Beruflich Dokumente
Kultur Dokumente
A.M.Takdir Musba
Dept. of Anesthesiology, ICU & Pain Management.
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
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
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
Glu
First Pain
C-Fiber
Polimodal Nociceptor
Slow Conduction
Glu sP
Secound Pain
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
Small fibers
A C
Peripheral sensory Nerve fibers
Dorsal Horn
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Without A fiber, any noxious stimuli will perceive as BURNING PAIN (TN, HZ)
SENSATIONS
SP & CGRP
heavily myelinated fast conducting thinly myelinated intermediate conducting unmyelinated slow conducting
VI
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
C Fiber
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Noxious Soup
Ca++ PeptidessP, CCK, CGRP Traumatic MediatorsK+, H+, ATP,PGE Neural MediatorsEpine, Norepine TRP
Action Potential
Na+
Tissue Injury
TRP
Ca++
Generator Potential
Pain pathway
Pain
Conduction Transduction
Spinothalamic tract
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
Lehmann, K. A.: From the first stimulus to pain memory. UN. Cologne, 2000
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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)
WDR
Transmission at DH
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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).
Modulation at DH
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NEUROTRANSMITTERS
Primary afferent neurons may release one or more
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
2.
SPINORETICULAR TRACT
3.
4.
SPINOMESENCEPHALIC TRACT
5.
SPINOHYPOTHALAMIC TRACT
SPINOTHALAMIC TRACT
MT
VPL
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
Spinal Cord
Sympathetic Efferent
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
Periaqueductal gray (PAG) Nuclei raphe magnus Locus ceruleus Sub ceruleus
SPINAL CORD
VPL
MT
Midbrain
LC
Ascending Pathaways
Brainstem NRM
Descending Pathaways
C-Fiber Sensory Afferent
Peripheral Nociceptor
Spinal Cord
Sympathetic Efferent
SEROTONIN NEOREPINEPHRINE
Modulation
Presynaptic Opioid Receptors (-) ENK Postsynaptic Opioid Receptors (-) ENK
Glutamate Receptors
ENK
(+)
Modified by AHT
Midbrain
PAG
Brain stem
NRM
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
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
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Central Control
Descending Modulation
Large fibers
Small fibers
The Gate control theory of pain processing. T = Second-order transmission cell; SG = substantia gelatinosa cell.
Modified by AHT
Pain perception is the net process starting from: Nociceptor activation Neural conduction Spinal transmission Noxious modulation Limbic & frontal cortical perception
CNS
Modulation Excitation
Nociception
X
CNS
Modulation
Inhibition
Excitation
Nociception
CNS
Modulation
Excitation
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
H+
serotoin
platelets
++
activate
histamine
mast cell
activate
leukotrienes
sensitize
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
7. Central Sensitization
Ca
Na
Gly NMDA
AMPA
Mg Zn PKC PCP
Dickenson, 1994
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
Ca Dickenson, 1994
Inhibitory Interneuron
NE MU SP
Glu
SP
SP
NMDA Receptor
Kainate Receptor
AMPA Receptor
NK-1 Receptor
MU
Na+
Fast Prime
Slow Prime
SEKIAN
TERIMA KASIH BANYAK
SEMOGA ADA MANFAATNYA
REVIEW
Cortex
PAG
Opioids
NRM
5-HT - Enkephalin
LC
- Norepinephrine
Opioids
Dorsal homs
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Afiber=first pain
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
Inhibitory Interneuron
NE MU SP
SP SP
Glu
Mg++
Glu
+
NMDA Receptor
Kainate Receptor
AMPA Receptor
NK-1 Receptor
MU
Na+
Fast Prime
Slow Prime
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NOCICEPTIVE TRANSMISSION
Glu ( SP ) (CGRP)
NMDA r
NO AA
C-fiber
Cortical structures
It has been long to divide higher neural center
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
GABA (gamma
Norepinephrine
Neuron III
Persepsion
Transduction Mechanical
Transmission
Thermal
Neuron II
Neuron I
Chemical
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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.
Ca2+
K+
K+
Na+
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)
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.
Anti-convulsants
Gabapentin, Pregabalin
Medulation
Descending modulation Ascending input Dorsal Horn Dorsal root ganglion
Conduction Transduction
Spinothalamic tract
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