Chronic Pain Flashcards
(309 cards)
1
Q
Give three general large categories of causes of neuropathic pain. (3)
A
- Diseases and infections
- Drug treatment
- Direct traumatic injury to nerves
2
Q
Give three diseases/infections which are known to cause neuropathic pain. (3)
A
- Diabetes
- Herpes zoster (shingles; especially in AIDS sufferers)
- Sickle cell disease
3
Q
Very briefly describe how diabetes may cause neuropathic pain. (1)
A
High levels of circulating glucose associated with nerve damage.
4
Q
Give the common name for neuropathic pain experienced following shingles. (1)
A
Post-herpetic neuralgia
5
Q
Describe how the intensity and persistence of post-herpetic neuralgia changes with age. (1)
A
Intensity and persistence increase with age
6
Q
Very briefly describe two ‘types’ of pain experienced by people with sickle cell disease. (2)
A
Acute pain episodes
Chronic ongoing pain with neuropathic features
7
Q
Give two drug treatments which may cause neuropathic pain. (2)
A
Chemotherapeutic agents for cancer treatment
Anti-retroviral drug therapy in AIDS
8
Q
Describe why neuropathic pain may be particularly troublesome when caused by chemotherapy. (1)
A
Because pain may limit the dose that can be used.
9
Q
Give two specific examples of direct traumatic injury to nerves which can cause neuropathic pain. (2)
A
High velocity gunshot wounds
Brachial plexus avulsion (in particular, motor cyclists)
10
Q
Fill the gaps relating to neuropathic pain. (6)
The neuropathic syndrome is the end result of an ……………………….. disease combined with individual contributing factors, such as …………………….. and ……………………, two examples of which are …………………….. and ……………………
All of these lead to individual combinations of …………………………, manifesting as an individual neuropathic pain phenotype.
A
initiating
genotype
environmental factors
diet
lifestyle
pathophysiological mechanisms
11
Q
Give a ‘negative symptom’ of neuropathic pain. (1)
A
Numbness
12
Q
By which mechanism does numbness occur in neuropathic pain? (1)
A
Deafferentation
13
Q
Give four ‘positive symptoms’ of neuropathic pain. (4)
A
Hyperpathia
Paraesthesia
Tenderness to stimuli
Referred pain
14
Q
What is meant by ‘hyperpathia’ when talking about neuropathic pain? (1)
A
Explosive, electric shock-like pain
15
Q
What is meant by ‘paraesthesia’ when talking about neuropathic pain? (1)
A
Abnormal but not painful sensation (eg. pins and needles)
16
Q
Give another name for the ‘tenderness to stimuli’ often experienced in neuropathic pain. (1)
A
Mechanical and thermal allodynia
17
Q
What is meant by ‘referred pain’ when talking about neuropathic pain? (1)
A
Abnormal spread of pain
18
Q
Give two types of mechanical allodynia experienced in neuropathic pain. (1)
A
Dynamic brush-evoked pain
Static mechanical pain
19
Q
Dynamic brush-evoked pain/allodynia is mediated by which type of nerve fibre in neuropathic pain? (1)
A
Ab fibres
20
Q
Static mechanical pain/allodynia is mediated by what type of nerve fibres in neuropathic pain? (1)
A
High threshold non-noxious Ad fibres
21
Q
Fill the gaps relating to pain symptoms in neuropathic pain. (3)
Brush-evoked pain correlates with overall levels of …………………. pain, and also other types of hyperalgesia, such as ……………….. and …………………. hyperalgesia.
A
ongoing
cold
hot
22
Q
Give two types of nerve damage mechanisms associated with neuropathic pain. (2)
A
Segmental dysmyelination/demyelination
Axopathy
23
Q
Describe what is meant by ‘axopathy’ when talking about neuropathic pain. (1)
A
Metabolic and axoplasmic transport deficits due to transection.
24
Q
What is the test called that can assess neuropathic pain and central sensitisation in clinical practice? (1)
A
Quantitative sensory testing
25
Very briefly describe what it meant by 'quantitative sensory testing'. (1)
Psychophysical test used to determine peripheral/central mechanisms of pain
26
Give four specific tests that are carried out during quantitative sensory testing. (4)
Pain pressure thresholds
Thermal thresholds
Cold pressor evoked pain
Pin-prick
27
Give three pain mechanisms that can be assessed during quantitative sensory testing. (3)
- Local vs referred pain mechanisms
- Temporal summation
- Changes in descending control pathways
28
Give three specific pain conditions/diagnoses which can be evaluated using quantitative sensory testing. (3)
Which condition was it first developed for? (1)
- Arthritis
- Neuropathic pain (FIRST DEVELOPED)
- Sickle cell disease
29
Fill the gaps relating to quantitative sensory testing. (6)
There is evidence for neuropathic pain mechanisms in a proportion of people with .........................., ........................., and ...........................
QST is useful for quantifying ................................, which may help treatment selection.
QST is used alongside ............................., and can also be used experimentally alongside .............................
sickle cell disease chronic pain
osteoarthritis pain
cancer pain
central sensitisation
questionnaires
imaging
30
Give two drawbacks of using quantitative sensory testing in clinical practice. (2)
- Labour intensive and can be quite a long process for patients (not suitable for GP assessment)
- Involves stimulating cutaneous structures (could evoke acute episode)
31
Neuropathic pain can show mechanisms of stimulus-independent, and stimulus-induced pain.
Describe what is meant by both stimulus-independent and stimulus-induced pain. (2)
Stimulus-independent refers to ongoing/spontaneous pain.
Stimulus-induced refers to hyperalgesia.
32
Describe ongoing/spontaneous pain in neuropathic pain, in terms of:
a) stimulus modality that triggers it
b) afferents involved
c) possible mechanisms at play
(3)
a) none
b) nociceptors (Ad and C)
c) ectopic neuronal activity
33
Describe thermal pain in neuropathic pain, in terms of:
a) stimulus modality that triggers it
b) afferents involved
c) possible mechanisms at play
(6 - there are two points for each)
a) heat and cold
b) C nociceptors and cold-sensitive C nociceptors
c) sensitisation of nociceptors (peripheral sensitisation) and central disinhibtion
34
Describe chemical pain in neuropathic pain, in terms of:
a) stimulus modality that triggers it
b) afferents involved
c) possible mechanisms at play
(3)
a) noradrenaline (mediated by SNS)
b) nociceptors
c) increased expression of a adrenoreceptors
35
Describe mechanical pain in neuropathic pain, in terms of:
a) stimulus modality that triggers it
b) afferents involved
c) possible mechanisms at play
(9 - there are three points for each)
a) light touch, pin prick, blunt pressure
b):
light touch = Ab fibres
pin prick = Ad fibres
blunt pressure = nociceptors
c):
light touch = central sensitisation
pin prick = central sensitisation
blunt pressure = sensitisation of nociceptors
36
Fill the gaps relating to neuropathic pain. (4)
One issue in neuropathic pain is that sensory fibres such as Ab fibres, are detecting ......................... stimuli, however when the signal gets to the spinal cord, it is being interpreted as .......................
In pain treatment we usually look at inhibiting ..................... while leaving .................... intact. This treatment would not work in this situation.
non-noxious
painful/nociceptive
C fibres
A fibres
37
In neuropathic pain and central sensitisation, Ab fibres are recruited to pain pathways, meaning normally innocuous stimuli are now interpreted as noxious.
Explain why this causes issues with treatment. (2)
Because in pain treatment we usually target C fibres, while leaving A fibres intact (so we can still receive touch input)
so Ab fibres are difficult to target directly, without affecting function.
38
Give a potential biomarker for neuropathic pain. (1)
microRNAs
39
Why would it be helpful to have biomarkers for neuropathic pain? (1)
They may help stratify patients for treatment
40
What are microRNAs? (1)
Non-coding sequences which regulate post-transcriptional gene expression.
41
Give two reasons why microRNAs may appear good biomarkers for neuropathic pain. (2)
- Relatively stable
- Present in most biofluids (fairly easy to measure)
42
Fill the gaps relating to microRNAs. (5)
microRNAs bind to target .................. and cause ..................... or inhibit ..................... of the target molecule.
They may also directly activate some ..................... and may be a means of ......................... between cells.
mRNA
degradation
translation
receptors
communication
43
Briefly describe current evidence regarding microRNAs as biomarkers for neuropathic pain. (2)
Multiple studies suggesting potential utility of microRNAs as useful biomarkers of neuropathic pain
however lack of reproducibility of data limits usefulness (different results regarding which specific miRNAs may be useful).
44
Give four general animal models of neuropathic pain. (4)
Damage to sciatic nerve
Diabetic neuropathy
Streptozotocin (STZ)
Chemotherapy induced neuropathy (Taxol)
45
Briefly describe what is meant by a 'traumatic' animal model of neuropathic pain. (1)
Causing partial injury or damage to the sciatic nerve
46
Briefly describe what is meant by a 'non-traumatic' animal model of neuropathic pain. (1)
Give three examples of non-traumatic models. (3)
Not causing direct damage or injury to nerves.
- Diabetic neuropathy
- Streptozotocin (STZ)
- Chemotherapy (Taxol)
47
Give three specific examples of traumatic animal models of neuropathic pain, where damage is inflicted on the sciatic nerve. (3)
- Chronic constriction injury (CCI)
- Partial sciatic nerve or spared nerve injury (SNI)
- Selective spinal nerve ligation (SNL)
48
Describe what is meant by selective spinal nerve ligation, when inducing animal models of neuropathic pain. (1)
Lesioning one of the spinal roots of the sciatic nerve.
49
Describe what is meant by spared nerve injury, when inducing animal models of neuropathic pain. (1)
Lesioning one of the branches of the sciatic nerve (eg. tibial, peroneal, or sural nerve)
50
Microneurography studies in humans and rats can compare animal models of neuropathic pain to that experienced in humans.
What could you measure in these studies to compare human and animal 'experiences'? (1)
Spontaneous activity in nociceptors (number of spontaneously active fibres as a percentage of total fibres)
51
Microneurography studies in humans and rats can compare animal models of neuropathic pain to that experienced in humans.
They measured the number of spontaneously active nociceptors as a percentage of the total number of nociceptor fibres.
Compare animal studies to the clinical problem seen in humans. (1)
Draw a conclusion. (1)
Animal models result in more spontaneously active fibres than humans.
They may not be reliable.
52
A systematic review looked at the literature surrounding spontaneous activity in peripheral sensory nerves.
Give two issues that this review found in investigating spontaneous activity in experiments. (2)
- Majority of data collected for non-humans was male rodents
- Study approaches were quite heterogenous
53
A systematic review looked at the literature surrounding spontaneous activity in peripheral sensory nerves.
They classified animal models differently to the traumatic or non-traumatic classification which is widely used.
How did they classify the types of animal models? (2)
Non-regenerating (ligation)
Regenerating (crush)
54
A systematic review looked at the literature surrounding spontaneous activity in peripheral sensory nerves in humans and animal models.
What were the overall conclusions of this paper? (2)
There were higher levels of spontaneously active fibres after nerve injury in both humans and animals.
So experimental conditions may be reasonably compared to clinical situations.
55
What is meant by 'ectopic activity' when referring to peripheral nerves following nerve injury? (1)
Spontaneous firing without a known trigger
56
Describe the firing pattern of spontaneous activity in peripheral nerves after nerve injury. (2)
Irregular bursts
almost like 'pacemaker activity'.
57
Fill the gaps relating to ectopic activity in neuropathic pain. (3)
Onset of ectopic activity arising from injured ....................... afferents correlates with onset of changes in behaviour.
Ectopic activity may initiate ............................., such as ........................... which is seen clinically.
A fibre
spontaneous pains
paraesthesia
58
Fill the gaps relating to neuropathic pain. (3)
Desensitisation of ......................., which are sensitive to ..........................., does not alter mechanical allodynia, but does increase thermal nociceptive thresholds.
These findings implicate a role for .................... in mechanical allodynia.
C fibres
capsaicin
A fibres
59
Name two general types of ion channels which may contribute to ectopic activity of injured peripheral nerves. (2)
- Sodium channels
- Potassium channels
60
Altered expression and activity of which three sodium channels may contribute to ectopic activity in injured peripheral nerves? (3)
Nav1.3
Nav1.8
Nav1.9
61
Changes in expression and activity of Nav1.3, Nav1.8, and Nav1.9 may have what effect on peripheral nerves? (2)
Cause sub-threshold membrane potential oscillations
which may contribute to ectopic activity.
62
Describe the normal expression of Nav1.3, and how this is changed after nerve injury. (2)
Normally expressed during development
but after nerve injury is expressed in adult.
63
Describe the significance of Nav1.3 being expressed in adult neurones after nerve injury. (3)
*Nav1.3 usually expressed during development
Nav1.3 has fast gating kinetics
which lead to depolarising after-potentials/oscillations
and these kinetics allow the neurone to fire repeatedly at high frequencies.
64
Fill the gaps relating to Nav channels and neuropathic pain. (2)
Nav1.7 is universally expressed by ........................., and gain of function mutations lead to .................................
sensory neurones
ectopic activity in C fibres
65
Fill the gaps relating to neuropathic pain. (4)
KCNK is a family of .............................., which are abundantly expressed in ..................................
They regulate the ........................... and regulate spontaneous firing by controlling ................................
Another name for KCNK channels is ........................
leak potassium channels
neuronal and non neuronal tissues
maximal firing frequency
the hyperpolarisaion
K2P channels
66
Name two types of KCNK/K2P channel which may be involved in neuropathic pain. (2)
TRESK
TREK-2
67
Fill the gaps relating to neuropathic pain. (4)
TWIK-related spinal cord K channel, abbreviated to ......................., is a .................. channel with a particularly enriched role in ........................... and in vivo ....................................
TRESK
K2p/KCNK
sensory neurones
pain pathways
68
Describe how TRESK channels are involved in neuropathic pain and changed after nerve injury. (2)
Changes in neuropathic pain models are complicated
but TRESK is down-regulated by 40% after nerve injury
69
Which two K2P channels regulate 85% of background K+ activity in dorsal root ganglion neurones? (2)
TRESK
TREK-2
70
A study by Weir et al (2019) investigated TRESK expression and the effects of ablating TRESK.
They found that TRESK mRNA is present in which 2 nerve fibre types? (2)
They also found that ablation of TRESK resulted in what effect on sensory neurones? (1)
How was this effect amplified? (1)
C and Ad fibres
hyperexcitability
by inflammatory challenge
71
Fill the gaps relating to a study by Wang et al (2023) regarding potassium channels and neuropathic pain. (2)
They found that rescuing downregulation of .......................................... in injured DRG neurones alleviated nerve injury-induced ..................................
calcium-activated potassium channel subfamily N member 1 (KCNN1)
nociceptive hypersensitivity
72
What would you expect the general effect to be of inhibiting or downregulating potassium channels in nociceptive afferents? (1)
Hyperexcitability
73
Very briefly describe a non-invasive way of investigating the role of potassium channels in pain (in rodents). (3)
Use a photoswitchable inhibitor
of TREK K channels
which becomes active and inhibits K channels only at certain wavelengths of light.
74
A study developed a photoswitchable inhibitor of TREK channels (called LAKI) and used it to investigate pain behaviour in rodents.
Describe the effects you would expect to see on nocifensive behaviour when LAKI is activated by light. (1)
Increases nocifensive behaviour
75
A study developed a photoswitchable inhibitor of TREK channels (called LAKI) and used it to investigate pain behaviour in rodents.
Describe the effects you would expect to see on mechanical withdrawal thresholds when LAKI is activated by light. (1)
Decreased mechanical withdrawal thresholds.
76
Describe how levels of TRPV1 are altered after nerve injury (SNL or PSL) in:
a) damaged DRG neurones
b) undamaged DRG neurones
(2)
a) significantly reduced
b) increased expression
77
Levels of TRPV1 changes in neurones following nerve injury.
Where specifically in the neurones has this been observed? (1)
Somata
78
Which type of nerve fibre (damaged/undamaged; A/C) shows the greatest level of increase of TRPV1 expression after nerve injury? (1)
Undamaged A fibres
79
Fill the gaps relating to TRPV1 and nerve injury. (4)
Changes in levels of TRPV1 in undamaged afferents may contribute to ..................................
TRPV1 activation threshold is modified by ............................ - it is possible that this occurs ........................... (location), not just at ........................... (location)
neuropathic pain behaviour
inflammatory mediators
across the whole nerve
terminals
80
Suggest a possible way to directly manipulate TRPV1 in order to treat pain. (1)
Why is this treatment not used in clinical practice? (1)
TRPV1 antagonists
They are associated with hyperthermia in studies (on target side effect)
81
Describe a way of indirectly modulating TRPV1 which could potentially treat pain. (4)
Inhibit kinases (p38/PKCe)
which modulate TRPV1 activity
and because NGF contributes to activation of kinases
you could sequester NGF
82
Describe the evidence surrounding sequestering NGF as a strategy for treating neuropathic pain. (1)
Unclear if sequestering NGF is a good strategy
83
When in life is the usual onset of pain in sickle cell disease? (1)
Early/late adulthood
84
Briefly describe the cause/mechanism of pain in sickle cell disease. (3)
Damage to peripheral nerves
due to vaso-occlusion
due to beta-hemoglobinopathies.
85
Give three general characteristics of acute pain in sickle cell disease. (3)
Sharp
Throbbing
Unpredictable
86
Give three cell types which are involved in acute pain in sickle cell disease. (3)
Endothelial
Macrophages
Nerves
87
How long does chronic sickle cell disease pain last? (1)
> 3 months
88
Give four general characteristics of chronic sickle cell disease pain. (4)
- Deep
- Achy
- Persistent
- Negative impact on mental health
89
Name a mouse model that could be used to investigate mechanisms of sickle cell disease pain. (1)
Berkeley SCD mice
90
Give two findings regarding TRPV1 and pain that have been seen in Berkeley sickle cell disease mice. (2)
Increased TRPV1 sensitivity of dorsal root ganglion neurones.
They exhibit mechanical allodynia which is blocked partly by TRPV1 antagonist.
91
Gene polymorphisms in which receptor/ion channel may influence acute pain crisis in sickle cell disease? (1)
TRPA1
92
Describe briefly the general mechanism of how microRNAs may be involved in the development of neuropathic pain. (1)
Regulation of voltage-gated Na channels
93
Give three examples of microRNAs which are thought to be involved in neuropathic pain. (3)
miR-7a
miR-30b
miR-182
94
Describe two experimental findings which may describe how miR-7a may be involved in neuropathic pain. (2)
- Downregulated in neurones of injured DRGs
- Over-expression suppresses increases in excitability of nociceptive neurones
95
Briefly describe how miR-30b may be involved in neuropathic pain. (1)
Regulates Nav1.7 expression in neuropathic rats
96
Briefly describe how miR-182 may be involved in neuropathic pain. (1)
Alleviates SNI-induced neuropathic pain through regulating Nav1.7
97
A study assessed the effects of miR-30b overexpression on Nav1.7 expression, colocalisation between miR-30b and Nav1.7, and effects of injecting miR-30b intrathecally on neuropathic pain behaviour.
Describe the results. (3)
miR-30b overexpression leads to downregulation of Nav1.7.
Nav1.7 and miR-30b colocalise in normal DRG neurones.
Intrathecal injections of miR-30b attenuates neuropathic pain behaviour (and expression of Nav1.7 (SCN9A)).
98
Fill the gaps relating to spinal plasticity after peripheral nerve injury. (8)
There is strengthening of synaptic input from ............................. and ................................. onto ............................ This amplifies the pain signal.
There is a ........................... in threshold, an .......................... in spatial extent, and a change in ............................ characteristics.
There is recruitment of ................................. to the nociceptive pathway, and this is an important aspect of .....................................
nociceptors
low-threshold mechanoreceptors
dorsal horn neurones
reduction
expansion
temporal
normally-innocuous afferent inputs
central sensitisation
99
Describe how calcium channels may be altered in the spinal cord in neuropathic pain. (1)
Why are these calcium channels important? (1)
Increased expression and function of pre-synaptic N type calcium channels on nociceptors
which are important for vesicular release and synaptic transmission.
100
Give two ways that excitation in the spinal cord may be altered during neuropathic pain. (2)
- NMDA receptors activated
- Decreased expression of glutamate transporter = decreased clearance of glutamate in spinal cord
101
Give two ways that inhibition in the spinal cord may be altered during neuropathic pain. (2)
Loss of GAD (glutamate decarboxylase) which converts glutamate into GABA in interneurones.
Small interneurones more vulnerable to excitotoxicity.
102
Fill in the gaps, relating to results from animal models investigating loss of inhibition in the spinal cord. (10)
Blockage of spinal GABA or ..................... results in behavioural ......................... in rats.
GABA blockade recruits previously absent .................. inputs onto lamina ................ neurones. This uncovers previously silent synaptic pathways, and shows that GABA plays a fundamental role in regulating ...................... and ...................... in the spinal cord.
Nerve injury reduces spinal .......................... synaptic currents due to apoptosis of ............................
....................... reduces GABAergic interneurone activity via ......................
glycine
allodynia
Ab fibre
II
connectivity
signalling
GABAergic
GABAergic inhibitory interneurones
TNFa
p38
103
Which immune cell type infiltrates the site of nerve injury and distal sites? (1)
Why is this cell important? (1)
Macrophages
Important source of immune mediators
104
Fill the gaps relating to immune cells and neuropathic pain. (4)
..................... cells are activated within the spinal cord at the ......................................
Two examples of these cells are ......................... and ..........................
Immune-like glial
termination areas of the injured sensory afferents
microglia
astrocytes
105
True or false? Explain your answer if necessary. (1)
Microglia in the spinal cord can be referred to as 'central monocytes'.
False - they are referred to as central macrophages
106
Give two conditions required for microglial activation in the spinal cord in neuropathic pain. (2)
- Axonal injury
- Nociceptive drive
107
Do microglia in the spinal cord contribute to the initial or maintenance stage of chronic pain? (1)
Initial
108
At which stage of chronic pain states do astrocytes play an important role? (1)
In later stages
109
Give six examples of signalling molecules which glial cells express receptors for in the CNS. (6)
Substance P
Essential amino acids (EAAs)
CGRP
ATP (P2X7 receptor)
Prostaglandins
NO
110
Name a type of adaptive immune cell which gets recruited into the dorsal horn in neuropathic pain. (1)
CD4+ T cells
111
What is the role of CD4+ T cells in the spinal cord following neuropathic injury? (1)
Give an example. (1)
Release cytokines which activate microglia.
Example: interferon y
112
True or false? Explain your answer if necessary. (1)
Glial cells are important sources of neurotrophic factors in neuropathic pain.
True
113
Give two important sources of neurotrophic factors following neuropathic injury. (2)
Peripheral tissue
Glial cells
114
Name two cell types which synthesise NGF and are important sources in nerve injury. (2)
Schwann cells
Immune cells
115
True or false? Explain your answer if necessary. (1)
The dorsal root ganglia (DRGs) make BDNF, which is released from peripheral terminals of afferent fibres.
False - it is released from central terminals of afferent fibres
116
Describe how synthesis of BDNF is altered following nerve injury in peptidergic neurones and large diameter neurones. (2)
Peptidergic = BDNF synthesis declines
Large diameter = BDNF synthesis increases
117
BDNF and mediators from activated microglia promote what change in the dorsal horn following neuropathic injury? (1)
Increased excitability
118
What would be the effect of sequestering BDNF on dorsal horn excitability? (1)
Reduced
119
Microglia-derived BDNF has what specific effect in the spinal cord regarding inhibition? (1)
Attenuates chloride-mediated GABA/glycine inhibition
120
Fill the gaps relating to BDNF and neuropathic pain. (3)
BDNF mediates the transfer of information between ...................... and ....................... during the process of ......................................
activated microglia
neurones
central sensitisation
121
A study used Avil-CreERT2 to delete BDNF from all adult peripheral sensory neurones.
What is another name for deleting a molecule like this? (1)
Conditional knockout
122
A study used Avil-CreERT2 to delete BDNF from all adult peripheral sensory neurones.
They then did a formalin test. Describe what is meant by this. (2)
Inject formalin into animal
to create a persistent, chemically-mediated pain state.
123
A study used Avil-CreERT2 to delete BDNF from all adult peripheral sensory neurones.
They then injected formalin to create a persistent pain state.
What was seen regarding nociceptive behaviour with BDNF deletion? (1)
Reduced nociceptive behaviour
124
A study used Avil-CreERT2 to delete BDNF from all adult peripheral sensory neurones.
They then injected formalin to create a persistent pain state.
Describe the time course of BDNF knockout's effect on nociceptive behaviour. (2)
Make a conclusion. (1)
Did not really affect pain behaviour (or withdrawal thresholds) early on.
However reduced pain behaviour (and withdrawal thresholds) later on.
BDNF derived from sensory neurones plays a critical role in mediating the transition from acute to chronic pain.
125
A study carried out spinal nerve ligation (SNL) in rats, then measured development of allodynia, BDNF, and GFAP in the dorsal horn.
Describe the results. (3)
Rats developed allodynia (neuropathic pain) on ipsilateral side to injury.
Both GFAP and BDNF were raised in the ipsilateral dorsal horn.
126
A study carried out spinal nerve ligation (SNL) in rats, then measured development of allodynia, BDNF, and GFAP in the dorsal horn.
Write a possible conclusion regarding the increase in BDNF and GFAP seen. (1)
BDNF plays a role in astrocyte activation after neuropathic injury.
127
A study carried out spinal nerve ligation (SNL) in rats, then measured development of allodynia, BDNF, and GFAP in the dorsal horn.
Describe the effect of adding in a BDNF sequestering fusion protein on allodynia (PWTs) and GFAP. (2)
What fusion protein did they use? (1)
Prevented the decrease usually seen of PWT on ipsilateral side.
GFAP was not upregulated.
TrkB/Fc
128
What are we looking for when we measure GFAP? (1)
Astrocytes
129
Fill the gaps relating to neuropathic pain and glia. (7)
In the early phase of neuropathic pain, ....................... are activated via ................. and .................. phosphorylation.
Disruption of this activation (eg. by ........................) prevents aberrant chronic pain responses.
In the later phase of neuropathic pain, ......................... are activated via .................... and .................
microglia
p38
ERK
minocycline
astrocytes
ERK
JNK
130
Which type of glial cell is activated more persistently under chronic pain conditions? (1)
What conclusion can you draw from this? (1)
Astrocytes
Astrocytes may have a greater contribution to hyperalgesia.
131
Fill the gaps relating to glial cells and neuropathic pain. (5)
......................... are the most abundant cell type in the CNS. After harmful stimulation or nerve damage, the ..................., ...................., and ....................... of these cells undergo significant changes.
This process is called ..............................
Astrocytes
phenotype
function
gene expression
reactive astrocyte proliferation
132
What is the blood spinal cord barrier? (1)
A physical/biochemical barrier between the CNS and systemic circulation.
133
Briefly describe the two main components of the blood spinal cord barrier. (2)
Monolayer of nonfenestrated endothelial cells with tight junctions
surrounded by the endfeet of astrocytes.
134
Briefly describe the critical role of the blood spinal cord barrier. (1)
Separating and conjoining the immune system and spinal cord.
135
True or false? Explain your answer if necessary. (1)
Electrical stimulation of A fibres increases BSCB permeability.
False - electrical stimulation of C fibres increases BSCB permeability
136
Describe how we can show experimentally whether leakage of the BSCB following peripheral nerve injury is dependent or independent of microglia. (1)
What would the results show? (1)
Add minocycline treatment after nerve injury and measure BSCB permeability.
BSCB leakage is not sensitive to minocycline treatment so leakage is independent of microglia.
137
Name two cytokines which are triggers for BSCB leakage after peripheral nerve injury. (2)
MCP-1
IL1b
138
Name two anti-inflammatory cytokines which can attenuate BSCB leakage after peripheral nerve injury. (2)
TFG-b1
IL-10
139
Briefly describe how you could measure the permeability of the BSCB after peripheral nerve injury. (1)
Apply Evans blue and measure levels within the spinal cord.
140
If the sciatic nerve is injured in an animal, which part/s of the spinal cord and brain would you expect to see increased Evans blue?
Lumbar spinal cord
141
Name two plasma proteins which could be measured in the ipsilateral spinal cord after peripheral nerve injury. (2)
IgG
Fibronectin
142
Describe the distribution throughout the spinal cord and brain of Evans blue extravasation in experimental autoimmune encephalomyelitis mice. (1)
Extravasation is seen throughout spinal cord and brain.
143
Give two consequences of a disrupted BSCB in neuropathic injury. (2)
Influx of inflammatory mediators into the spinal cord.
Recruitment of blood borne monocytes/macrophages/T lymphocytes into the spinal cord.
144
What is the significance of circulating monocytes being allowed to enter the spinal cord after neuropathic injury? (1)
They can differentiate into microglia
145
Fill the gaps relating to the consequences of a disrupted BSCB in neuropathic pain. (4)
There is good evidence for .............. permeation from blood to spinal cord, and alterations in systemic levels of ................... seen in neuropathic patients may influence ................. and ............... permeability.
IL1b
cytokines
BBB
BSCB
146
Fill the gaps relating to descending modulation and neuropathic pain. (5)
Lesioning the RVM with .................... at this time point: ................................, has this effect on tactile allodynia and thermal hyperalgesia in neuropathic rats: .......................................
This suggests that ................................ initiate neuropathic pain, and ............................. maintain pain behaviour.
local anaesthetic
6-12 days post-injury, but not earlier
attenuation
primary afferent fibre mechanisms
supraspinal mechanisms
147
In an STZ-diabetic rat, describe the changes seen in the RVM with regards to:
a) descending inhibition
b) descending facilitation
c) spontaneous activity of OFF cells
d) spontaneous activity of ON cells
e) number of active OFF cells
a) decrease
b) increase
c) decrease
d) increase
e) decrease
148
Sum up the altered activity in the RVM seen in an animal model of neuropathic pain. (1)
Decreased inhibition and increased facilitation
149
Fill the gaps relating to cancer. (2)
For cancers that do not have ........................., pain is often the ................ sign of cancer and the reason for seeking medical attention.
screening tests
first
150
What percentage of patients with metastatic or advanced cancer will experience significant pain? (1)
75-90%
151
Why is it bad that pain is often the first symptom of cancer? (1)
Once patients experience pain, the tumour is often advanced and may have metastasized to other organs.
152
Give three very broad causes of cancer pain. (3)
- Direct tumour infiltration
- Diagnostic/therapeutic surgical procedures
- Toxicity of therapies used to treat cancer
153
Name three common tumours which metastasize to bone. (3)
- Breast
- Prostate
- Lung
154
Give seven common skeletal sites that cancers tend to metastasize to. (7)
- Vertebrae
- Scapula
- Humerus
- Pelvis
- Femur
- Sternum
- Ribs
155
Give three common 'side-effects' of bone cancer. (3)
Pain
Anaemia
Infection
156
Describe the time course of pain in bone cancer. (2)
Starts dull but constant
intensifies with time.
157
What is the most common type of cancer pain? (1)
Tumour-induced bone pain
158
True or false? Explain your answer if necessary. (1)
Bone is a sparsely innervated, but dynamic tissue.
False - it is highly innervated and dynamic
159
Bone is constantly remodelling.
What are the consequences of bone remodelling on pain? (1)
As remodelling of bone increases, spontaneous pain occurs which is unpredictable and debilitating.
160
Very briefly describe the mechanism which drives the pain experience (at least early on) in bone cancer. (1)
Activation of sensory nerves at the site of the tumour.
161
Fill the gaps relating to bone cancer pain. (7)
Adult bone is predominantly innervated by .............................. fibres and ............................... fibres.
There is little or no innervation by ................... fibres or ......................... fibres.
This unique phenotype is established by .......................................
Therefore, most if not all sensory input from the bone is about ...................... or .......................
thinly-myelinated TrkA+ (Ad)
TrkA+ C
Ab
TrkA-
specific transcription factors
pain
injury
162
How does the amount of TrkA+ sensory fibres innervating bone compare to skin? (1)
About 30% of sensory fibres in skin are TrkA+
About 80% of sensory fibres in bone are TrkA+
163
What is TrkA? (1)
NGF receptor
164
What could be the significance of bone containing higher levels of TrkA+ sensory fibres than skin? (1)
NGF plays a much greater role in bone pain than in skin pain.
165
Give four cell types that can be considered stromal cells associated with cancer cells. (4)
- Endothelial
- Fibroblasts
- Inflammatory
- Immune
166
Give four factors which can be released by cancer cells and their associated stromal cells. (4)
What effect do these factors have on sensory neurones? (1)
Prostaglandins (PGs)
NGF
Interleukins
Endothelins
They can activate/sensitise sensory neurones.
167
NGF directly activates what receptor? (1)
TrkA
168
Describe the dual roles of NGF in sensory neurones. (4)
Alters the kinetics of channels (TRPV1) and the insertion of Na channels into membrane.
These are fast effects.
Alters gene expression of substance P, CGRP, BDNF, and Na channels in dorsal root ganglia.
These are slow effects.
169
Give four genes/molecules whose expression is altered by NGF binding to peripheral sensory neurones. (4)
Substance P
CGRP
BDNF
Na channels
170
Fill the gaps relating to NGF. (16)
During inflammation and injury, ................... cells, ......................... cells, and .......................... cells release NGF that binds to ..............., which directly .......................... and/or ................... nociceptors. The ligand/receptor complex is ............................ transported to the ...................., resulting in increased synthesis of ..........................., such as substance P, ............................, and ............................... There is also increased synthesis of ......................... and ......................
There is ......................... transport of certain neurotransmitters, receptors, and ion channels from the DRG to the .......................... and ......................
inflammatory
immune
Schwann
TrkA
activates
sensitises
retrogradely
DRG
neuropeptides
BDNF
CGRP
receptors
ion channels
anterograde
periphery tissue
spinal cord
171
Briefly describe how you could induce a bone cancer model in a mouse. (2)
Embed cancer cells (fibrosarcoma, prostate cancer cells, etc)
in long bones to stimulate tumour growth.
172
A study embedded prostate cancer cells in mouse bone to stimulate tumour growth.
They then looked at the number of CGRP+, NF200+, and TrkA+ nerve fibres in tumour-bearing mice.
What would you expect to see? (3)
What does this indicate? (1)
Increased numbers of CGRP+, NF200+, and TrkA+ fibres.
Potentially indicates increased neuronal sprouting.
173
A study embedded prostate cancer cells in mouse bone to stimulate tumour growth.
They observed increased numbers of CGRP+, NF200+, and TrkA+ fibres in tumour-bearing mice.
How was this affected with early and late treatment with anti-NGF antibody? (2)
What conclusion can you draw from this? (1)
Anti-NGF antibody reduced numbers of these nerve fibres with both early and late treatment.
NGF plays a role in sprouting of nerve fibres in bone cancer.
174
A study embedded prostate cancer cells in mouse bone to stimulate tumour growth.
They then looked at time spent guarding and number of flinches in tumour-bearing mice.
What were the results? (2)
How were these affected with early and late anti-NGF treatment? (4)
Tumour-bearing mice showed increased time spent guarding
and also increased number of flinches.
Both pain behaviours reduced with both early and late anti-NGF treatment.
175
Suggest a way of treating bone cancer pain that involves targeting NGF. (1)
Block NGF (eg. anti-NGF antibody)
176
In general, does NGF cause or reduce pain? (1)
Cause
177
True or false? Explain your answer if necessary. (1)
Cancer cells are known to cause direct bone damage, which causes significant pain.
False - they do not directly cause bone damage, but lead to osteoclast activation
178
Name a cell type essential for the remodelling of bone, and bone damage in cancer. (1)
Osteoclasts
179
How do cancer cells cause osteoclast activation? (1)
Via activation of a signalling molecule called RANKL.
180
What is the signalling molecule called that activates osteoclasts? (1)
RANKL
181
Describe osteoclasts in terms of their differentiation state and lineage. (1)
Terminally differentiated multinucleated monocyte lineage cells.
182
What is the main role of osteoclasts? (1)
Resorb bone
183
How does osteoclast activity affect the local environment, and how do they do this? (2)
Maintain acidic pH
by releasing protons.
184
Is osteoclast proliferation and hypertrophy mainly seen in bone destroying (osteolytic) or bone forming (osteoblastic) cancers? (1)
Seen in most cancers of both type.
185
The acidic environment produced by osteoclast activation in bone cancer directly activates sensory nerves mainly via which channels? (1)
ASIC 3 channels (but there are others)
186
The acidic environment produced by osteoclast activation in bone cancer is able to alter the activation state of which channel? (1)
TRPV1
187
True or false? Explain your answer if necessary. (1)
In bone cancer, many cell types other than the cancer cells release a whole range of inflammatory factors, which act to sensitise peripheral nerve endings.
True
188
Suggest two potential treatments for bone cancer pain which target osteoclasts. (2)
- Bisphosphonates
- Osteoprotegerin (OPG)
189
Fill the gaps relating to bisphosphonates. (5)
Bisphosphonates bind to .................... and are taken up by .........................
They interfere with ......................... and other pathways in these cells, ultimately causing .................... and .................... in these cells.
bone
cells resorbing the bone (osteoclasts)
energy metabolism
dysfunction
apoptosis
190
Describe the effect of bisphosphonates on pain in patients with osteolytic and osteoblastic skeletal metastases. (2)
Decrease pain in both sets of patients
191
Describe the clinical use of bisphosphonates. (1)
They were rapidly incorporated into clinical use
192
Describe the effects of bisphosphonates on tumour growth and patient survival in bone cancer. (2)
Describe how these effects alter how they are used clinically. (1)
Effects on both tumour growth and patient survival are controversial.
However does not alter clinical use because they substantially improve quality of life.
193
Fill the gaps relating to the mechanism of ibandronate on bone cancer pain. (7)
Ibandronate is a ........................... (class of drug). It is taken up by ......................., and causes loss of normal ........................ and inhibits the generation of the ........................ extracellular environment.
This results in a decrease in the activation of ................................ and .......................... receptors, and results in decreased nociceptive input to the ..............................
bisphosphonate
osteoclasts
function
acidic
acid-sensing
TRPV1
spinal cord
194
What is osteoprotegerin (OPG)? (2)
A secreted soluble receptor (member of TNF receptor family)
which can bind to RANKL and act as a decoy receptor.
195
Briefly describe the mechanism by which osteoprotegerin affects osteoclasts. (3)
OPG binds to RANKL (acts as a decoy receptor)
RANKL usually triggers osteoclast differentiation, activation, and proliferation
so OPG mops up RANKL so it cannot bind to osteoclasts
196
Describe the general effect of OPG on pain behaviour in models of bone cancer. (1)
Decreases pain behaviour
197
Describe the effects of giving OPG treatment on allodynia in bone cancer:
a) on day of induction of tumour
b) from day 8 onwards
in animal models where bone cancer is induced. (2)
a) decreases development of allodynia
b) does not alter existing allodynia
198
Describe why using OPG to treat bone cancer pain in clinical practice is limited. (2)
Giving OPG early in the disease process (at onset of tumour growth) as a preventative measure gives the best results
however this would not be possible in a clinical scenario.
199
Give four effects of OPG given from onset of tumour growth in animal models, on bone changes seen in cancer. (4)
- Increased bone mineral density
- Reduced number of osteoclasts
- Decreased tumour-induced bone destruction
- Suppressed bone resorption
200
Fill the gaps relating to bone cancer. (2)
....................... make an important contribution to the changes in bone function that lead to bone ....................., and the generation of chronic pain.
Osteoclasts
destruction
201
Newer research suggests that what molecule, contained in exosomes, may contribute to cancer pain? (1)
Lysophosphatidic acid (LPA)
202
Describe the levels of lysophosphatidic acid (LPA) seen in tumour bearing mice compared to naive mice. (1)
Serum LPA increased
203
Describe the effect that you would see when adding an LPAR antagonist on withdrawal frequencies and latencies in tumour-bearing mice. (2)
Reverses increased withdrawal frequencies
Reverses reduced latencies
204
Describe the effect of adding exosomes from tumour-bearing mice to naive mice on withdrawal frequencies and latencies. (2)
What molecules in the exosomes causes this? (1)
How could you prove that it is this molecule having an effect? (3)
Increased withdrawal frequencies
Reduced latencies
Lysophosphatidic acid (LPA)
Use an LPA receptor antagonist
or inhibit ATX (enzyme which produces LPA) in the exosome
and look for a reversal of the hypersensitivity.
205
Name three initial symptoms of pancreatic cancer. (3)
Weight loss
Fatigue
GI problems
206
True or false? Explain your answer if necessary. (1)
Pain is not usually an initial symptom of pancreatic cancer. It is usually only experienced at late stages of the disease.
True
207
Fill the gaps relating to pancreatic cancer pain. (4)
The fact that pancreatic cancer ..................... (does / does not) usually cause pain is confusing because the pancreas has extensive ....................... and ..................... innervation, and .............................. is a very painful condition.
does not
sensory
sympathetic
acute pancreatitis
208
True or false? Explain your answer if necessary. (1)
In pancreatic cancer, early cellular changes due to tumour growth don't cause pain.
True
209
Describe two methods of how pain can be measured in a mouse model that spontaneously develops pancreatic cancer. (2)
Hunching profiles
Degree of vocalisation
210
Describe the changes to pathological markers and pain behaviours seen in early stages of pancreatic cancer. (2)
Significant increases in pathological markers.
No pain behaviours are shown.
211
Describe the changes to pathological markers and pain behaviours seen in late stages of pancreatic cancer. (2)
Some changes in pathological markers.
Lots of pain behaviour.
212
Give five things that you could measure as pathological makers in pancreatic cancer. (5)
Which molecule could you stain for for each of these markers? (5)
Vascularisation (CD31)
Macrophages (CD68)
Myelinated sensory fibres (RT97)
Peptidergic sensory fibres (CGRP)
Sympathetic nerve fibres (TH)
213
Does weight loss in pancreatic cancer start before or after pain onset? (1)
How can we show this? (1)
Weight loss starts before pain
Look to see when weight loss and hunching start
214
Fill the gaps relating to pancreatic cancer. (2)
There seems to be a mismatch between .................... and ......................... in pancreatic cancer mice.
pain
pathology
215
An experiment looked at hunching behaviours in mice with pancreatic cancer.
They started giving weekly high-dose morphine from one week after hunching is first seen.
Describe the effects of morphine on hunching. (2)
What conclusion can you draw from this? (1)
Morphine decreases progression of hunching behaviour
however the effect size is not huge, as would be expected with the high dose given.
Conclusion: alterations to the opioidergic system may have occurred in pancreatic cancer
216
Describe two histological/morphological changes seen in pancreatic cancer relating to blood vessels and sensory nerve fibres. (2)
Disorganised appearance of blood vessels
Increase in density of CGRP-expressing sensory fibres (sprouting near newly formed blood vessels)
217
Describe how you could show that endogenous opioids play a role in the lack of pain behaviour early on in pancreatic cancer. (1)
Describe the results that you would expect to see. (2)
Give naloxone (opioid antagonist) into the CNS and assess pain behaviour.
Shifts graph of development of pain to the left (so pain begins earlier)
so the development of pain now mirrors changes in vascularisation and pathology.
218
Describe the proposed site of action of opioids in pancreatic cancer. (2)
How could this be shown experimentally? (2)
CNS site of action
potentially descending pain modulatory systems.
- Give CNS penetrant opioid antagonist (naloxone) and this causes more pain early in disease state
- However a peripherally-restricted opioid antagonist does not produce the same effect
219
Very briefly describe why early stages of pancreatic cancer does not cause pain. (1)
Because there are changes in the endogenous opioidergic system (likely within the CNS) which prevents pain development.
220
Describe two specific observations regarding pancreatic cancer cells and endogenous opioid production. (2)
- Met-enkephalin is expressed by pancreatic tumour cells
- Patients with pancreatic cancer have higher plasma levels of met-enkephalin
221
According to a systematic literature review, chronic pain affects what proportion of the UK population? (1)
1/3 to 1/2
222
Give four causes of chronic musculoskeletal pain. (4)
- Osteoarthritis
- Rheumatoid arthritis
- Low back pain
- Fibromyalgia
223
True or false? Explain your answer if necessary. (1)
OA is the most prevalent functional limitation in the adult population, affecting 0.001% of the adult population.
False - first part is correct, but it affects 4-5% of the adult population
224
True or false? Explain your answer if necessary. (1)
OA affects 18% of men and 9.6% of women over 60 years of age world-wide.
False - it affects 9.6% of men and 18% of women
225
What is the lifetime risk for developing symptomatic knee OA? (1)
About 45%
226
What is the most prominent symptom of arthritis? (1)
Pain
227
What is the most important determinant of disability in OA? (1)
Pain
228
Fill the gaps relating to joint structure, as relevant to osteoarthritis. (5)
The joint surface is covered by a thin layer of .................................., which is made of ..............................
This layer rests on the .............................. and allows static and dynamic ................................ and decreases .............................
articular cartilage
chondrocytes
subchondral bone
joint loading
friction
229
Compare the innervation and vascularisation of cartilage and bone in a joint. (4)
Cartilage:
- no nerves
- no blood vessels
Bone:
- highly innervated
- highly vascularised
230
The cells in cartilage maintain a matrix rich in what two substances? (2)
- Collagen
- Proteoglycans
231
Fill the gaps relating to OA. (7)
OA results from ................... and .................... events that destabilise the normal coupling of ..................... and ...................... of articular cartilage, ........................ cells, extracellular ...................., and ......................... bone.
mechanical
biological
degradation
synthesis
chondrocyte
matrix
subchondral
232
Briefly describe four joint changes that are seen in osteoarthritis. (4)
- Loss of articular cartilage
- Subchondral bone remodelling
- Osteophytes (formation of new bone at joint margins)
- Cysts (vascular invasion at the junction between the cartilage and bone and angiogenesis)
233
Describe how the prevalence of OA changes with age. (1)
Why is this? (1)
OA prevalence majorly increases with age
because ageing is the primary factor contributing to abnormal cartilage repair.
234
Give four signs/symptoms of OA. (4)
- Joint pain
- Tenderness
- Limitation of movement
- Variable degree of inflammation
235
Give three risk factors for development of osteoarthritis. (3)
- Mechanical injury
- Hereditary factors
- Ageing
236
Describe what is thought to cause initiation of OA. (1)
Activation of stress-induced pathways
237
Describe three cellular/molecular mechanisms that are taking place in early-stage OA. (3)
Metalloproteinase formation
Cytokines
Collagen degradation
238
Describe five cellular/molecular mechanisms that are taking place in progressing and late-stage OA. (5)
- Cell death
- Collagen gene activation
- Changes in collagen
- Osteophyte formation
- Synovial inflammation and thickening
239
Give three 'risk factors' or pathological mechanisms which contribute to the progression from early to late stage OA. (3)
Inflammation
Repetitive injury
Subchondral bone changes
240
Fill the gaps relating to development of OA. (2)
As OA progresses, there is an imbalance in the expression, activity, and signalling of both ....................... and ...........................
cytokines
growth factors
241
Fill the gaps relating to mechanisms of joint damage in OA. (8)
Chondrocytes express receptors that respond to ........................................
Abnormal biomechanical loads up-regulate production of ............................., and this includes the release of ..................... by chondrocytes in the OA joint.
OA chondrocytes also have differential expression of ......................... subunits.
It has also been found that there are increased levels of this neurotransmitter in the OA knee joint and synovial fluid of patients: ...................................
The synovium releases .......................... due to joint damage and inflammation, and ........................... pathways are up-regulated.
............................... (an inflammatory cytokine) plays a major role in activating cartilage catabolism.
changes in load
inflammatory cytokines
NGF
NMDA receptor
glutamate
cytokines
inflammatory
IL-1b
242
True or false? Explain your answer if necessary. (1)
Osteoarthritis is a purely mechanical disease, with no signs of inflammatory mechanisms.
False - inflammation plays a huge role in OA
243
Briefly describe how nociceptors may be sensitised in OA. (5)
- Cartilage degradation, subchondral bone remodelling, and synovitis release inflammatory mediators
- Such as TNF, NGF, PGE2, cytokines etc
- And many tissues (not cartilage) in joints are innervated by nociceptors
- Inflammatory mediators bind to their receptors on nociceptors
- And nociceptors become activated and sensitised
244
True or false? Explain your answer if necessary. (1)
In osteoarthritis, the extent of joint damage on Xray bears little relationship to the level of pain.
True
245
Fill the gaps relating to joint damage vs pain in OA. (2)
More advanced MRI scans reveal .............................. in about .................% of symptomatic OA patients.
bone marrow lesions
80
246
Fill the gaps relating to joint damage vs pain in OA. (2)
Arthroscopy shows ....................... in about ...............% of symptomatic OA patients.
synovitis
50
247
Fill the gaps relating to OA. (2)
Pathological changes do not line up 100% with symptoms, so there is a mismatch between ..................... and .....................
pain
pathology
248
Fill the gaps relating to osteoarthritis pain. (4)
The pain experienced in osteoarthritis has both .......................... and ............................ like features.
Pain is associated with ................................. and ............................, and this shows that joint inflammation contributes to pain.
nociceptive
neuropathic
synovitis
bone marrow lesions
249
Why may joint replacement not be particularly effective in reducing OA pain in about 20% of patients? (1)
About 20% of patients have features consistent with central sensitisation mechanisms
250
Compare the pain relief given by oral NSAIDs vs opioids in osteoarthritis. (1)
Offer similar pain relief
251
True or false? Explain your answer if necessary. (1)
Opioid analgesics are the gold standard for treating OA pain.
False - they are not particularly useful in chronic OA pain.
252
True or false? Explain your answer if necessary. (1)
Opioids are not particularly useful in osteoarthritis pain, so they are rarely prescribed.
False - they are not particularly useful however are still often prescribed (1.1mil opioid prescriptions for OA pain is Australia)
253
True or false? Explain your answer if necessary. (1)
High opioid use for OA pain continues even 4 years post total knee replacement.
True
254
Give another aspect of pain that is associated with high rate of opioid use even after total joint replacement in OA. (1)
Pain catastrophising
255
What aspect of pain is a major predictor for opioid misuse in chronic pain patients? (1)
Pain catastrophising
256
Why is it unlikely for pain to be coming directly from the articular cartilage in OA? (1)
Cartilage is aneural
257
Name four structures in the joint that are richly innervated and contain nerve endings. (4)
- Subchrondral bone
- Synovium
- Ligaments
- Joint capsule
258
Suggest two specific tissues that are thought to be the source of pain in OA. (2)
Why is this? (2)
Synovium
Subchrondral bone
Because there is a correlation between pain and synovitis
and between pain and subchondral bone changes.
259
True or false? Explain your answer if necessary. (1)
The features of OA pain phenotype support both peripheral and central sensitisation mechanisms.
True
260
A research paper entitled:
'Subjects with knee osteoarthritis exhibit widespread hyperalgesia to pressure and cold'
concludes that people with OA experience central sensitisation and CNS involvement in pain.
Describe why this can be concluded. (2)
'Widespread hyperalgesia' suggests that secondary hyperalgesia is occurring
and secondary hyperalgesia is caused by CNS changes.
261
A research paper entitled:
'Subjects with knee osteoarthritis exhibit widespread hyperalgesia to pressure and cold'
made comparisons between participants, including activity levels and BMI.
Why is it important to compare these characteristics between groups in a study? (3)
Similar activity levels ensure similar stress and joint loading.
Similar BMI is important because obesity is an inflammatory state so could affect inflammation and pain.
So comparing these makes the study more valid.
262
Describe how you could test for the presence of widespread hyperalgesia, or secondary hyperalgesia in knee OA patients. (2)
Measure pressure pain thresholds (not thermal because secondary hyper does not include thermal)
do this not only in the knee but at distal sites such as ankle and elbow as well.
263
A study took patients with knee OA, and measured pressure pain thresholds in the knee, ankle, and elbow.
Describe the results you would expect to see for these regions. (3)
What can you conclude from this? (2)
Decreased pressure pain thresholds in all three areas compared to non-OA group.
- There is primary hyperalgesia
- And secondary hyperalgesia involving the central nervous system
264
Briefly describe how you could look for changes in brainstem areas such as the RVM in response to pain, in human patients with osteoarthritis. (2)
Use fMRI
to measure brain activation in response to a painful stimulus.
265
A study used fMRI to measure brain activation in different regions in OA patients and non-OA patients following punctate stimuli.
Describe the general reaction that OA patients had to punctate stimuli. (2)
Lower thresholds
Hyperalgesic
266
A study used fMRI to measure brain activation in different regions in OA patients and non-OA patients following punctate stimuli.
Which brain region in particular was different, and how was activation different in OA vs non-OA patients? (2)
Brainstem
Activation was greater in OA patients.
267
A study correlated painDETECT score of OA patients (which uses QST to measure pain responses in adjacent areas to injury) with activation of the PAG.
What were the results regarding this correlation? (1)
What can be concluded from this? (1)
Positive correlation (increased pain means more PAG activation).
There may be a difference in descending pain modulation in OA.
268
Briefly describe two pieces of evidence supporting the fact that there may be a difference in descending pain modulation in OA patients. (2)
fMRI shows increased brainstem activation in OA patients after punctate stimuli.
Positive correlation between referred pain score and PAG activation in OA patients.
269
Describe three animal models of osteoarthritis. (3)
Surgical model (meniscal transection)
Spontaneous model (Dunkin Hartley guinea pig)
Metabolic model (monosodium iodoacetate)
270
Give two pathological changes in the joint that are seen with the meniscal transection animal model of OA. (2)
- Erosion of cartilage and bone
- Osteophyte formation
271
Give a potential drawback of the meniscal transection animal model of OA. (1)
Pain responses are limited
272
Give a benefit and a drawback of using the Dunkin Hartley guinea pig as an animal model of OA. (2)
- Natural cartilage degeneration from 3 months (more closely mimics disease pathogenesis)
- No suitable controls
273
Briefly describe what MIA is and how it induces OA in animal models. (3)
- Inhibitor of glycolysis
- Disrupts chondrocyte metabolism
- So causes cartilage degeneration
274
Name a pathological change in the joint that is seen with the MIA model of OA in rodents. (1)
Cartilage degeneration
275
In terms of pain behaviour, what is the advantage of using the MIA model to induce OA in animals? (1)
This model produces reproducible pain behaviour
276
Describe the difference in firing rates you would expect from young and aged Dunkin Hartley guinea pig knee joint afferent, in response to both non-noxious and noxious movements of the joint. (2)
*Non-noxious was normal joint rotation, noxious was knee hyperrotation
Non-noxious:
- firing rates the same in young and old animals (no significant difference)
Noxious:
- Higher firing rate in aged animals
277
Describe the difference in weight-bearing that is seen with MIA, MNX, and MNX-sham animal models of OA. (3)
Describe how MNX-sham is carried out. (1)
MIA causes difference in weight bearing
MNX also causes differences in weight bearing
MNX-sham causes a difference at first but quickly recovers
- MNX-sham still had surgery but did not have any meniscal damage inflicted (MNX = medial meniscal transection)
278
Describe how the paw withdrawal thresholds change after induction of an MIA model of OA in rodents. (1)
PWT gradually decreases
279
Describe how firing frequency in response to von Frey hairs changes after induction of an MIA model of OA in rodents. (1)
Increased response (firing frequency) to von Frey hairs
280
Briefly describe the DMM animal model of OA. (1)
Is this a slowly-developing or a rapidly-developing animal model of OA? (1)
Destabilisation of medial meniscus
Slowly-developing
281
Describe what you would see in terms of cartilage damage in the following animal models of OA:
- MIA
- MNX
- DMM
(3)
MIA = increased cartilage damage
MNX = increased cartilage damage
DMM = increased cartilage damage
282
Describe what you would see in terms of synovitis in the following animal models of OA:
- MIA
- MNX
- DMM
(3)
MIA = increased synovitis
MNX = increased synovitis
DMM = increased synovitis
283
Describe what you would see in terms of changes in subchondral bone in the following animal models of OA:
- MIA
- MNX
- DMM
(3)
MIA = increased TRAP positive osteoclasts
MNX = increased osteophytes
DMM = larger osteophytes
284
Fill the gaps relating to animal models of OA. (4)
Animal models are generally ......................... (representative or not representative) of OA in humans, because it was found that the MIA, MNX, and DMM animal models showed the following joint pathologies:
...................................
..................................
..................................
representative
cartilage damage
synovitis
changes in subchondral bone
285
Describe three specific cartilage changes that are seen in MIA, MNX, and DMM animal models of OA. (3)
- Increased cartilage damage (both microscopically and macroscopically)
- Increased chondrocyte hypertrophy
- Increased proteoglycan loss
286
True or false? Explain your answer if necessary. (1)
The MIA, MNX, and DMM animal models of OA all show signs of increased osteophytosis in the joint.
True
287
Which animal model of OA (out of MIA, MNX, DMM) shows an increased number of TRAP positive osteoclasts in the joint? (1)
MIA
288
Which animal model of OA (out of MIA, MNX, DMM) shows increased Nav1.8 positive nerve fibre sprouting? (1)
DMM
289
Fill the gaps relating to neuronal sprouting in animal models of OA. (5)
Nav1.8-tdTomato can be used to visualise ......................... in different compartments of the knee.
This shows evidence for ..................... and ....................... of nociceptive afferents in the DMM model of OA.
This sprouting is seen at around 16 weeks, around the same time that ..................... is seen in the DMM model. This process may replicate what is seen in ........................., showing that animal models can replicate pathology as well as symptoms and behaviour.
Nav1.8 positive afferents
remodelling
sprouting
pain behaviour
human OA conditions
290
Give three different structural compartments of the knee where there is evidence for increased Nav1.8 sprouting in a DMM model of OA. (3)
- Medial synovium
- Medial meniscus
- Subchondral channels/bone
291
Is NGF increased or decreased in an osteoarthritic joint? (1)
Increased
292
Give two targets that NGF binds to. (2)
TrkA
p75
293
Is p75 a low or high affinity receptor for NGF? (1)
Low affinity
294
Give two general cell types which express receptors for NGF in an OA joint. (2)
Nerve terminals
Immune cells
295
True or false? Explain your answer if necessary. (1)
The sole source of NGF in an osteoarthritic joint is macrophages.
False - there are multiple sources of NGF including macrophages
296
Fill the gaps relating to NGF and OA. (5)
Activation of the NGF receptor, ........................, sensitises ......................... to other stimuli.
One example is the sensitisation of ........................ (receptor / ion channel).
NGF binding to its receptor also alters ............................ of other molecules.
This is likely an important mechanism in OA pain because bone is heavily innervated by ...................................
TrkA
nociceptor terminals
TRPV1
gene expression
TrkA positive sensory nerves
297
Describe a human experiment which shows that NGF specifically leads to pain and OA symptoms. (4)
Experimental group = symptomatic chondropathy (pts who have had joint replacement)
Control group = asymptomatic chondropathy (cadaver knees with cartilage damage but no reports of pain)
The groups will be matched for degree of cartilage damage, but differ depending on whether they experienced pain or not.
Then can measure NGF levels in different areas of the joint (eg. via immunoreactivity).
298
A study compared NGF immunoreactivity in synovium and osteochondral channels in patients with symptomatic chondropathy (OA) and asymptomatic chondropathy.
Describe what you would expect the results to show. (2)
Write a short conclusion. (1)
Increased NGF immunoreactivity in synovium of symptomatic pts
and also increased NGF in osteochondral channels of symptomatic pts.
The results show that NGF may play a role in determining whether cartilage damage will lead to pain or not.
299
An experiment looked at the effects of PKCdelta null mutations in a DMM mouse model of OA.
How did loss of PKCdelta affect cartilage damage and pain in these mice? (2)
Decreased cartilage damage
Increased pain (hyperalgesia)
300
An experiment looked at the effects of PKCdelta null mutations in a DMM mouse model of OA.
How did PKCdelta KO affect the density of nerve fibres in the synovium? (1)
How does this compare to painful knee OA in humans? (1)
- Increased synovial nerve fibre densities with PKCd KO
- There is also increased synovial nerve fibre densities in humans with OA pain
301
An experiment looked at the effects of PKCdelta null mutations in a DMM mouse model of OA.
They found that cartilage damage was reduced, but pain and nerve fibre density in the synovium were increased.
How did the presence of the PKCd KO affect NGF and TrkA levels in the synovium of DMM animals? (1)
How does this compare to painful knee OA in humans? (1)
Write a short conclusion. (1)
Increased NGF and TrkA in synovium of PKCd KO mice
Increased NGF and TrkA in synovium of human OA pain patients
Increased NGF and TrkA levels in the synovium seem to be important for OA pain.
302
Suggest a potential treatment for OA pain which targets NGF. (1)
Humanized anti-NGF monoclonal antibodies (eg. Tanezumab)
303
Describe how clinical trials are currently going for using anti-NGF antibodies to treat OA pain. (7)
There are a number of clinical trials
The antibody produced clinically meaningful and significant pain relief in patients with moderate to severe OA pain
however a class effect of these drugs was that some people had worsening of joint damage
this was only significantly greater than the expected rate of joint damage if the patients also took NSAIDs
but non-weight-bearing joints also showed worsening damage (so it was not related to greater use of the joints with less pain)
and it was also not related to the extent of the analgesia
so trials have currently stopped
304
Describe a potential way of modulating osteoclast function to treat OA pain. (1)
Osteoprotegerin (OPG)
305
Describe how pre-emptive treatment with osteoprotegerin alters weight-bearing asymmetry in MIA rats (compared to vehicle-treated MIA rats). (1)
OPG reduces weight-bearing asymmetry
306
Describe how pre-emptive treatment with osteoprotegerin alters paw withdrawal thresholds in MIA rats (compared to vehicle-treated MIA rats). (2)
PWTs higher with OPG
but only partially recovered (still not as high as non-MIA rats).
307
Describe how pre-emptive treatment with osteoprotegerin alters the following pathological markers in MIA rats (compared to vehicle-treated MIA rats):
- cartilage damage
- osteophyte number
- synovial inflammation
(3)
CARTILAGE DAMAGE:
- No cartilage damage with OPG
OSTEOPHYTE NUMBER:
- Reduced osteophyte score but still not as low as non-MIA rats
SYNOVIAL INFLAMMATION:
- Reduced inflammation but still not as low an non-MIA rats
308
Describe how pre-emptive treatment with osteoprotegerin alters the following pathological markers in MIA rats (compared to vehicle-treated MIA rats):
- number of channels crossing the osteochondral junction
- chrondrocyte appearance score
- proteoglycan loss
(3)
Slightly reduced channels crossing OCJ
Higher chondrocyte appearance score (it is supposed to be low)
Same amount of proteoglycan loss
309
Describe how pre-emptive treatment with osteoprotegerin alters the number of osteoclasts in the knee joint of MIA rats (compared to vehicle-treated MIA rats and non-MIA rats). (2)
Write a short conclusion about using OPG to treat OA pain. (1)
- Completely wiped out osteoclasts (no osteoclasts)
- But even the non-MIA rats had some osteoclasts
Even though modulating osteoclasts can alter pain, osteoclasts are needed for normal function so it's not a viable treatment.
