Nyeri Nosisepsi
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Transcript of Nyeri Nosisepsi
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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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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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
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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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