nociception, pain - chariténociception is a sensory activity, which is induced by. ......
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Nociception, pain
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1. Kandel ER, Schwartz JH, Jessel TM (2000) Principles of Neural Science, McGraw-Hill, Ch. xx. 2. Berne EM, Levy MN, Koeppen BM, Stanton BA (2004) Physiology, Mosby, Ch. 7.3. Schmidt RF, Lang F, Thews G (2005) Physiologie des Menschen, Springer, Ch. 15.
Recommended literature
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What is nociception, what is pain? Q1
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Nociception is a sensory activity, which is induced bya noxious stimulus, i.e an actual or potential tissue damage.
- nociceptive pain- neuropathic pain
Pain is a sensation that contains other components in addition tonociception.
The activation of nociceptors is not always associated with pain: pharmacologically induced anaesthesia. And, vice versa, pain is possible without the activation of nociceptors.
Basics
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ST
L-20
00-1
3-10
Basics
Example: neuropathic pain
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-thermical nociceptors-mechanical nociceptors
-polymodal nociceptors
These nociceptors have differentfunctions and differ in their -afferent pathways-axonal conduction velocity-size of neurons/axons-neurochemichal/pharmacological properties(transmitters, peptide co-transmitters)
Classification of nociceptors
Basics
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In comparison with other sensory systems, nociception is characterized by sensitization, i.e. a decrease of sensory Threshold with stimulus repetition
2 mechanisms:- receptor sensibilization (silent nociceptors)- central sensibilization
Two forms:- allodynia (normally not painful stimuli become painful:the touch of sunburned skin)
- hyperalgesia (stronger perception, less toleranceagainst noxious stimuli, permanent pain)
Silent nociceptors: perception only after sensitization
Basics
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How are nociceptors activated?Q2
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A,B
Nociception is based on the interaction of free nerve endingswith damaged cells, mast cells and capillaries.This induces additional depolarization by means of the released pain mediators
noxiousstimulus
capillaries
mast cells
synapticterminal
histamine
serotonin
bradykinin(from plasma kininogen)
(from plaxelets)
HR
BR
SR
K+
H+depolarization according to Nernst‘s equationdepolarization by H+-activated Na+ current
lesioned cells
1
2
3
Peripheral mechanisms
nociceptive neuron
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Another specific property of nociceptive neurons:The free endings in the sensory fiels not only serve perception and receive information through pain mediators, they also release peptide transmitters
('axon reflex')
nociceptive fiber
depolarization
release of -substance P
- CGRP
AP
Peripheral mechanisms
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The pain mediators bradykinin, serotonin and histamine facilitate the release of neuropeptides from the peripheral endings of nociceptive axons (substance P, CGRP). This leads to an enhancement of the nociceptive signals (positive feed-back)
C
substance PCGRP
SPR,CGRPR
noxiousstimulus
exozytosis
SPR,CGRPR
depolarization
lesioned cells
4
5
Peripheral mechanisms
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The lesioned cells themselves can liberate sensitizing substances. This also leads to a positive feedback signaling
D
substance PCGRP
SPR,CGRPR
noxiousstimulus
exocytosis
SPR,CGRPR
depolarization
lesioned cells
arachidonic acid
prostaglandine E2,leukotrienes
cyclo-oxygenase
7
6
Peripheral mechanisms
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KS
-200
1-21
-18The main endogenous pain mediators in humans
Peripheral mechanisms
sensitization
Pla
sma
kini
noge
n
Thr
ombo
cyte
s
Mas
t cel
ls,
leuc
ocyt
es
Cel
l dam
age
Cel
l dam
age
Cel
l dam
age
Effect on nociceptors
stimulus
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After sensitization, the pain (dolor) is accompanied by inflammation:
local heat (calor)reddening (rubor)swelling (tumor)
Please note:Not only pain, but also inflammation can beinduced by a neurogenic mechanism, i.e. in response to
- activation of specific receptors in the membrane ofnociceptive fibers: capsaicin acting on vanilloid receptors
- electrical stimulation of nociceptive fibers: elbow, tooth
Peripheral mechanisms
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How are nociceptive signals conducted to and processed in the spinal cord?Q3
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Nociceptive afferent fibers
The compound action potential after electrical stimulation of amixed nerve displays several components, according to differentconduction velocities (classification of fibers according to Erlanger/Gasser)
Electrical stimulation separates signals in nociceptive afferents signals, since they have higher thresholds and lower conduction velocities
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Simultaneous stimulation of non-nociceptive sensoryafferents can reduce the perception of nociceptive afferent signals (due to convergence + activation of inhibitory interneurons)
AcupunctureTENS(transcutaneous electrical stimulation)
III
IIIIV
V
VI
wide rangeneuron
specificnociceptive neurons
Aβ
Aδ
Cinhibitory interneuron
The termination in the spinal cord is fiber-specific
Spinal mechanisms
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The transmitter of nociceptive afferents in the dorsal horn is glutamate
Modulators of synaptic transmission and exitability are: - neuropeptides (substance P)- neurotrophins (NGF, BDNF)- endogenous opiates (enkephalines, β-endorphins, dynorphins)
glutamate
substance P
opiate
NMDAR AMPAR
Ca receptors for endogenous und exogenous opiates(morphine)
Spinal mechanisms
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Synaptically released endogenous opiates act via 3 classes of receptors (µ, δ, κ ) that are coupled to G proteins
Opiates cause - presynaptically: decrease gCa, increase gK- postsynaptically: increase gK- in the network: transmitter release bydisinhibition of enkephalinergic neurons
control
+opiate
control
+opiate
AP
EPSP
presynaptic terminal
postsynaptic site
G
G
Spinal mechanisms
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The mechanism of central sensitization (sensibilization, 'wind-up') is based, first of all, on an up-regulation of the number and open probability of NMDAR channels (LTP-like mechanism);This process is facilitated by NGF (nerve growth factor)
NGF
NMDAR AMPARCa signal
--> Increase of the discharge ratein the postsynaptic cell;In case of ongoing spontaneous activity -chronic hyperalgesia ('pain memory')
TrkA
Spinal mechanisms
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How are nociceptive signals processed above the level of the spinal cord?Q4
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Wie
den
, Spi
egel
(200
4) 1
6:18
0-18
2
The perception of pain also depends on the social environment. It is learned and stored in the pain memory
Supra-spinal pain mechanisms
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Supra-spinal pain mechanisms
Pain signals are orderly represented in the postcentral gyrus; changes after limb removal
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-Tr. spino-thalamicus(perception of where?)
-Tr. spino-reticularis(vigilance level)
-Tr. spino-mesencephalicus(emotional components; fear,due to connections to amygdala)
-Tr. spino-hypothalamicus(vegetative component)
At least 4 ascending systemsparticipate in the transmission of pain signals:
Supra-spinal pain mechanisms
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Nociception is, at all levels, under efferentcontrol. The latter plays a dramatic role in pain perception.
Opiate-containing neurons are localized in the - spinal dorsal horn- raphe-nuclei- central gray
As there is no re-uptake of opiates, they mediate more widespread reactions than other neurotransmitters.The endogenous opiates circulate in the blood ('enjoy by suffering')
Supra-spinal pain mechanisms
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The opiates circulating with blood act, first of all, by disinhibitinglocal enkaphalinergic interneurons
C afferent
spinal neuron
enkephalinergicneuron
GABAergic interneuron
efferent from central gray
If the 'brake' is removed, opiates are released and the transmission of nociceptive signals is reduced
Supra-spinal pain mechanisms
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Increased tolerance and addiction to opiatesare based on different mechanisms
Tolerance: reduced density of opiate receptorsAddiction: changes in the dopaminergic system of reward
Supra-spinal pain mechanisms
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Measurement of pain threshold
Methods
STL
-200
0-13
-3
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ST
L-20
00-1
3-7
Experimental sensitization by injection of a substance into theknee joint of an experimental animal; test response to flexion.
Injection
Methods
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BLK
S_2
004_
7.4
Methods
Experimentally induced hyperalgesia