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

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

ATP capsaicin heat

Tissue damage and pain in the periphery

Mechanical?

COX1/2
H+ PGs cold warm ATP

DRG

TRPVs ASICs
Na+, K+, Ca2+ channels

EPs

TRPs

P2X

C-fibre

Nociceptors;is
by their response;

characterized

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
Rapid Conduction

Mechano Thermal Nociceptors

Glu
First Pain

First Pain Secound Pain

C-Fiber
Polimodal Nociceptor
Slow Conduction

Glu sP

Secound Pain

2. PERIPHERAL SENSORY AFFERENT FIBERS

Anatomy of peripheral sensory nerve fibers

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

Two sensory afferent neurons

Large fibers

A
Dorsal root ganglion

Small fibers

A C
Peripheral sensory Nerve fibers

Dorsal Horn

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

peripheral endings dorsal root ganlgia
A

SENSATIONS
SP & CGRP

I NS IIo IIi III IV

WDR

low intensity non-noxious stimuli

heavily myelinated fast conducting thinly myelinated intermediate conducting unmyelinated slow conducting

VI

high intensity noxious stimuli

C 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
A Fiber
First Pain
Secound Pain

pricking, well-localised and brief. Responded by mechanoreceptors , conveyed by Ad fiber.

Second pain: dull and

diffuse and prolonged . Responded by polimodal nociceptors , conveyed by C fiber

C Fiber
Modified by AHT

Role of nociceptors and primary afferent neurons are:

1. TRANSDUCTION 2. CONDUCTION

Noxious Soup

TRANSDUCTION PROCESS (NOCICEPTORS ACTIVATION)

Local & Vescular MediatorsBradykinin, Cytokines Histamine, 5HT.

Ca++ PeptidessP, CCK, CGRP Traumatic MediatorsK+, H+, ATP,PGE Neural MediatorsEpine, Norepine TRP

Action Potential

Na+

Tissue Injury

In Creased Synthesis Pro Inflammatory Cytocaines -(IL) 1 -IL-6

TRP

Ca++

Generator Potential

TRP (Transient Receptor Potential) Ion Channel is a Transducer molecules.

Modified by AHT R. Sinatra 2007

Pain pathway
Pain

Descending modulation Ascending input

Dorsal Horn Dorsal root ganglion

Conduction Transduction

Spinothalamic tract

Peripheral 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

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.

Substance P

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)

Transmission of visceral pain Behavioral response

3.

DORSAL HORN COLUMN TRACT

4.

SPINOMESENCEPHALIC TRACT

5.

SPINOHYPOTHALAMIC TRACT

Sensational from the skin, lips & sex organs

SSC FLC Cortex and Thalamus

SPINOTHALAMIC TRACT
MT

VPL

Hypothalamus and Pituitary PAG

Sympathetic Outflow HypothalamicPituitary Outflow

Midbrain

LC

Neo Spino Thalamic Tract direct to Thalamus SSC Localizing and discriminative information withdrawal reflex. Pleo Spino Thalamic Tract FLC (Frontal Limbic Cortex) Affecting circulation, respiration, endocrine, emotional, behavioral responses (fear, anxiety, helplessness, avoidance).
Peripheral Nociceptor C-Fiber Sensory Afferent

Ascending Pathaways
Brainstem NRM

Descending Pathaways

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 PAG

Sympathetic Outflow HypothalamicPituitary Outflow

Midbrain

LC

Ascending Pathaways
Brainstem NRM

Descending Pathaways
C-Fiber Sensory Afferent

Peripheral Nociceptor

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 Fiber

Presynaptic Opioid Receptors (-) ENK Postsynaptic Opioid Receptors (-) ENK

Glutamate Receptors

ENK

(+)

Descending Enkephalinergic Fiber (Inhibitory)

ENK

Spinal Sensory Neuron

Modified by AHT

Presynaptic & Post Synaptic Receptors

Dorsal Horn Neurons

Descending Pain Control

Brain
Cortex Hypothalamus Thalamus

Midbrain

PAG

Releases Endogenous opioids GABA NE

Brain stem

NRM

Releases Serotonin NE Inhibit WDR neurons NS neurons

Spinal cord

DHN

Analgesia

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 Ascending input Dorsal Horn Dorsal root ganglion

Conduction Transduction

Spinothalamic tract

Peripheral 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 Perception
SS SS

A number of theories:
Brain
Limbic Cortex
Sensory Cortex Thalamus

1. Specificity theory by Descartes (16 century) 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 Control

Descending 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
CNS
Modulation

Inhibition

Excitation

Nociception

Example: Stress Induced Analgesia

Nociception without pain

Pain without noxious stimulus

Pain
Inhibition

CNS

Modulation

Excitation

Nociception

Example: Phantom Pain Neurophatic Pain

Pain without nociception

6. Peripheral Sensitization

Activation of neciceptor
Nociceptive stimulation Axon reflex Primary afferent nerve
vessel

Nocicepto r
K+H+ Tissue cell HT Platelet Hist. Mast cell
PGE2 PGI2 LTB4

Redness Swelling Pain Fever

BK Kininogen NOR

H+

Membrane 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
Cell injury
Kinins H+ K

Immuno Cells
Cytokines Neurotrophins Histamine 5HT Cannabioids Opioids Adenosine

Prostaglandin Bradikynin

Nociceptors
Neuropeptides Primary Afferent Neurones

NO Kinins Vasculature

Prostaglandins Sympathetic Efferent Neurones

Secondary hyperalgesia (allodynia) Primary hyperalgesia

7. Central Sensitization

NMDA RECEPTOR / CHANNEL IS BLOCKED BY Mg ion

Na
NKr

Ca

Na

Gly NMDA

AMPA

Mg Zn PKC PCP

Dickenson, 1994

3 conditions are needed to release Mg blockade.

NMDA is binding by Glu, Gly and Long depolarisation
Mg

SP
NKr

Glu

Glu

Na Gly NMDA

Ca

Na AMPA

Zn PKC

PCP

DEPOLARIZATION

Dickenson, 1994

When NMDA channel is open large of Ca and Na influx into the cell
SP
NKr Glu
Na Gly NMDA Ca

Mg Glu
Na AMPA

Zn PKC

PCP

DEPOLARIZATION

Increased excitability Long term changes Cell death

Ca Dickenson, 1994

Central sensitization Processing in Spinal Cord

Inhibitory Interneuron

Nociceptor Terminal ending

Glu
SP

NE MU SP

Glu

Post Synaptic Membrane of the Spinal Sensory Neuron

Glu Glu Glu
Ca++
Mg++

SP

SP

NMDA Receptor

Kainate Receptor

AMPA Receptor

NK-1 Receptor

MU

Na+

Fast Prime

Slow Prime

Second Messenger Formation, (cAMP, PKA)

NMDA Receptor: Requires voltage dependent priming for activation -

mRNA synthesis, and 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

Cortex

Descending Modulatory Systems

PAG
Opioids

NRM
5-HT - Enkephalin

LC
- Norepinephrine

Opioids

Dorsal homs

Modified by AHT

Two distinct sensations

(dual pain sensation) Pain intensity

Afiber=first pain

early sharp, relatively brief pricking sensation

C fiber=second pain
later dull, somewhat prolonged sensation

Time

Injury

Limbic Cortex
Sensory Cortex

Thalamus
Trauma Descending Pathway Nociceptor Ascending Pathways Central Grey Mid Brain

Noxious Fiber

Dorsal Horn

Motor Efferent

Spinal Cord

Adapted from Julius & Basbaum. Nature 2001;413(6852):203

Pain Processing in Spinal Cord

Inhibitory Interneuron

Nociceptor Terminal ending

Glu
SP

NE MU SP

SP SP

Glu

Post Synaptic Membrane of the Spinal Sensory Neuron Na+ Na+

Glu Glu

Mg++
Glu

+
NMDA Receptor

Kainate Receptor

AMPA Receptor

NK-1 Receptor

MU

Na+

Fast Prime

Slow Prime

Second Messenger Formation, (cAMP, PKA)

NMDA Receptor: Requires voltage dependent priming for activation -

mRNA synthesis, and upregulation of inducible enzymes/ protein

Modified by AHT

NOCICEPTIVE TRANSMISSION

Glu ( SP ) (CGRP)

NMDA r

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
Norepinephrine

amino butiric acid)

Noxious afferent fibers

A myelinated fiber
C unmyelinated fiber Responds to noxious stimuli

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 Modulation

Transmission

Thermal

Neuron II

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 2. Spike Initiation

3. Propagation (conduction) 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 Ascending input Dorsal Horn Dorsal root ganglion

Conduction Transduction

Spinothalamic tract

Peripheral 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