Analgesics: Pain Pathways Flashcards
1
Q
what is pain referred to as?
A
a perception
2
Q
Define somatosensation.
A
Somatosensation is the sense of touch, including tactile stimulation, pressure, and vibration against the skin.
how we sense physical stimuli
3
Q
What is proprioception?
A
Proprioception is the perception of the position and movement of one’s body parts.
subcomponent of somatosensation
4
Q
What is nociception?
A
Nociception is our sense of tissue damage, which leads to pain.
not part of somatosensation
5
Q
True or False: Pain is the same as nociception.
A
False.
6
Q
How is pain defined?
A
Pain is defined as an unpleasant sensory or emotional experience associated with actual or potential tissue damage.
it is not a sensory input/ it is produced in the brain as a perception
7
Q
What is the relationship between nociception and pain?
A
Nociception is the neural signal of processing and encoding noxious stimuli that leads to the perception of pain.
8
Q
what is the difference between nociception and pain ?
A
nociception is a sensory input, pain is a peception (not an input)
9
Q
what are noxious stimuli ?
A
dangerous/damaging stimuli such as mechanical or heat
10
Q
What are nociceptive fibers?
A
Nociceptive fibers are sensory neurons that relay signals of tissue damage to the spinal cord and brain.
11
Q
List the two major classes of nociceptors.
A
- C fibers
- A fibers
12
Q
where are cell bodies of nociceptive fibres ?
A
dorsal root ganglion
13
Q
where do nociceptive fibres synapse ?
A
dorsal horn of spinal cord
synapse at different layers here
14
Q
What is the ascending pathway in pain processing?
A
The ascending pathway sends nociceptive signals from the spinal cord to the brain.
15
Q
what is the descending pain pathway ?
and what does this do ?
A
from brain to spinal cord
top-down control of pain helps modulate signals
16
Q
What is the purpose of feeling pain?
A
The purpose of feeling pain is to protect us and help us navigate our environment.
17
Q
What do nociceptors encode?
A
Nociceptors encode damaging or noxious stimuli as neural information
e.g. bee sting, burn, broken limb
18
Q
What does the brain do with nociceptive signals?
and what does this to for our behaviour ?
A
The brain perceives and interprets nociceptive signals as painful/dangerous
allows us to avoid the stimulus and protect from injury
input to the brain are all just APs
19
Q
if a stimulus is noxious, what do nociceptors do compared to when it’s not?
A
if it is noxious signal persists, if not we won’t get a signal
20
Q
Fill in the blank: Pain is a _______ generated centrally as a result of nociceptive signals.
A
perception
21
Q
What factors can influence the perception of pain?
A
- Strength of the stimulus (how many APs and persistance)
- Internal state of the individual
(* and external situation)
nociceptive information combines with information about internal state
22
Q
What is the role of descending pathways in pain modulation?
A
Descending pathways modulate pain signals sent from the brain back down to the spinal cord.
23
Q
What is the significance of the reflex action in response to pain?
A
Reflex actions allow for immediate responses to harmful stimuli to prevent injury.
24
Q
How does the brain differentiate between pain and other sensations?
A
The brain differentiates sensations based on the pathways that the action potentials take.
25
True or False: Pain can be sensed outside of the body.
False.
## Footnote
it is an internal CNS perception
26
examples of internal states that can affect our perception of pain ?
- attention
- arousal
27
How does attention affect pain perception?
Attention can alter the perception/interpretation of pain, making it feel less intense when focused on other tasks.
28
What is pain described as in the text?
An internal central nervous system perception
## Footnote
Pain cannot be sensed outside of the body.
29
What does pain perception combine?
Nociceptive information and information about the internal state
## Footnote
This combination allows for different interpretations of pain.
30
How does attention affect pain perception?
It can alter the way we feel pain depending on our focus
## Footnote
For example, we may not feel a cut if we are distracted.
31
Where does the integration of pain perception occur?
In higher brain centers
## Footnote
The brain combines various sensory signals to interpret pain.
32
What can change our perception of pain in different scenarios?
The external situation
## Footnote
Examples include battlefield injuries and pregnancy.
33
What happens to nociceptive input during critical situations?
It can be ignored subconsciously for a period of time
## Footnote
This has an evolutionary justification for survival.
34
What is an evolutionary reason for ignoring pain?
To allow escape from dangerous situations
## Footnote
Pain could immobilize us, making us vulnerable.
35
What elements contribute to pain perception?
Central elements and peripheral elements
## Footnote
Both types of elements integrate to form the final perception of pain.
36
True or False: Emotional connections can modulate the perception of pain.
True
## Footnote
Arousal and attention also play significant roles.
37
Fill in the blank: Pain perception is influenced by both the internal state of the body and the _______.
external situation
## Footnote
This influences how we experience pain.
38
types of nociceptors:
- Thermal
- Mechanical
- Polymodal
- Silent
## Footnote
send information from skin to spinal cord
39
thermal nociceptors
- Hot/cold (>45 degrees or <10 degrees)
- Adelta fibres
40
Mechanical nociceptors
- sense squeezing, stretching, penatrating skin
- sharp, intense pain
- Adelta fibres
41
A delta nociceptive fibres
- myelinated
- fast signal
42
Polymodal nociceptors
- dull, diffuse, burning pain
- C fiber
43
Silent nociceptors
- visceral swelling/ distension
- intense, poorly localised pain
- don't need to know exact location
- C fiber
44
C fiber
unmyelinated, slower
45
Mechanical nociceptors in test
1. no response to strong pressure from blunt probe (we still sense it but it is not a noxious stimulus so no response from afferent nociceptive fibres)
BUT
2. (pinprick) equal pressure over a small area (sharp) gives a robust response (afferent Adelta nociceptor fibres fire, rapid onset of response and fire for duration of response)
3. Even stronger response by pinching (damaging tissue) over larger area (stronger output from Adelta fiber, more APs) (APs fired is proprtion to amount of damage that could occur)
## Footnote
afferent fibres - up into the brain
46
what do heat-sensing A-delta fibres express?
a family of 6 TRPs
## Footnote
transient receptor potentials = TRPs
47
what do TRPs do ?
- respond to either low or high threshold temperatures (cover range of temps)
- respond to various chemical compounds in foods e.g. garlic, chillies, THC
48
what TRP channels are related to detection of low temperatures ?
TRPA1
TRPM8
49
what TRP channels are related to detecting high threshold temperatures ?
TRPM3
TRPV3
TRPV1
TRPV2
50
what TRP channel can be used for detecting ambient temperatures ?
TRPV4
51
What are the two major pathways that allow activation of nociceptors ?
- cental pathway
- positive feedback loop
52
nociceptor activation via the central pathway
1. tissue damage occurs
2. local release of inflammatory mediators
3. Activates nociceptor (A-delta)
4. AP travels through DRG and provides sensory input to spinal cord
5. Synapses on neuron in spinal cord; ascends
53
what is the positive feedback loop for in nociceptor activation ?
- allows potentiation
- allows inflammation to occur
54
what happens in the postive feedback look for nociceptor activation ?
1. activated A-delta fibre may have branched points, which will propagate APs
2. Branch points can terminate locally (in tissue) with the release of compounds such as substance P (SP) or CGRP
3. Substance P stimulates activation of granular immune cells (mast cells, neurtophils) to release histamine (degranulation)
4. CGRP and SP dilate local peripheral blood vessels
55
what is Substance P (SP) ?
neuropeptide
56
what is CGRP ?
calcitonin-gene related peptide
57
what does histamine do in the positive feedback loop for nociceptors ?
release drives activation of A-delta fiber (and vasodilation, recruit immune cells etc.)
58
what does local inflammation lead to ?
- neurogenic inflammation
- which leads to mechanical hyperalgesia (part of neurogenic inflammation)
59
what is neurogenic inflammation ?
local inflammation at tissue level
60
how does neurogenic inflammation occur ?
## Footnote
at a local level in tissue
- spreads through mediators (e.g. histamine)
- we start to produce prostaglandins from COX enzymes
- these all spread rom inital site of damage
61
what are prostoglandins produced by ?
COX enzymes
62
what does neurogenic inflammation lead to ?
mechanical hyperalgesia
- spreading of nociceptive signal around initial site
63
what is mechanical hyperalgesia ?
sensitivity of skin around site is higher, more painful close to wound due to local inflammation turning into neurogenic inflammation
| it is part of neurogenic inflammation
## Footnote
threshold for pain where burn is decreases, less stimulus to feel pain
64
what is mechanical hyperalgesia for ?
to further protect damaged region by making it more sensitive
| protective reflex
65
the neurotransmission of pain
- primary afferent neurons sense noxious stimulus (e.g. C fiber or A-delta)
- signal transmitted to spinal cord from dorsal root ganglion (where primary afferent neurons synapse onto secondary afferents)
- through secondary afferent neurons in the spinal cord dorsal horn to the brain
66
what are the two primary neurotransmitters involved in pain signalling ?
- Glutamate (Glu)
- Substance P (SP)
67
where can we find Glu and SP and where do these transmit to ?
in vesicles of DRG cells (e.g. C fiber) which is co-released onto dendrite of second order neuron (secondary afferent) in the spinal cord
68
what is the affect of glutamate in the first order neuron potentiated by ?
the depolarisation of the second order neuron provided by substance P
69
what happens when substance P is released onto second order neuron ?
SLOW depolarization of post synaptic membrane which prolongs the action of glutamate
70
why is depolarization of substance P slow and what may this explain ?
- it is not rapidly broken down
- similar to paracrine signalling (released onto adjacent target cell and sits there for a long time causing slow depolarisation of target cell)
- diffuses laterally (out of synapse) through paracrine action which may stimulate nearby synapses
- may partially explain why pain can be difficult to localise
71
why are some pathologies associated with abnormal regulation of pain ?
Substance P can be upregulated in various pathological states, so may get increased amounts of substance P
72
what may C-fibre 'wind up' contribute to?
to the way in which we percieve pain and temporal summation
73
what is C-fibre 'wind up' associted with?
the repetitive activation of C fibres (not a-delta !) which causes them to have increased excitability ('wind up')
74
what happens in spinal cells as a result of C-fibre 'wind up' ?
the firing rate of spinal cells (secondary neurons) can be increased in response to the same nociceptive input
- this is a form of sensitization as a result of the C fibres
## Footnote
repetitive activation of C fibres (through repeated stimulation) increases the excitability of second order neurons
75
what is temporal summation in pain perception and how does this relate to C-fiber wind up?
we get an increase in pain perception when a stimulus is repeated (due to increased excitability of second order neurons (more APs) as a result of repetitive activation of C fibres)
## Footnote
this does not happen with A-delta fibres
76
what neurotransmitters do A-delta or A-beta fibres release ?
Glutamate
77
what neurotransmitters do C fibres release ?
Glutamate and Substance P (SP)
78
C-fibre 'wind up'
- A-delta and beta fibres we get slight depolarisation of post-synaptic membrane: largley though AMPA receptors as NMDA are bloked by Mg 2+ at resting potential (ion only rleased by strong depolarisation)
- influx of Na+ ions through AMPA receptors
- delayed signal from C-fibre comes in, influx of Calcium into terminal causes release of Glu and SP
- release of SP binds to NK1 receptors and we have a stronger depolarisation meaning magnesium can be removed from NMDA receptors and Glu can bind to NMDA (dual action)
- this causes calcium influx into PSN, affecting other membrane ion channels, making PSN (second order neuron) more likely to fire
79
why is A-delta fibre depolarisation through AMPA and not NMDA ?
not a large enough depolarisation to dislodge magnesium ion that blocks NMDA receptors at resting potential
80
what is congential pain insensitivity ?
- a genetic abnormality that causes an indivudal to be insensitve to pain
- due to autosomal recessive mutations
81
what is the result of congential pain insensitivity ?
loss of physiological as well as pathological pain sensation
## Footnote
e.g. cannot detect severe damage such as broken bones or often burn themelves drinking hot drinks
82
what are sodium channel mutations ?
a rare condition involving the gene SCN9A that codes for voltage gated sodium channel NaV1.7
83
What do sodium channel mutations cause ?
people with this have an otherwise normal phenotype but are insensitive (cannot detect) or indifferent (can ignore) to stimuli that would be painful to other individuals
84
what does the NaV1.7 channel do ?
plays an important role in dorsal root ganglion nociceptive neruons
## Footnote
which explains how mutations in these cannels can abolish pain sensations
85
what is FAAH-OUT ?
a gene associated with the endocannabinoid system
86
what does the FAAH-OUT mutation cause ?
- very high levels of anandamide
- hence pain insensitivity
## Footnote
only been found in one indivudal
87
what is diabetic neuropathy ?
- long term uncontrolled diabetes that leads to nerve damage (neurpathy)
88
what are the stages of diabetic neuropathy ?
- legs and feet are often first tissue to be affected
- damage to sensory neurons manifests as pain: paraesthesia (pins and pain)
- constant pain
- later stages pain sensation is lost due to comprimised immune system, poor circulation and poor wound healing
89
why is diabetic neuropathy a common cause of amputation ?
lack of pain sensation means diabetics may not detect damage to the feet resulting in infected wounds that don't heal
90
ascending pathway
from periphery to the bain
## Footnote
afferents = ascending
91
descending pathway
brain down to spinal cord
## Footnote
'top-down' control
92
what kind of modulation do nociceptive signals show ?
bidirectional
93
what is pain information encoded by ?
afferent neurons in periphery
94
what are A-delta fibres for ?
nociceptive
95
what are A-beta fibres for ?
mechanoreceptive
## Footnote
pressure/vibration etc.
96
where do A and C fibres go ?
project information through DRG (where cell bodies of these first order neurons are) onto second order neurons at various laminae of the dorsal root (in the spinal cord) which project to the brain stem or thalamus and up into the brain (ascending pathway)
97
what kind of matter is the dorsal horn ?
grey matter
## Footnote
cell bodies and dendrites
98
how can we modulate C fibre input and what does this do ?
- through integration of nociceptive and non-noiciceptive information (fom mechanoreceptors)
- the 'Pain Gate'
- modulates pain
99
what is the 'Pain Gate' ?
- wall & Melzak
- nociceptive C fibre directly excites projection neuron (second order neuron) which send pain signal
- at the same time C fibre inhibits spinal inhibitory interneuron (disinhibition) which indirectly excites second order projection neuron
- at the same time we also have A-beta (non-nociceptive) fibre also excites projection neuron and excites inhibitory interneuron
- excitation of the inhibitoy interneuron via the non-nociceptive fibre dampens the pain signal from the second order projection neuron (e.g. rubbing a wound)
## Footnote
rubbing a wound better to make it feel less painful
100
summarise the 'Pain Gate' in a sentance
activating low-threshold non-nociceptive A-beta fibres reduces pain signal from C fibres
101
what is referred pain ?
poor localisation of pain
- we feel pain away from the site of injury at a distal part of the body
102
where do we often get referred pain ?
viscera with silent nocicpetors and some areas of the skin that lack fine sensory input (areas with less nociceptors)
103
what is an example of referred pain ?
when intestinal pain is sensed through silent nociceptors on a distal part of the skin because they snapse at the same projection neuron as noiciceptive input from the distal site e.g. skin
104
where do we often get referred pain from a myocardial infraction ?
often felt away from the heart e.g. jaw
## Footnote
due to synapsing on same projection neuron and feeling pain distally where there is no injury
105
what is the importance of the spinothalamic pathway ?
major ascending pathway of CNS
106
spinothalamic tract
from the spinal cord through brain stem into thalamus and then projections to the rest of the brain
(spinal cord -> crosses to contralateral side -> ascends through medulla -> pons (brain stem) -> thalamus -> into rest of brain)
107
what is the difference between nociceptive input and somatosensory input in the spinal cord ?
nocicieptive input crosses over in the spinal cord, somatosensory input ascends first then crosses over in the brain
108
what happens after noiciceptive information is processed and encoded in the thalamus ?
projects to somatosensory cortex and other areas such as the cingluate cortex
109
what allows us to modulate nociceptive input and pain perception ?
descending and ascending pathways
110
what are descending pathways?
from brain to spinal cord
111
where does descending control stem from and where does this project down to?
## Footnote
descending pathway
- Insular cortex (IC), hypothalamus (H), amygdala
- to periaqueductal grey (PAG) in midbrain
112
where to PAG neurons project down to ?
## Footnote
descending pathway
rostral ventromedial medulla (RVM)
113
wher to RVM neurons project down to ?
## Footnote
descending pathway
second order neurons in spinal cord
114
waht is the purpose of the descending pathway ?
can modulate how second order neurons respond to A/C fibre input
## Footnote
similar to the pain gate (modulation of second order neurons) so we don't feel pain endlessly
115
what are some pieces of evidence for top down modulation (descending pathways) ?
- Electrical stimulation of PAG leads to profound and selective analgesia without a loss of sensation
- effect of opiods both endogenous and exogenous modulate and dampens down pain signals
- PAG signals throufh NEergic neruons in LC and 5HTergic in Raphe which drives spinal interneurons and decreases excitability of projection neurons
116
what kind of interneurons does PAG activation of Nergic and 5HTergic drive ?
## Footnote
top down modulation
activates enkephalin-containing spinal interneurons (inhibitory)
117
what is enkephalin ?
## Footnote
top down modulation
endogenous opiate
118
what does enkephalin do in terms of top down modulation?
## Footnote
top down modulation
decreases excitability of projection neurons passing on noiciceptive information
119
what happens when enkephalin is released into synapse between noiciceptive neuron and projection neuron and what does this do for pain perception?
decrease excitability of projection neuron by decreasing calcium influx pre and post synaptically, dampening down the ability for the projection neuron to pass on nociceptive information, reducing pain perception going afferently to the brain
120
where si the dorsal root ganglion ?
just outside of the spinal cord
## Footnote
where cell bodies of primary afferent neurons are
121
what two brain regions involved in the PAG descending control contain neurons that help modulate nociception in the spinal cord ?
Raphe Nuclei
Locus coeruleus
122
Which two neurotransmitters are responsible for signalling from DRG neurons to spinal cord neurons?
glutamate and substance P
123
what are 3 mast cell mediators and what is not a mast cell medaitor ?
mediators: ATP, serotonin, histamine
NOT: enkephalin as it is an endogenous opiod
124
where does the spinothalamic tract cross the midline
in the spinal cord
125
what doesa TRPM8 respond to ?
- temperatures between 8-28C
- (L-) methanol
126
what does TRP1A respond to ?
low temperatures
127
what do the TRPV channels respond to ?
painful heat
