibitors(classical
NSAIDs)
Selective COX-2 inhibitors, the coxibs
Acetaminophen is probably COX-3 Local anesthetics
Opioids
NMDA antagonists Ketamine, dextromethorphan
Anti-convulsants
Gabapentin, Pregabalin
Pain Pathway and Drug
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Pain Pathway and Drug
Spinothalamictract Peripheralnerve
Dorsal Horn
Dorsal rootganglion
Pain
Medulation
Ascendinginput
Descendingmodulation
Peripheralnociceptors
Trauma
Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Conduction
Modified by AHT
Transduction
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