PHYSIOLOGY of PAIN NOSCICEPTION.

Nur Surya Wirawan

Dept. of Anesthesiology, ICU & Pain Management.

Faculty of Medicine Hasanuddin University

Makassar 2012

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Setelah kuliah ini mahasiswa peserta mampu menjelaskan.

Apa itu nosiseptor

Perjalanan suatu nosisepsi;

Transduksi

Konduksi

Modulasi

Transmisi

Persepsi

Apa itu nyeri nosisepsi, Nosisepsi tanpa nyeri

Serta nyeri tanpa nosisepsi

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3

Poisons

mechanical thermal chemical electrical

Tissue damage

Release of mediators

Hydrogen and potassium ions, neurotransmitters, kinins, prostaglandins

Stimulation of nociceptors

Transmission to CNS

via afferent pathways

What is pain?

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What the textbooks would have you believe

about pain

Noxious (painfull) stimulus to the body

What PAIN is?

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A-Alpha Motor Efferent

Sympathetic Efferent

Delta Sensory Afferent

C-Fiber Sensory Afferent

Peripheral Nociceptor

Spinal Cord

NSTT

PSTT

NRM Brainstem

Midbrain

Hypothalamus and Pituitary

Cortex and Thalamus

LC

PAG

MT VPL

SSC FLC

Ascending Pathaways

Descending Pathaways

Sympathetic Outflow

Hypothalamic- Pituitary Outflow

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Nociceptive Pain is pain that generated from nociceptors

1. NOCICEPTORS

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What is a nociceptor? Nociceptors are peripheral sensory

neurons that respond selectively to noxious stimuli.

Or 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,

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TRPVs ASICs TRPs P2X

capsaicin

H+

PGs

EPs

cold warm ATP

COX1/2

ATP

heat

Na+, K+, Ca2+

channels

DRG

C-fibre

Tissue damage and pain in the periphery

Mechanical?

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Characteristic of A and C-fiber

Polimodal Nociceptors

A Fiber Rapid Conduction

C-Fiber Slow Conduction

Mechano Thermal Nociceptors

Glu

First Pain

Secound Pain

Glu

sP

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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.

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Injury

C fiber=second pain

Aδfiber=first pain

Pain intensity

Time

Two distinct sensations (dual pain sensation)

early sharp, relatively brief pricking sensation

later dull, somewhat prolonged sensation

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2. PERIPHERAL SENSORY AFFERENT FIBERS

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Anatomi

Neuron Afferen Primer Mempunyai badan sel unipolar yang

berlokasi pada radix ganglion dorsalis Diklasifikasikan berdasarkan ukuran

serabut dalam 3 group mayor (A, B, C). Group A selanjutnya disubklasifikasikan

dalam 4 subgroup (Aα, Aβ, Aγ, dan Aδ

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Nerve fibers

12〜20

5〜12

3〜6

2〜5

＜ 3

0.4〜1

0.3〜1.3

70〜120

70〜80

15〜80

12〜30

3〜15

0.5〜2

0.7〜2.3

β

γ

δ

d.r. S

（μ） （ｍ / ｓ）

temperature pain

motor

spindle fiber

sympatheic preganglionic

sympathetic postganglionic

pain

myelin

+

+

－

diameter funtion nerve fiber

A

B

C

α proprioceptive

Tactile sense pressure

velocity

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Anatomy of peripheral sensory nerve fibers

A

A C 17

Dorsal Horn

Dorsal root

ganglion

Peripheral sensory

Nerve fibers

A

A

C

Large

fibers

Small

fibers

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

Modified by AHT 18

Although in normal condition A fiber does not response to noxious stimuli, but it plays a big role in NORMAL SENSATION.

The Role of A fiber

Without A fiber, any noxious stimuli will perceive

as BURNING PAIN (TN, HZ)

A

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20

IIIo

IIi

III

IV

V

VI

VII

VIIIIX

X

A

WDR

A

C

heavily myelinated

fast conducting

thinly myelinated intermediate conducting

unmyelinated slow conducting

peripheral

endingsdorsal root

ganlgia

high intensity noxious stimuli

low intensity

non-noxious stimuli

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 and SECOUND PAIN

• First pain: sharp and 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

A Fiber First Pain

Secound Pain

Modified by AHT 22

1. TRANSDUCTION 2. CONDUCTION

Role of nociceptors and primary afferent neurons are:

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Noxious afferent fibers

A myelinated fiber

C unmyelinated fiber Responds to noxious stimuli

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Mechanical

Thermal

Chemical

Transduction

Conduction/ Transmission

Modulation

Transmission

Persepsion

Neuron I

Neuron II

Neuron III

Modified by AHT 25

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.

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TRANSDUCTION PROCESS (NOCICEPTORS ACTIVATION)

Action Potential

Na+

Ca++

TRP Peptides-

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 Creased

Synthesis

Pro

Inflammatory

Cytocaines

-(IL) 1

-IL-6

Modified by AHT

R. Sinatra 2007

“Noxious Soup”

Tissue Injury

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

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K+ K+

Ca2+

Na+

1. Transduction

4. Transmission 2. Spike Initiation

3. Propagation (conduction)

Modified Meliala, 2006

Transduction and Conduction Process

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3. DORSAL HORN NEURONS

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Lehmann, K. A.: From the first stimulus to pain memory. UN. Cologne, 2000

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

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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 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)

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Targets of Primary Afferent Neurons in the posterior gray (dorsal) horn

33 Transmission at DH

NS

WDR

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NS vs WDR

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”.

NMDA receptors is responsible for “Wind-up” while AMPA receptors responsible for short-lasting depolarization (brief pain).

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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.

NEUROTRANSMITTERS

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Neurotransmitters and receptors on Dorsal Horn

37 Modulation at DH 37

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WIDE DYNAMIC RANGE SPINAL

NEURON

Brain

NMDAr

“Wind-up”

Gene induction

Glutamate

(Subs P)

GABA

Glycine

Opioids

NA, 5HT

C

A

A

+

-

Glutamate

Glutamate

Inhibitory

Fibers

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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

Sympathetic Efferent

Delta Sensory Afferent

C-Fiber Sensory Afferent

Peripheral Nociceptor

Spinal Cord

NSTT

PSTT

NRM Brainstem

Midbrain

Hypothalamus and Pituitary

Cortex and Thalamus

LC

PAG

MT VPL

SSC FLC

Ascending Pathaways

Descending Pathaways

Sympathetic Outflow

Hypothalamic- Pituitary Outflow

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Response Cortical

Response Suprasegmental

Response Segmental

Response Local

- anxiety - fear - apprehension

- neurohumoral response - catecholamines - cortisol - dll.

- muclespasm - vasospasm - bronchospasm - decreased gastrointestinal motility

-release pain substances -inflammation

RESPONSES TO NOXIOUS STIMULI INDUCED BY AN ABDOMINAL SURGERY 43

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 descending modulating pathways in several higher centers;

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Descending pathways

Ascending pathways

Brain is a huge Pharmacetucal Factory.

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Presynaptic & Post Synaptic Receptors

Dorsal Horn Neurons 47

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.

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Postsynaptic

Opioid

Receptors

(-)

(+)

Glutamate

Receptors

Enkephalinergic

Interneuron

(Inhibitory)

Descending

Enkephalinergic

Fiber (Inhibitory)

Presynaptic Opioid

Receptors

(-)

Primary

Nociceptive

Fiber

Spinal Sensory

Neuron

ENK ENK

ENK

ENK

SITES OF ENKEPHALIN BINDING IN SPINAL CORD. ROLED BY INTRNEURON INHIBITORY AND DESCENDING FIBER INHIBITORY

Modified by AHT 49

Dorsal homs Opioids

NRM LC

PAG

Cortex

Opioids

Descending Modulatory Systems

5-HT - - Enkephalin - Norepinephrine

Modified by AHT 50

Descending Pain Control

Cortex Hypothalamus

Thalamus

PAG

NRM

DHN

Brain

Midbrain

Brain stem

Spinal cord

Releases • Endogenous opioids • GABA • NE

Releases • Serotonin • NE

Inhibit • WDR neurons • NS neurons

Analgesia

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Apapun yg dilakukan shg endorfin dilepasakan menghilangkan nyeri

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1. MODULATION 2. TRANSMISSION

Thus, the role of DHN, is the place where interaction between afferent ascendern input and descedern input.

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Modulation

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Spinothalamic tract

Peripheral nerve

Dorsal Horn

Dorsal root ganglion

Pain

Medulation

Ascending input

Descending modulation

Peripheral nociceptors

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 Brain

Pain Perception Is the end result of the neural activity starting from Transduction, Conduction, Modulation and Transmission pain, where pain becomes a conscious multidimensional experience. Pain has affective-motivational, sensory-discriminative, emotional and behavioral components.

Perception

Perception

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Brain has no discrete pain counter

Brain does not have a discrete pain center, so when the impulses arrive in the thalamus they are directed to multiple areas in the brain where they are processed.

So, pain is translated from the brain stem, thalamus, and in multiple cortical areas produce subjective feeling.

A. Basbaun 57

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Those experience were translated in: 1. Reticular system

Responsible for outonomic & motor response to pain withdrawal reflex

Affective – motivational response to pain looking at and assessing the injury.

2. Somatosensory cortex Perception and interpretation of sensation Identify the intensity, type and location of pain.

What pain feels like.

3. Limbic system Responsible for the emotional and behavioral response

to pain. Attention, mood and motivation to find helper.

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Pain has multidimensional experience

1. Affective – motivational

Assessing the injury the meaning of injury

2. Sensory – discriminative

Identifies the intensity, type and location of pain

3. Emotional – behavioral component

Attention, mood and behavioral due to pain

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Beecher

Prof. Hyodo

The Meaning of injury

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Pain Perception Brain

Noxious perception?

A number of theories:

1. Specificity theory by Descartes (16 century)

3. Gate control theory by Melzack and Wall (i965)

4. Sensitization theory by Woolf et al (1990 an)

PAIN PERCEPTION How pain perception is processed, still obscured, and Where pain perceptions in the brain still unclear.

Limbic Cortex

Sensory Cortex

Thalamus

SS

SS

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Pain was faithfully

transmitted from

periphery to brain

1. Specificity theory

Descartes (17th Century)

Modified by AHT 63

2.GATE CONTROL THEORY by MELZACK and Wall

Ascending Action

System

Large

fibers

Central

Control

Descending

Modulation

Small

fibers Dorsal Horn “Gate”

The Gate control theory of pain processing. T = Second-order transmission cell; SG = substantia

gelatinosa cell.

Modified by AHT 64

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Sensitization theory by Woolf et

Is the net process starting from:

Nociceptor activation

Neural conduction

Spinal transmission

Noxious modulation

Limbic & frontal – cortical perception

Spinal & supra spinal response.

After the injury is occurred sensitization in the periphery and centrally. (Hyperalgesia and allodynia)

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After tissue damage it occurs peripheral and central sensitization

Increasing Stimulus Intensity

Stimulus response alteration observed with hyperalgesia

No Pain

Allodynia

“Hyperalgesia” Normal

Response

Worst Pain

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Primary hyperalgesia

Secondary hyperalgesia (allodynia)

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So, there are three possibilities how do we feel pain.

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Noxious stimulus with Pain

Pain

CNS

Nociception exp. normal situation

Nociception with Pain

Inhibition

Excitation

Modulation

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Pain

CNS

Nociception

Nociception without pain

Inhibition

Excitation

Example:

Stress Induced Analgesia

X

Modulation

Noxious stimulus without Pain

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Pain

CNS

Nociception

Pain without nociception

Inhibition

Excitation

Example: Phantom Pain

Neurophatic Pain

X

Modulation

Pain without noxious stimulus

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panthom pain 77

Net Result of Excitatory and Inhibitory stimuli

time

NEUROPATHIC PAIN

Excitatory

Inhibitory

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Burning, feeling like the feet are on fire

Stabbing, like sharp knives Lancinating, like electric shocks

Freezing, like the feet are on ice,

although they feel warm to touch

Modified by Meliala 2006 79

Pain is unlike our other senses

Is a sensation

Is a motor response

Is an affective response

Survive, escape, avoid and rest

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SEKIAN TERIMA KASIH BANYAK SEMOGA ADA MANFAATNYA

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