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Neuroscience Y3S1 > Chronic Pain > Flashcards

Chronic Pain Flashcards

1
Q

Give three general large categories of causes of neuropathic pain. (3)

A
  • Diseases and infections
  • Drug treatment
  • Direct traumatic injury to nerves
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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
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3
Q

Very briefly describe how diabetes may cause neuropathic pain. (1)

A

High levels of circulating glucose associated with nerve damage.

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4
Q

Give the common name for neuropathic pain experienced following shingles. (1)

A

Post-herpetic neuralgia

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5
Q

Describe how the intensity and persistence of post-herpetic neuralgia changes with age. (1)

A

Intensity and persistence increase with age

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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

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7
Q

Give two drug treatments which may cause neuropathic pain. (2)

A

Chemotherapeutic agents for cancer treatment

Anti-retroviral drug therapy in AIDS

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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.

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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)

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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

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11
Q

Give a ‘negative symptom’ of neuropathic pain. (1)

A

Numbness

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12
Q

By which mechanism does numbness occur in neuropathic pain? (1)

A

Deafferentation

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13
Q

Give four ‘positive symptoms’ of neuropathic pain. (4)

A

Hyperpathia

Paraesthesia

Tenderness to stimuli

Referred pain

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14
Q

What is meant by ‘hyperpathia’ when talking about neuropathic pain? (1)

A

Explosive, electric shock-like pain

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15
Q

What is meant by ‘paraesthesia’ when talking about neuropathic pain? (1)

A

Abnormal but not painful sensation (eg. pins and needles)

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16
Q

Give another name for the ‘tenderness to stimuli’ often experienced in neuropathic pain. (1)

A

Mechanical and thermal allodynia

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17
Q

What is meant by ‘referred pain’ when talking about neuropathic pain? (1)

A

Abnormal spread of pain

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18
Q

Give two types of mechanical allodynia experienced in neuropathic pain. (1)

A

Dynamic brush-evoked pain

Static mechanical pain

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19
Q

Dynamic brush-evoked pain/allodynia is mediated by which type of nerve fibre in neuropathic pain? (1)

A

Ab fibres

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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

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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

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22
Q

Give two types of nerve damage mechanisms associated with neuropathic pain. (2)

A

Segmental dysmyelination/demyelination

Axopathy

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23
Q

Describe what is meant by ‘axopathy’ when talking about neuropathic pain. (1)

A

Metabolic and axoplasmic transport deficits due to transection.

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24
Q

What is the test called that can assess neuropathic pain and central sensitisation in clinical practice? (1)

A

Quantitative sensory testing

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25
Q

Very briefly describe what it meant by ‘quantitative sensory testing’. (1)

A

Psychophysical test used to determine peripheral/central mechanisms of pain

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26
Q

Give four specific tests that are carried out during quantitative sensory testing. (4)

A

Pain pressure thresholds

Thermal thresholds

Cold pressor evoked pain

Pin-prick

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27
Q

Give three pain mechanisms that can be assessed during quantitative sensory testing. (3)

A
  • Local vs referred pain mechanisms
  • Temporal summation
  • Changes in descending control pathways
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28
Q

Give three specific pain conditions/diagnoses which can be evaluated using quantitative sensory testing. (3)

Which condition was it first developed for? (1)

A
  • Arthritis
  • Neuropathic pain (FIRST DEVELOPED)
  • Sickle cell disease
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29
Q

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 ………………………..

A

sickle cell disease chronic pain

osteoarthritis pain

cancer pain

central sensitisation

questionnaires

imaging

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30
Q

Give two drawbacks of using quantitative sensory testing in clinical practice. (2)

A
  • Labour intensive and can be quite a long process for patients (not suitable for GP assessment)
  • Involves stimulating cutaneous structures (could evoke acute episode)
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31
Q

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)

A

Stimulus-independent refers to ongoing/spontaneous pain.

Stimulus-induced refers to hyperalgesia.

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32
Q

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

a) none

b) nociceptors (Ad and C)

c) ectopic neuronal activity

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33
Q

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

a) heat and cold

b) C nociceptors and cold-sensitive C nociceptors

c) sensitisation of nociceptors (peripheral sensitisation) and central disinhibtion

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34
Q

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

a) noradrenaline (mediated by SNS)

b) nociceptors

c) increased expression of a adrenoreceptors

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35
Q

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

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

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36
Q

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.

A

non-noxious

painful/nociceptive

C fibres

A fibres

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37
Q

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)

A

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.

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38
Q

Give a potential biomarker for neuropathic pain. (1)

A

microRNAs

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39
Q

Why would it be helpful to have biomarkers for neuropathic pain? (1)

A

They may help stratify patients for treatment

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40
Q

What are microRNAs? (1)

A

Non-coding sequences which regulate post-transcriptional gene expression.

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41
Q

Give two reasons why microRNAs may appear good biomarkers for neuropathic pain. (2)

A
  • Relatively stable
  • Present in most biofluids (fairly easy to measure)
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42
Q

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.

A

mRNA

degradation

translation

receptors

communication

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43
Q

Briefly describe current evidence regarding microRNAs as biomarkers for neuropathic pain. (2)

A

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).

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44
Q

Give four general animal models of neuropathic pain. (4)

A

Damage to sciatic nerve

Diabetic neuropathy

Streptozotocin (STZ)

Chemotherapy induced neuropathy (Taxol)

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45
Q

Briefly describe what is meant by a ‘traumatic’ animal model of neuropathic pain. (1)

A

Causing partial injury or damage to the sciatic nerve

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46
Q

Briefly describe what is meant by a ‘non-traumatic’ animal model of neuropathic pain. (1)

Give three examples of non-traumatic models. (3)

A

Not causing direct damage or injury to nerves.

  • Diabetic neuropathy
  • Streptozotocin (STZ)
  • Chemotherapy (Taxol)
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47
Q

Give three specific examples of traumatic animal models of neuropathic pain, where damage is inflicted on the sciatic nerve. (3)

A
  • Chronic constriction injury (CCI)
  • Partial sciatic nerve or spared nerve injury (SNI)
  • Selective spinal nerve ligation (SNL)
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48
Q

Describe what is meant by selective spinal nerve ligation, when inducing animal models of neuropathic pain. (1)

A

Lesioning one of the spinal roots of the sciatic nerve.

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49
Q

Describe what is meant by spared nerve injury, when inducing animal models of neuropathic pain. (1)

A

Lesioning one of the branches of the sciatic nerve (eg. tibial, peroneal, or sural nerve)

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50
Q

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)

A

Spontaneous activity in nociceptors (number of spontaneously active fibres as a percentage of total fibres)

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51
Q

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)

A

Animal models result in more spontaneously active fibres than humans.

They may not be reliable.

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52
Q

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)

A
  • Majority of data collected for non-humans was male rodents
  • Study approaches were quite heterogenous
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53
Q

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)

A

Non-regenerating (ligation)

Regenerating (crush)

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54
Q

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)

A

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.

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55
Q

What is meant by ‘ectopic activity’ when referring to peripheral nerves following nerve injury? (1)

A

Spontaneous firing without a known trigger

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56
Q

Describe the firing pattern of spontaneous activity in peripheral nerves after nerve injury. (2)

A

Irregular bursts

almost like ‘pacemaker activity’.

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57
Q

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

A fibre

spontaneous pains

paraesthesia

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58
Q

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.

A

C fibres

capsaicin

A fibres

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59
Q

Name two general types of ion channels which may contribute to ectopic activity of injured peripheral nerves. (2)

A
  • Sodium channels
  • Potassium channels
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60
Q

Altered expression and activity of which three sodium channels may contribute to ectopic activity in injured peripheral nerves? (3)

A

Nav1.3

Nav1.8

Nav1.9

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61
Q

Changes in expression and activity of Nav1.3, Nav1.8, and Nav1.9 may have what effect on peripheral nerves? (2)

A

Cause sub-threshold membrane potential oscillations

which may contribute to ectopic activity.

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62
Q

Describe the normal expression of Nav1.3, and how this is changed after nerve injury. (2)

A

Normally expressed during development

but after nerve injury is expressed in adult.

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63
Q

Describe the significance of Nav1.3 being expressed in adult neurones after nerve injury. (3)

*Nav1.3 usually expressed during development

A

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.

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64
Q

Fill the gaps relating to Nav channels and neuropathic pain. (2)

Nav1.7 is universally expressed by ……………………., and gain of function mutations lead to ……………………………

A

sensory neurones

ectopic activity in C fibres

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65
Q

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 ……………………

A

leak potassium channels

neuronal and non neuronal tissues

maximal firing frequency

the hyperpolarisaion

K2P channels

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66
Q

Name two types of KCNK/K2P channel which may be involved in neuropathic pain. (2)

A

TRESK

TREK-2

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67
Q

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 ………………………………

A

TRESK

K2p/KCNK

sensory neurones

pain pathways

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68
Q

Describe how TRESK channels are involved in neuropathic pain and changed after nerve injury. (2)

A

Changes in neuropathic pain models are complicated

but TRESK is down-regulated by 40% after nerve injury

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69
Q

Which two K2P channels regulate 85% of background K+ activity in dorsal root ganglion neurones? (2)

A

TRESK

TREK-2

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70
Q

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)

A

C and Ad fibres

hyperexcitability

by inflammatory challenge

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71
Q

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 …………………………….

A

calcium-activated potassium channel subfamily N member 1 (KCNN1)

nociceptive hypersensitivity

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72
Q

What would you expect the general effect to be of inhibiting or downregulating potassium channels in nociceptive afferents? (1)

A

Hyperexcitability

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73
Q

Very briefly describe a non-invasive way of investigating the role of potassium channels in pain (in rodents). (3)

A

Use a photoswitchable inhibitor

of TREK K channels

which becomes active and inhibits K channels only at certain wavelengths of light.

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74
Q

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)

A

Increases nocifensive behaviour

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75
Q

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)

A

Decreased mechanical withdrawal thresholds.

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76
Q

Describe how levels of TRPV1 are altered after nerve injury (SNL or PSL) in:

a) damaged DRG neurones

b) undamaged DRG neurones

(2)

A

a) significantly reduced

b) increased expression

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77
Q

Levels of TRPV1 changes in neurones following nerve injury.

Where specifically in the neurones has this been observed? (1)

A

Somata

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78
Q

Which type of nerve fibre (damaged/undamaged; A/C) shows the greatest level of increase of TRPV1 expression after nerve injury? (1)

A

Undamaged A fibres

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79
Q

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)

A

neuropathic pain behaviour

inflammatory mediators

across the whole nerve

terminals

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80
Q

Suggest a possible way to directly manipulate TRPV1 in order to treat pain. (1)

Why is this treatment not used in clinical practice? (1)

A

TRPV1 antagonists

They are associated with hyperthermia in studies (on target side effect)

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81
Q

Describe a way of indirectly modulating TRPV1 which could potentially treat pain. (4)

A

Inhibit kinases (p38/PKCe)

which modulate TRPV1 activity

and because NGF contributes to activation of kinases

you could sequester NGF

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82
Q

Describe the evidence surrounding sequestering NGF as a strategy for treating neuropathic pain. (1)

A

Unclear if sequestering NGF is a good strategy

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83
Q

When in life is the usual onset of pain in sickle cell disease? (1)

A

Early/late adulthood

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84
Q

Briefly describe the cause/mechanism of pain in sickle cell disease. (3)

A

Damage to peripheral nerves

due to vaso-occlusion

due to beta-hemoglobinopathies.

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85
Q

Give three general characteristics of acute pain in sickle cell disease. (3)

A

Sharp

Throbbing

Unpredictable

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86
Q

Give three cell types which are involved in acute pain in sickle cell disease. (3)

A

Endothelial

Macrophages

Nerves

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87
Q

How long does chronic sickle cell disease pain last? (1)

A

> 3 months

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88
Q

Give four general characteristics of chronic sickle cell disease pain. (4)

A
  • Deep
  • Achy
  • Persistent
  • Negative impact on mental health
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89
Q

Name a mouse model that could be used to investigate mechanisms of sickle cell disease pain. (1)

A

Berkeley SCD mice

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90
Q

Give two findings regarding TRPV1 and pain that have been seen in Berkeley sickle cell disease mice. (2)

A

Increased TRPV1 sensitivity of dorsal root ganglion neurones.

They exhibit mechanical allodynia which is blocked partly by TRPV1 antagonist.

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91
Q

Gene polymorphisms in which receptor/ion channel may influence acute pain crisis in sickle cell disease? (1)

A

TRPA1

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92
Q

Describe briefly the general mechanism of how microRNAs may be involved in the development of neuropathic pain. (1)

A

Regulation of voltage-gated Na channels

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93
Q

Give three examples of microRNAs which are thought to be involved in neuropathic pain. (3)

A

miR-7a

miR-30b

miR-182

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94
Q

Describe two experimental findings which may describe how miR-7a may be involved in neuropathic pain. (2)

A
  • Downregulated in neurones of injured DRGs
  • Over-expression suppresses increases in excitability of nociceptive neurones
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95
Q

Briefly describe how miR-30b may be involved in neuropathic pain. (1)

A

Regulates Nav1.7 expression in neuropathic rats

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96
Q

Briefly describe how miR-182 may be involved in neuropathic pain. (1)

A

Alleviates SNI-induced neuropathic pain through regulating Nav1.7

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97
Q

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)

A

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)).

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98
Q

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 ……………………………….

A

nociceptors

low-threshold mechanoreceptors

dorsal horn neurones

reduction

expansion

temporal

normally-innocuous afferent inputs

central sensitisation

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99
Q

Describe how calcium channels may be altered in the spinal cord in neuropathic pain. (1)

Why are these calcium channels important? (1)

A

Increased expression and function of pre-synaptic N type calcium channels on nociceptors

which are important for vesicular release and synaptic transmission.

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100
Q

Give two ways that excitation in the spinal cord may be altered during neuropathic pain. (2)

A
  • NMDA receptors activated
  • Decreased expression of glutamate transporter = decreased clearance of glutamate in spinal cord
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101
Q

Give two ways that inhibition in the spinal cord may be altered during neuropathic pain. (2)

A

Loss of GAD (glutamate decarboxylase) which converts glutamate into GABA in interneurones.

Small interneurones more vulnerable to excitotoxicity.

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102
Q

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 ………………….

A

glycine

allodynia

Ab fibre

II

connectivity

signalling

GABAergic

GABAergic inhibitory interneurones

TNFa

p38

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103
Q

Which immune cell type infiltrates the site of nerve injury and distal sites? (1)

Why is this cell important? (1)

A

Macrophages

Important source of immune mediators

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104
Q

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 ……………………..

A

Immune-like glial

termination areas of the injured sensory afferents

microglia

astrocytes

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105
Q

True or false? Explain your answer if necessary. (1)

Microglia in the spinal cord can be referred to as ‘central monocytes’.

A

False - they are referred to as central macrophages

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106
Q

Give two conditions required for microglial activation in the spinal cord in neuropathic pain. (2)

A
  • Axonal injury
  • Nociceptive drive
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107
Q

Do microglia in the spinal cord contribute to the initial or maintenance stage of chronic pain? (1)

A

Initial

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108
Q

At which stage of chronic pain states do astrocytes play an important role? (1)

A

In later stages

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109
Q

Give six examples of signalling molecules which glial cells express receptors for in the CNS. (6)

A

Substance P

Essential amino acids (EAAs)

CGRP

ATP (P2X7 receptor)

Prostaglandins

NO

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110
Q

Name a type of adaptive immune cell which gets recruited into the dorsal horn in neuropathic pain. (1)

A

CD4+ T cells

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111
Q

What is the role of CD4+ T cells in the spinal cord following neuropathic injury? (1)

Give an example. (1)

A

Release cytokines which activate microglia.

Example: interferon y

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112
Q

True or false? Explain your answer if necessary. (1)

Glial cells are important sources of neurotrophic factors in neuropathic pain.

A

True

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113
Q

Give two important sources of neurotrophic factors following neuropathic injury. (2)

A

Peripheral tissue

Glial cells

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114
Q

Name two cell types which synthesise NGF and are important sources in nerve injury. (2)

A

Schwann cells

Immune cells

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115
Q

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.

A

False - it is released from central terminals of afferent fibres

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116
Q

Describe how synthesis of BDNF is altered following nerve injury in peptidergic neurones and large diameter neurones. (2)

A

Peptidergic = BDNF synthesis declines

Large diameter = BDNF synthesis increases

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117
Q

BDNF and mediators from activated microglia promote what change in the dorsal horn following neuropathic injury? (1)

A

Increased excitability

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118
Q

What would be the effect of sequestering BDNF on dorsal horn excitability? (1)

A

Reduced

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119
Q

Microglia-derived BDNF has what specific effect in the spinal cord regarding inhibition? (1)

A

Attenuates chloride-mediated GABA/glycine inhibition

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120
Q

Fill the gaps relating to BDNF and neuropathic pain. (3)

BDNF mediates the transfer of information between …………………. and ………………….. during the process of ………………………………..

A

activated microglia

neurones

central sensitisation

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121
Q

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)

A

Conditional knockout

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122
Q

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)

A

Inject formalin into animal

to create a persistent, chemically-mediated pain state.

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123
Q

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)

A

Reduced nociceptive behaviour

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124
Q

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)

A

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
Q

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)

A

Rats developed allodynia (neuropathic pain) on ipsilateral side to injury.

Both GFAP and BDNF were raised in the ipsilateral dorsal horn.

126
Q

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)

A

BDNF plays a role in astrocyte activation after neuropathic injury.

127
Q

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)

A

Prevented the decrease usually seen of PWT on ipsilateral side.

GFAP was not upregulated.

TrkB/Fc

128
Q

What are we looking for when we measure GFAP? (1)

A

Astrocytes

129
Q

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 ……………..

A

microglia

p38

ERK

minocycline

astrocytes

ERK

JNK

130
Q

Which type of glial cell is activated more persistently under chronic pain conditions? (1)

What conclusion can you draw from this? (1)

A

Astrocytes

Astrocytes may have a greater contribution to hyperalgesia.

131
Q

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 …………………………

A

Astrocytes

phenotype

function

gene expression

reactive astrocyte proliferation

132
Q

What is the blood spinal cord barrier? (1)

A

A physical/biochemical barrier between the CNS and systemic circulation.

133
Q

Briefly describe the two main components of the blood spinal cord barrier. (2)

A

Monolayer of nonfenestrated endothelial cells with tight junctions

surrounded by the endfeet of astrocytes.

134
Q

Briefly describe the critical role of the blood spinal cord barrier. (1)

A

Separating and conjoining the immune system and spinal cord.

135
Q

True or false? Explain your answer if necessary. (1)

Electrical stimulation of A fibres increases BSCB permeability.

A

False - electrical stimulation of C fibres increases BSCB permeability

136
Q

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)

A

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
Q

Name two cytokines which are triggers for BSCB leakage after peripheral nerve injury. (2)

A

MCP-1

IL1b

138
Q

Name two anti-inflammatory cytokines which can attenuate BSCB leakage after peripheral nerve injury. (2)

A

TFG-b1

IL-10

139
Q

Briefly describe how you could measure the permeability of the BSCB after peripheral nerve injury. (1)

A

Apply Evans blue and measure levels within the spinal cord.

140
Q

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?

A

Lumbar spinal cord

141
Q

Name two plasma proteins which could be measured in the ipsilateral spinal cord after peripheral nerve injury. (2)

A

IgG

Fibronectin

142
Q

Describe the distribution throughout the spinal cord and brain of Evans blue extravasation in experimental autoimmune encephalomyelitis mice. (1)

A

Extravasation is seen throughout spinal cord and brain.

143
Q

Give two consequences of a disrupted BSCB in neuropathic injury. (2)

A

Influx of inflammatory mediators into the spinal cord.

Recruitment of blood borne monocytes/macrophages/T lymphocytes into the spinal cord.

144
Q

What is the significance of circulating monocytes being allowed to enter the spinal cord after neuropathic injury? (1)

A

They can differentiate into microglia

145
Q

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.

A

IL1b

cytokines

BBB

BSCB

146
Q

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.

A

local anaesthetic

6-12 days post-injury, but not earlier

attenuation

primary afferent fibre mechanisms

supraspinal mechanisms

147
Q

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

a) decrease

b) increase

c) decrease

d) increase

e) decrease

148
Q

Sum up the altered activity in the RVM seen in an animal model of neuropathic pain. (1)

A

Decreased inhibition and increased facilitation

149
Q

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.

A

screening tests

first

150
Q

What percentage of patients with metastatic or advanced cancer will experience significant pain? (1)

A

75-90%

151
Q

Why is it bad that pain is often the first symptom of cancer? (1)

A

Once patients experience pain, the tumour is often advanced and may have metastasized to other organs.

152
Q

Give three very broad causes of cancer pain. (3)

A
  • Direct tumour infiltration
  • Diagnostic/therapeutic surgical procedures
  • Toxicity of therapies used to treat cancer
153
Q

Name three common tumours which metastasize to bone. (3)

A
  • Breast
  • Prostate
  • Lung
154
Q

Give seven common skeletal sites that cancers tend to metastasize to. (7)

A
  • Vertebrae
  • Scapula
  • Humerus
  • Pelvis
  • Femur
  • Sternum
  • Ribs
155
Q

Give three common ‘side-effects’ of bone cancer. (3)

A

Pain

Anaemia

Infection

156
Q

Describe the time course of pain in bone cancer. (2)

A

Starts dull but constant

intensifies with time.

157
Q

What is the most common type of cancer pain? (1)

A

Tumour-induced bone pain

158
Q

True or false? Explain your answer if necessary. (1)

Bone is a sparsely innervated, but dynamic tissue.

A

False - it is highly innervated and dynamic

159
Q

Bone is constantly remodelling.

What are the consequences of bone remodelling on pain? (1)

A

As remodelling of bone increases, spontaneous pain occurs which is unpredictable and debilitating.

160
Q

Very briefly describe the mechanism which drives the pain experience (at least early on) in bone cancer. (1)

A

Activation of sensory nerves at the site of the tumour.

161
Q

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 …………………..

A

thinly-myelinated TrkA+ (Ad)

TrkA+ C

Ab

TrkA-

specific transcription factors

pain

injury

162
Q

How does the amount of TrkA+ sensory fibres innervating bone compare to skin? (1)

A

About 30% of sensory fibres in skin are TrkA+

About 80% of sensory fibres in bone are TrkA+

163
Q

What is TrkA? (1)

A

NGF receptor

164
Q

What could be the significance of bone containing higher levels of TrkA+ sensory fibres than skin? (1)

A

NGF plays a much greater role in bone pain than in skin pain.

165
Q

Give four cell types that can be considered stromal cells associated with cancer cells. (4)

A
  • Endothelial
  • Fibroblasts
  • Inflammatory
  • Immune
166
Q

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)

A

Prostaglandins (PGs)

NGF

Interleukins

Endothelins

They can activate/sensitise sensory neurones.

167
Q

NGF directly activates what receptor? (1)

A

TrkA

168
Q

Describe the dual roles of NGF in sensory neurones. (4)

A

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
Q

Give four genes/molecules whose expression is altered by NGF binding to peripheral sensory neurones. (4)

A

Substance P

CGRP

BDNF

Na channels

170
Q

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 ………………….

A

inflammatory

immune

Schwann

TrkA

activates

sensitises

retrogradely

DRG

neuropeptides

BDNF

CGRP

receptors

ion channels

anterograde

periphery tissue

spinal cord

171
Q

Briefly describe how you could induce a bone cancer model in a mouse. (2)

A

Embed cancer cells (fibrosarcoma, prostate cancer cells, etc)

in long bones to stimulate tumour growth.

172
Q

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)

A

Increased numbers of CGRP+, NF200+, and TrkA+ fibres.

Potentially indicates increased neuronal sprouting.

173
Q

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)

A

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
Q

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)

A

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
Q

Suggest a way of treating bone cancer pain that involves targeting NGF. (1)

A

Block NGF (eg. anti-NGF antibody)

176
Q

In general, does NGF cause or reduce pain? (1)

A

Cause

177
Q

True or false? Explain your answer if necessary. (1)

Cancer cells are known to cause direct bone damage, which causes significant pain.

A

False - they do not directly cause bone damage, but lead to osteoclast activation

178
Q

Name a cell type essential for the remodelling of bone, and bone damage in cancer. (1)

A

Osteoclasts

179
Q

How do cancer cells cause osteoclast activation? (1)

A

Via activation of a signalling molecule called RANKL.

180
Q

What is the signalling molecule called that activates osteoclasts? (1)

A

RANKL

181
Q

Describe osteoclasts in terms of their differentiation state and lineage. (1)

A

Terminally differentiated multinucleated monocyte lineage cells.

182
Q

What is the main role of osteoclasts? (1)

A

Resorb bone

183
Q

How does osteoclast activity affect the local environment, and how do they do this? (2)

A

Maintain acidic pH

by releasing protons.

184
Q

Is osteoclast proliferation and hypertrophy mainly seen in bone destroying (osteolytic) or bone forming (osteoblastic) cancers? (1)

A

Seen in most cancers of both type.

185
Q

The acidic environment produced by osteoclast activation in bone cancer directly activates sensory nerves mainly via which channels? (1)

A

ASIC 3 channels (but there are others)

186
Q

The acidic environment produced by osteoclast activation in bone cancer is able to alter the activation state of which channel? (1)

A

TRPV1

187
Q

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.

A

True

188
Q

Suggest two potential treatments for bone cancer pain which target osteoclasts. (2)

A
  • Bisphosphonates
  • Osteoprotegerin (OPG)
189
Q

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.

A

bone

cells resorbing the bone (osteoclasts)

energy metabolism

dysfunction

apoptosis

190
Q

Describe the effect of bisphosphonates on pain in patients with osteolytic and osteoblastic skeletal metastases. (2)

A

Decrease pain in both sets of patients

191
Q

Describe the clinical use of bisphosphonates. (1)

A

They were rapidly incorporated into clinical use

192
Q

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)

A

Effects on both tumour growth and patient survival are controversial.

However does not alter clinical use because they substantially improve quality of life.

193
Q

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 …………………………

A

bisphosphonate

osteoclasts

function

acidic

acid-sensing

TRPV1

spinal cord

194
Q

What is osteoprotegerin (OPG)? (2)

A

A secreted soluble receptor (member of TNF receptor family)

which can bind to RANKL and act as a decoy receptor.

195
Q

Briefly describe the mechanism by which osteoprotegerin affects osteoclasts. (3)

A

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
Q

Describe the general effect of OPG on pain behaviour in models of bone cancer. (1)

A

Decreases pain behaviour

197
Q

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

a) decreases development of allodynia

b) does not alter existing allodynia

198
Q

Describe why using OPG to treat bone cancer pain in clinical practice is limited. (2)

A

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
Q

Give four effects of OPG given from onset of tumour growth in animal models, on bone changes seen in cancer. (4)

A
  • Increased bone mineral density
  • Reduced number of osteoclasts
  • Decreased tumour-induced bone destruction
  • Suppressed bone resorption
200
Q

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.

A

Osteoclasts

destruction

201
Q

Newer research suggests that what molecule, contained in exosomes, may contribute to cancer pain? (1)

A

Lysophosphatidic acid (LPA)

202
Q

Describe the levels of lysophosphatidic acid (LPA) seen in tumour bearing mice compared to naive mice. (1)

A

Serum LPA increased

203
Q

Describe the effect that you would see when adding an LPAR antagonist on withdrawal frequencies and latencies in tumour-bearing mice. (2)

A

Reverses increased withdrawal frequencies

Reverses reduced latencies

204
Q

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)

A

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
Q

Name three initial symptoms of pancreatic cancer. (3)

A

Weight loss

Fatigue

GI problems

206
Q

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.

A

True

207
Q

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.

A

does not

sensory

sympathetic

acute pancreatitis

208
Q

True or false? Explain your answer if necessary. (1)

In pancreatic cancer, early cellular changes due to tumour growth don’t cause pain.

A

True

209
Q

Describe two methods of how pain can be measured in a mouse model that spontaneously develops pancreatic cancer. (2)

A

Hunching profiles

Degree of vocalisation

210
Q

Describe the changes to pathological markers and pain behaviours seen in early stages of pancreatic cancer. (2)

A

Significant increases in pathological markers.

No pain behaviours are shown.

211
Q

Describe the changes to pathological markers and pain behaviours seen in late stages of pancreatic cancer. (2)

A

Some changes in pathological markers.

Lots of pain behaviour.

212
Q

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)

A

Vascularisation (CD31)

Macrophages (CD68)

Myelinated sensory fibres (RT97)

Peptidergic sensory fibres (CGRP)

Sympathetic nerve fibres (TH)

213
Q

Does weight loss in pancreatic cancer start before or after pain onset? (1)

How can we show this? (1)

A

Weight loss starts before pain

Look to see when weight loss and hunching start

214
Q

Fill the gaps relating to pancreatic cancer. (2)

There seems to be a mismatch between ……………….. and ……………………. in pancreatic cancer mice.

A

pain

pathology

215
Q

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)

A

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
Q

Describe two histological/morphological changes seen in pancreatic cancer relating to blood vessels and sensory nerve fibres. (2)

A

Disorganised appearance of blood vessels

Increase in density of CGRP-expressing sensory fibres (sprouting near newly formed blood vessels)

217
Q

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)

A

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
Q

Describe the proposed site of action of opioids in pancreatic cancer. (2)

How could this be shown experimentally? (2)

A

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
Q

Very briefly describe why early stages of pancreatic cancer does not cause pain. (1)

A

Because there are changes in the endogenous opioidergic system (likely within the CNS) which prevents pain development.

220
Q

Describe two specific observations regarding pancreatic cancer cells and endogenous opioid production. (2)

A
  • Met-enkephalin is expressed by pancreatic tumour cells
  • Patients with pancreatic cancer have higher plasma levels of met-enkephalin
221
Q

According to a systematic literature review, chronic pain affects what proportion of the UK population? (1)

A

1/3 to 1/2

222
Q

Give four causes of chronic musculoskeletal pain. (4)

A
  • Osteoarthritis
  • Rheumatoid arthritis
  • Low back pain
  • Fibromyalgia
223
Q

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.

A

False - first part is correct, but it affects 4-5% of the adult population

224
Q

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.

A

False - it affects 9.6% of men and 18% of women

225
Q

What is the lifetime risk for developing symptomatic knee OA? (1)

A

About 45%

226
Q

What is the most prominent symptom of arthritis? (1)

A

Pain

227
Q

What is the most important determinant of disability in OA? (1)

A

Pain

228
Q

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 ………………………..

A

articular cartilage

chondrocytes

subchondral bone

joint loading

friction

229
Q

Compare the innervation and vascularisation of cartilage and bone in a joint. (4)

A

Cartilage:
- no nerves
- no blood vessels

Bone:
- highly innervated
- highly vascularised

230
Q

The cells in cartilage maintain a matrix rich in what two substances? (2)

A
  • Collagen
  • Proteoglycans
231
Q

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.

A

mechanical

biological

degradation

synthesis

chondrocyte

matrix

subchondral

232
Q

Briefly describe four joint changes that are seen in osteoarthritis. (4)

A
  • 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
Q

Describe how the prevalence of OA changes with age. (1)

Why is this? (1)

A

OA prevalence majorly increases with age

because ageing is the primary factor contributing to abnormal cartilage repair.

234
Q

Give four signs/symptoms of OA. (4)

A
  • Joint pain
  • Tenderness
  • Limitation of movement
  • Variable degree of inflammation
235
Q

Give three risk factors for development of osteoarthritis. (3)

A
  • Mechanical injury
  • Hereditary factors
  • Ageing
236
Q

Describe what is thought to cause initiation of OA. (1)

A

Activation of stress-induced pathways

237
Q

Describe three cellular/molecular mechanisms that are taking place in early-stage OA. (3)

A

Metalloproteinase formation

Cytokines

Collagen degradation

238
Q

Describe five cellular/molecular mechanisms that are taking place in progressing and late-stage OA. (5)

A
  • Cell death
  • Collagen gene activation
  • Changes in collagen
  • Osteophyte formation
  • Synovial inflammation and thickening
239
Q

Give three ‘risk factors’ or pathological mechanisms which contribute to the progression from early to late stage OA. (3)

A

Inflammation

Repetitive injury

Subchondral bone changes

240
Q

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 ………………………

A

cytokines

growth factors

241
Q

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.

A

changes in load

inflammatory cytokines

NGF

NMDA receptor

glutamate

cytokines

inflammatory

IL-1b

242
Q

True or false? Explain your answer if necessary. (1)

Osteoarthritis is a purely mechanical disease, with no signs of inflammatory mechanisms.

A

False - inflammation plays a huge role in OA

243
Q

Briefly describe how nociceptors may be sensitised in OA. (5)

A
  • 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
Q

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.

A

True

245
Q

Fill the gaps relating to joint damage vs pain in OA. (2)

More advanced MRI scans reveal ………………………… in about ……………..% of symptomatic OA patients.

A

bone marrow lesions

80

246
Q

Fill the gaps relating to joint damage vs pain in OA. (2)

Arthroscopy shows ………………….. in about ……………% of symptomatic OA patients.

A

synovitis

50

247
Q

Fill the gaps relating to OA. (2)

Pathological changes do not line up 100% with symptoms, so there is a mismatch between ………………… and …………………

A

pain

pathology

248
Q

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.

A

nociceptive

neuropathic

synovitis

bone marrow lesions

249
Q

Why may joint replacement not be particularly effective in reducing OA pain in about 20% of patients? (1)

A

About 20% of patients have features consistent with central sensitisation mechanisms

250
Q

Compare the pain relief given by oral NSAIDs vs opioids in osteoarthritis. (1)

A

Offer similar pain relief

251
Q

True or false? Explain your answer if necessary. (1)

Opioid analgesics are the gold standard for treating OA pain.

A

False - they are not particularly useful in chronic OA pain.

252
Q

True or false? Explain your answer if necessary. (1)

Opioids are not particularly useful in osteoarthritis pain, so they are rarely prescribed.

A

False - they are not particularly useful however are still often prescribed (1.1mil opioid prescriptions for OA pain is Australia)

253
Q

True or false? Explain your answer if necessary. (1)

High opioid use for OA pain continues even 4 years post total knee replacement.

A

True

254
Q

Give another aspect of pain that is associated with high rate of opioid use even after total joint replacement in OA. (1)

A

Pain catastrophising

255
Q

What aspect of pain is a major predictor for opioid misuse in chronic pain patients? (1)

A

Pain catastrophising

256
Q

Why is it unlikely for pain to be coming directly from the articular cartilage in OA? (1)

A

Cartilage is aneural

257
Q

Name four structures in the joint that are richly innervated and contain nerve endings. (4)

A
  • Subchrondral bone
  • Synovium
  • Ligaments
  • Joint capsule
258
Q

Suggest two specific tissues that are thought to be the source of pain in OA. (2)

Why is this? (2)

A

Synovium

Subchrondral bone

Because there is a correlation between pain and synovitis

and between pain and subchondral bone changes.

259
Q

True or false? Explain your answer if necessary. (1)

The features of OA pain phenotype support both peripheral and central sensitisation mechanisms.

A

True

260
Q

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)

A

‘Widespread hyperalgesia’ suggests that secondary hyperalgesia is occurring

and secondary hyperalgesia is caused by CNS changes.

261
Q

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)

A

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
Q

Describe how you could test for the presence of widespread hyperalgesia, or secondary hyperalgesia in knee OA patients. (2)

A

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
Q

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)

A

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
Q

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)

A

Use fMRI

to measure brain activation in response to a painful stimulus.

265
Q

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)

A

Lower thresholds

Hyperalgesic

266
Q

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)

A

Brainstem

Activation was greater in OA patients.

267
Q

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)

A

Positive correlation (increased pain means more PAG activation).

There may be a difference in descending pain modulation in OA.

268
Q

Briefly describe two pieces of evidence supporting the fact that there may be a difference in descending pain modulation in OA patients. (2)

A

fMRI shows increased brainstem activation in OA patients after punctate stimuli.

Positive correlation between referred pain score and PAG activation in OA patients.

269
Q

Describe three animal models of osteoarthritis. (3)

A

Surgical model (meniscal transection)

Spontaneous model (Dunkin Hartley guinea pig)

Metabolic model (monosodium iodoacetate)

270
Q

Give two pathological changes in the joint that are seen with the meniscal transection animal model of OA. (2)

A
  • Erosion of cartilage and bone
  • Osteophyte formation
271
Q

Give a potential drawback of the meniscal transection animal model of OA. (1)

A

Pain responses are limited

272
Q

Give a benefit and a drawback of using the Dunkin Hartley guinea pig as an animal model of OA. (2)

A
  • Natural cartilage degeneration from 3 months (more closely mimics disease pathogenesis)
  • No suitable controls
273
Q

Briefly describe what MIA is and how it induces OA in animal models. (3)

A
  • Inhibitor of glycolysis
  • Disrupts chondrocyte metabolism
  • So causes cartilage degeneration
274
Q

Name a pathological change in the joint that is seen with the MIA model of OA in rodents. (1)

A

Cartilage degeneration

275
Q

In terms of pain behaviour, what is the advantage of using the MIA model to induce OA in animals? (1)

A

This model produces reproducible pain behaviour

276
Q

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

A

Non-noxious:
- firing rates the same in young and old animals (no significant difference)

Noxious:
- Higher firing rate in aged animals

277
Q

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)

A

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
Q

Describe how the paw withdrawal thresholds change after induction of an MIA model of OA in rodents. (1)

A

PWT gradually decreases

279
Q

Describe how firing frequency in response to von Frey hairs changes after induction of an MIA model of OA in rodents. (1)

A

Increased response (firing frequency) to von Frey hairs

280
Q

Briefly describe the DMM animal model of OA. (1)

Is this a slowly-developing or a rapidly-developing animal model of OA? (1)

A

Destabilisation of medial meniscus

Slowly-developing

281
Q

Describe what you would see in terms of cartilage damage in the following animal models of OA:

  • MIA
  • MNX
  • DMM

(3)

A

MIA = increased cartilage damage

MNX = increased cartilage damage

DMM = increased cartilage damage

282
Q

Describe what you would see in terms of synovitis in the following animal models of OA:

  • MIA
  • MNX
  • DMM

(3)

A

MIA = increased synovitis

MNX = increased synovitis

DMM = increased synovitis

283
Q

Describe what you would see in terms of changes in subchondral bone in the following animal models of OA:

  • MIA
  • MNX
  • DMM

(3)

A

MIA = increased TRAP positive osteoclasts

MNX = increased osteophytes

DMM = larger osteophytes

284
Q

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:
……………………………..
…………………………….
…………………………….

A

representative

cartilage damage

synovitis

changes in subchondral bone

285
Q

Describe three specific cartilage changes that are seen in MIA, MNX, and DMM animal models of OA. (3)

A
  • Increased cartilage damage (both microscopically and macroscopically)
  • Increased chondrocyte hypertrophy
  • Increased proteoglycan loss
286
Q

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.

A

True

287
Q

Which animal model of OA (out of MIA, MNX, DMM) shows an increased number of TRAP positive osteoclasts in the joint? (1)

A

MIA

288
Q

Which animal model of OA (out of MIA, MNX, DMM) shows increased Nav1.8 positive nerve fibre sprouting? (1)

A

DMM

289
Q

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.

A

Nav1.8 positive afferents

remodelling

sprouting

pain behaviour

human OA conditions

290
Q

Give three different structural compartments of the knee where there is evidence for increased Nav1.8 sprouting in a DMM model of OA. (3)

A
  • Medial synovium
  • Medial meniscus
  • Subchondral channels/bone
291
Q

Is NGF increased or decreased in an osteoarthritic joint? (1)

A

Increased

292
Q

Give two targets that NGF binds to. (2)

A

TrkA

p75

293
Q

Is p75 a low or high affinity receptor for NGF? (1)

A

Low affinity

294
Q

Give two general cell types which express receptors for NGF in an OA joint. (2)

A

Nerve terminals

Immune cells

295
Q

True or false? Explain your answer if necessary. (1)

The sole source of NGF in an osteoarthritic joint is macrophages.

A

False - there are multiple sources of NGF including macrophages

296
Q

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 ……………………………..

A

TrkA

nociceptor terminals

TRPV1

gene expression

TrkA positive sensory nerves

297
Q

Describe a human experiment which shows that NGF specifically leads to pain and OA symptoms. (4)

A

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
Q

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)

A

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
Q

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)

A

Decreased cartilage damage

Increased pain (hyperalgesia)

300
Q

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)

A
  • Increased synovial nerve fibre densities with PKCd KO
  • There is also increased synovial nerve fibre densities in humans with OA pain
301
Q

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)

A

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
Q

Suggest a potential treatment for OA pain which targets NGF. (1)

A

Humanized anti-NGF monoclonal antibodies (eg. Tanezumab)

303
Q

Describe how clinical trials are currently going for using anti-NGF antibodies to treat OA pain. (7)

A

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
Q

Describe a potential way of modulating osteoclast function to treat OA pain. (1)

A

Osteoprotegerin (OPG)

305
Q

Describe how pre-emptive treatment with osteoprotegerin alters weight-bearing asymmetry in MIA rats (compared to vehicle-treated MIA rats). (1)

A

OPG reduces weight-bearing asymmetry

306
Q

Describe how pre-emptive treatment with osteoprotegerin alters paw withdrawal thresholds in MIA rats (compared to vehicle-treated MIA rats). (2)

A

PWTs higher with OPG

but only partially recovered (still not as high as non-MIA rats).

307
Q

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)

A

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
Q

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)

A

Slightly reduced channels crossing OCJ

Higher chondrocyte appearance score (it is supposed to be low)

Same amount of proteoglycan loss

309
Q

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)

A
  • 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.

Neuroscience Y3S1 (7 decks)

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