PATOPHYSIOLOGY of PAIN

A.M.Takdir Musba

Dept. of Anesthesiology, ICU & Pain Management.

Faculty of Medicine Hasanuddin University
Makassar
OBJECTIVES
Nociceptors.
Primary afferent neuron
Dorsal horn Neurons
Ascending pathway
Descending control of pain
Pathophysiology
Peripheral Sensitization
Central Sensitization
Pain perception.
What is Pain.
Pain can be defined as the conscious awareness
of 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 spinal
cord and processing within the dorsal horn and
supra spinal center.
3. Pain perception is depend on the net result of
interaction between ascendent input and
descendent control.
4. In general, pain is an alarm mechanism to
protect our body.
Anatomy
Primary afferent neurons
1. 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 noxious
stimulation include myelinated A, or
unmyelinated C- fiber.
5. Most A and all C fiber originate as free nerve
endings which is called NOCICEPTORS
Classification
of
Peripheral
nerve

5
1. NOCICEPTORS
What is a nociceptor?

A number of receptors/channels that

sense damage
VR1 - vanilloid receptor family
ASICs - respond to low pH
P2X receptors - respond to ATP
TRPs receptors respond temp.
Chemical sensors - prostaglandins,
5HT etc
 Tissue damage and pain in the periphery
ATP
capsaicin
Mechanical?
heat DRG
COX1/2

H+ cold
PGs warm ATP

C-fibre
TRPVs ASICs EPs TRPs P2X
Na+, K+,
Ca2+
channels
 Nociceptors;is characterized
by 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.
 Characteristic of A and C-fiber

A Fiber
Mechano Rapid Conduction Glu
Thermal
Nociceptors First Pain
First
Pain
Secound Pain

C-Fiber
Slow Conduction Glu
Polimodal
Nociceptor sP
Secound
Pain
2. PERIPHERAL SENSORY
AFFERENT FIBERS
Anatomy of peripheral sensory
nerve fibers

C A
 Two sensory afferent neurons
1. Large myelinated A fibers, very fast conduction velocity.
Respond to innocuous stimuli
2. Small myelinated A & C unmyelinated fibers, have slow
conduction velocity. Respond to noxious stimuli

Large
fibers A

Dorsal root
ganglion Dorsal Horn
A
Small
fibers
C Peripheral sensory
Nerve fibers

Modified by AHT
 The Role of A fiber
Although in normal condition A fiber does not
response to noxious stimuli, but it plays a big
role in NORMAL SENSATION.

Without A fiber, any noxious stimuli will perceive

as BURNING PAIN (TN, HZ)
 Peripheral fibre systems SENSATIONS

SP & CGRP
I NS
peripheral dorsal root IIo
endings ganlgia IIi
III

IV
A
heavily
low V
intensity
myelinated WDR

non-noxious fast conducting

stimuli
A VI
thinly myelinated
intermediate
high intensity
noxious
conducting
stimuli unmyelinated C X

slow conducting VII

INPUTS
VIII
IX
REFLEXES
 It is important to know that two
distinct responses to a noxious
stimulus FIRST PAIN and SECOND PAIN

First pain: sharp and

pricking, well-localised
and brief. Responded by
A Fiber mechanoreceptors ,
First Pain
conveyed by Ad fiber.
Secound Pain Second pain: dull and
diffuse and prolonged .
Responded by polimodal
C Fiber nociceptors , conveyed by
C fiber

Modified by AHT
Role of nociceptors
and primary afferent
neurons are:

1. TRANSDUCTION
2. CONDUCTION
 TRANSDUCTION PROCESS
Noxious Soup
(NOCICEPTORS ACTIVATION)

Local &
Vescular
Mediators- Action Potential
Ca++
Bradykinin,
Cytokines Peptides- TRP Na+
Histamine, sP, CCK,
5HT. CGRP

Traumatic
Tissue Mediators-
Injury K+, H+,
ATP,PGE

In Creased Neural
Synthesis Mediators- TRP Ca++
Pro Epine,
Inflammatory Norepine
Generator
Cytocaines
Potential
-(IL) 1
-IL-6
TRP (Transient Receptor Potential) Ion
Channel is a Transducer molecules. Modified by AHT
R. Sinatra 2007
 Pain pathway

Pain

Descending
modulation Dorsal Horn

Ascending Dorsal root

Conduction
input ganglion

Transduction
Spinothalamic Peripheral
tract nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Modified by AHT
3. DORSAL HORN NEURONS
Dorsal Horn of Spinal cord
Plays a big role in pain perception
Is the first gate to control pain
Nociception (Pain) is born in DHN

Lehmann, K. A.: From the first stimulus to pain memory. UN. Cologne, 2000 22
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 receiving
neurons (second order neurons) synapse.
Where interaction between excitatory and
inhibitory system.
Two types of second order nociceptive neurons
are found in DHN.
1. NS (Nociceptive-Specific Neurons
2. WDR (Wide-Dynamic Range Neuros)
Targets of Primary Afferent Neurons in
the posterior gray (dorsal) horn

NS

WDR

Transmission at DH 24
NS : Respond exclusively to noxious stimuli
from A & C fiber.
WDR :
Respond to both noxious and innocuous
stimuli.
May receive afferent input from skin, muscle,
joint and visceral nociceptors referred pain.
Low frequency stimulation of C fiber lead to
gradually increase WDR discharge, until
continuous discharge wind up.
These responsible by NMDA receptors, while
AMPA receptors responsible for short-lasting
depolarization (brief pain).
Neurotransmitters and receptors
on Dorsal Horn

Modulation at DH 27
NEUROTRANSMITTERS
Primary afferent neurons may release one or more
excitatory
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 lasting
depolarization.
4. ASCENDING PATHWAYS
 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
 SSC FLC SPINOTHALAMIC TRACT
Neo Spino Thalamic Tract direct to
Cortex and
Thalamus Thalamus SSC Localizing and
VPL MT
discriminative information withdrawal
reflex.
Hypothalamus Pleo Spino Thalamic Tract FLC (Frontal
and Pituitary
PAG
Sympathetic
Outflow Limbic Cortex) Affecting circulation,
Hypothalamic- respiration, endocrine, emotional,
Midbrain
Pituitary Outflow
behavioral responses (fear, anxiety,
LC
helplessness, avoidance).

Ascending Descending
Peripheral
Pathaways Pathaways
Nociceptor

Brainstem NRM
C-Fiber Sensory
Afferent

NSTT

PSTT Delta Sensory

Afferent

Spinal Cord
Sympathetic
Efferent

A-Alpha Motor
Efferent
 Response Cortical
- anxiety
- fear
- apprehension

Response Suprasegmental
- neurohumoral response
- catecholamines
- cortisol
- dll.

Response Segmental
- muclespasm
- vasospasm
- bronchospasm
- decreased gastrointestinal
motility

Response Local
-release pain substances
-inflammation
RESPONSES TO NOXIOUS STIMULI INDUCED BY AN ABDOMINAL SURGERY
5. DESCENDING MODULATING
PATHWAYS
 Descending Modulating
Pathways
Those ascending pathways is modulated by descending
modulating pathways in several higher centers;
CEREBRAL CORTEX
THALAMUS
HYPOTHALAMUS
BRAINSTEM/ MIDBRAIN
Periaqueductal gray (PAG)
Nuclei raphe magnus
Locus ceruleus
Sub ceruleus
SPINAL CORD
 SSC FLC

Cortex and
Thalamus
VPL MT

Hypothalamus
and Pituitary Sympathetic
PAG Outflow

Hypothalamic-
Pituitary Outflow
Midbrain
LC

Ascending Descending
Peripheral
Pathaways Pathaways
Nociceptor

Brainstem NRM
C-Fiber Sensory
Afferent

NSTT

PSTT Delta Sensory

Afferent

Spinal Cord
Sympathetic
Efferent

A-Alpha Motor
Efferent
SEROTONIN
NEOREPINEPHRINE
Modulation
SITES OF ENKEPHALIN BINDING IN SPINAL CORD.
ROLED BY INTRNEURON INHIBITORY AND DESCENDING FIBER INHIBITORY

Enkephalinergic
Interneuron
(Inhibitory)

Primary
Nociceptive
Presynaptic Opioid
Fiber
Receptors
(-)

ENK ENK

Postsynaptic
Opioid Glutamate
Receptors Receptors ENK
(-)
Descending
(+)
Enkephalinergic
Fiber (Inhibitory)

ENK

Spinal Sensory
Neuron
Modified by AHT
Presynaptic & Post Synaptic Receptors

Dorsal Horn Neurons

 Descending Pain Control
Cortex
Brain Hypothalamus
Thalamus

Releases
Endogenous opioids
Midbrain PAG GABA
NE

Releases
Brain stem NRM Serotonin
NE

Inhibit
Spinal cord DHN WDR neurons Analgesia
NS neurons
NO BRAIN, NO PAIN
Role of DHN, is the place
where interaction between
afferent ascendern input
and descedern modulation
pain control.

1. MODULATION
2. TRANSMISSION
 Pain Perception

Pain

Medulation
Descending
modulation Dorsal Horn

Ascending Dorsal root

Conduction
input ganglion

Transduction
Spinothalamic Peripheral
tract nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Modified by AHT
 PAIN PERCEPTION
How pain perception is processed, still obscured, and
Where pain perceptions in the brain still unclear.

Noxious perception?
Pain A number of theories:
Perception Brain
SS
1. Specificity theory by Descartes
Limbic Cortex
(16 century)
SS

Sensory Cortex
Thalamus
2. Gate control theory by
Melzack and Wall (i965)
3. Sensitization theory by Woolf
et al (1990 an)
1. Specificity theory
Descartes
(17th Century)

Pain was
faithfully
transmitted
from
periphery to
brain
Modified by AHT
2.GATE CONTROL THEORY by MELZACK and Wall

Central Descending
Control Modulation

Large
fibers

Ascending Action
System

Small
fibers Dorsal Horn Gate

The Gate control theory of pain processing. T = Second-order transmission cell; SG = substantia
gelatinosa cell.
Modified by AHT
3.Sensitization theory by Woolf
After the injury sensitization in the periphery
and centrally is occurred. (Hyperalgesia and
allodynia).
Pain perception is the net process starting
from:
Nociceptor activation
Neural conduction
Spinal transmission
Noxious modulation
Limbic & frontal cortical perception
 So, there are three
possibilities how do
we feel pain.
Noxious stimulus with Pain
Pain

Inhibition
CNS Modulation
Excitation

Nociception exp. normal situation

Nociception with Pain
Noxious stimulus without Pain
Pain
X Inhibition
CNS Modulation
Excitation

Example:
Nociception Stress Induced Analgesia

Nociception without pain

Pain without noxious stimulus
Pain

Inhibition
CNS Modulation
Excitation

X Example: Phantom Pain

Nociception Neurophatic Pain

Pain without nociception

6. Peripheral Sensitization
 Activation of neciceptor
Nociceptive stimulation

Axon reflex
Primary afferent nerve
vessel

Nocicepto
Redness
r Swelling
Pain
Fever
PGE2
K+H+ HT Hist. PGI2 BK NOR
H+
LTB4
Tissue Platelet Mast Membrane
cell Kininogen
cell phospholopid

Tissue damage
Chemical intermediaries in nociceptive transduction

serotoin platelets ++ activate

histamine mast cell + activate

leukotrienes arachidonic acid-damaged cell sensitize

Pain: Howard L. Fields p.32

Primary Hyperalgesia
Immuno Cells
Cell injury
Kinins Cytokines Cannabioids
H+ Neurotrophins Opioids
K Histamine Adenosine
5HT
Prostaglandin
Bradikynin

Nociceptors NO
Kinins
Vasculature
Neuropeptides
Primary Afferent Neurones

Prostaglandins
Sympathetic Efferent Neurones
Secondary hyperalgesia
(allodynia)

Primary hyperalgesia
7. Central Sensitization
NMDA RECEPTOR / CHANNEL
IS BLOCKED BY Mg ion

Ca
Na Na
NKr
Gly NMDA AMPA

Mg
Zn PCP

PKC

K K Dickenson, 1994
3 conditions are needed to release Mg blockade.
NMDA is binding by Glu, Gly and Long depolarisation

Mg
SP Glu Glu
Ca
Na Na
NKr
Gly NMDA AMPA

DEPOLARIZATION
Zn PCP

PKC

K K Dickenson, 1994
When NMDA channel is open large of
Ca and Na influx into the cell
Mg
SP Glu Glu
Ca
Na Na
NKr Gly NMDA AMPA

DEPOLARIZATION
Zn PCP

PKC

K K

Increased excitability
Long term changes Ca
Cell death Dickenson, 1994
Central sensitization Processing in Spinal Cord

Inhibitory
Interneuron

Nociceptor NE

Terminal ending MU

Glu SP SP
Glu SP
Post Synaptic Membrane of
the Spinal Sensory Neuron SP
Glu
Glu Ca++
Glu Mg++ NMDA
Receptor NK-1 MU
AMPA Receptor
Kainate Receptor
Receptor Second Messenger
Fast Prime
Na+ Slow Prime Formation, (cAMP, PKA)

NMDA Receptor: Requires voltage

mRNA synthesis, and
dependent priming for activation -
upregulation of inducible
enzymes/ protein
SEKIAN
TERIMA KASIH BANYAK

SEMOGA ADA MANFAATNYA

REVIEW
What PAIN is?

What the textbooks

would have you believe
about pain
Noxious (painfull)
stimulus to the body
 Descending
Cortex
Modulatory Systems

PAG
Opioids

NRM LC

5-HT - - Enkephalin - Norepinephrine

Opioids Dorsal homs

Modified by AHT
 Two distinct sensations
(dual pain sensation)

Pain intensity

early sharp, relatively brief

Afiber=first pain pricking sensation

C fiber=second pain
later dull, somewhat
prolonged sensation

Time
Injury
 Limbic Cortex

Sensory Cortex
Thalamus
Trauma

Descending Ascending
Pathway Pathways
Central Grey
Nociceptor
Mid Brain
Dorsal
Horn
Noxious Fiber

Spinal Cord
Motor Efferent
Adapted from Julius & Basbaum.
Nature 2001;413(6852):203
Pain Processing in Spinal Cord

Inhibitory
Interneuron

Nociceptor NE

Terminal ending MU

Glu
SP SP -
Glu
SP
Post Synaptic Membrane of
Mg++
the Spinal Sensory Neuron
Na+
Na+
Glu
Glu + SP

Glu NMDA
Receptor
AMPA
Receptor
NK-1
Receptor
MU
-
Kainate
Receptor Second Messenger
Fast Prime
Na+ Slow Prime Formation, (cAMP, PKA)

NMDA Receptor: Requires voltage

mRNA synthesis, and
dependent priming for activation -
upregulation of inducible
enzymes/ protein

Modified by AHT
NOCICEPTIVE TRANSMISSION

Glu
( SP )
NMDA r

(CGRP)

NO
AA

C-fiber Dorsal Horn Neuron

Cortical structures
It has been long to divide higher neural center
in 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 PERCEPTION
remains unclear.
( Philip Siddal )
 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
A myelinated fiber
Responds to noxious stimuli
C unmyelinated fiber
 ACUTE (NOCICEPTIVE)
PAIN PATHWAYS
A nociception has at least 4 components

1. TRANSDUCTION
2. CONDUCTION
TRANSMISSION
3. MODULATION
4. PERCEPTION
 Neuron III Persepsion

Transduction

Mechanical Conduction/
Transmission
Transmission
Modulation
Neuron II
Thermal

Neuron I
Chemical

Modified by AHT
1.TRANSDUCTION (NOCICEPTOR ACTIVATION)

Defines as noxious stimuli are converted into a

calcium ion-(Ca2+) mediated electrical
depolarization within the distal nociceptor
endings.

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.
 Transduction and Conduction Process

Ca2+

K+
K+

Na+

1. Transduction 3. Propagation (conduction)

2. Spike Initiation 4. Transmission

Modified Meliala, 2006

TRANSMISSION (spinal transmission)

Refers to the transfer of noxious impulses

from primary nociceptors cells in the dorsal
horn neurons.
Ad and C fibers are the axons of unipolar
neurons that have distal projections known as
nociceptive field.
Two nociceptive fields in dorsal horn neurons;
1. Nociceptive-specific neurons (NS)
2. Wide dynamic range (WDR)
MODULATION (noxious modulation)

Refers to pain- suppressive mechanism within the

spinal cord dorsal horn neurons and at higher levels
of the brainstem and midbrain.
In the spinal cord, this intrinsic breaking
mechanism inhibits oxious transmission at the
first synapse between the primary noxious afferent
and second order WDR and NS neurons.
Thereby reducing spinothalamic relay of noxious
impulses.
Spinal modulation is mediated by spinal-inter
neurons and terminal descending inhibitory.
Pharmacologic Modalities of
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

Pain

Medulation
Descending
modulation Dorsal Horn

Ascending Dorsal root

Conduction
input ganglion

Transduction
Spinothalamic Peripheral
tract nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Modified by AHT