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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

22


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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


Trauma


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


Trauma


Conduction

Modified by AHT

Transduction


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