Animal models of pain Flashcards

1
Q

2 types of chronic pain

A
  • inflammatory

- neuropathic

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2
Q

Chronic pain arises due to

A

diseases (HIV, MS, cancer) or

injury (peripheral nerve, spinal cord)

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3
Q

Chronic pain is often ____ and responds poorly to ______

A

Often intractable and respond poorly to standard analgesics (NSAIDS, Opioids)

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4
Q

Animal models of pain important b/c

A

it is essential to understand the pathophysiology of these conditions and to (hopefully) develop new and better agents for pain relief
affect 11-29% of canadians

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5
Q

Pain definition

A

An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

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6
Q

Pain is influenced by _____ and _____ processes

A

Physiological and cognitive processes

Ex. Emotion, Memory, Culture

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7
Q

Understanding pain in animal research–needs to model…

A

affect/emotion and culture

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8
Q

Nociception

A

The perception of real or potential tissue-damaging stimuli

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9
Q

In the lab we typically measure

A

nociceptive withdrawal reflexes

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10
Q

Noicieptive assays process

A

a) Establish baseline response
-latency to respond to a stimulus
-duration of response to a stimulus
-quantitative measure i.e force or grams required to elicit response
b) Manipulate
c) Re-assess the response
Change from baseline reflects altered sensory processing

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11
Q

Hyperalgesia

A

An increased response to a stimulus which is normally painful

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12
Q

Allodynia

A

Pain due to a stimulus which does not normally evoke pain

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13
Q

Things measured in assays: latency to response

A

time to respond

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14
Q

Things measured in assays: duration of response

A

how long the response lasts

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15
Q

Things measured in assays: quantative measures

A

How much stimulus does it take to elicit a response

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16
Q

Manipulations in assays

A

can be damage to a peripheral nerve (mimic neuropathic pain) OR induced inflammation

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17
Q

Common sensory modalities tested in assays

A
  • Thermal
  • mechanical
  • chemical
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18
Q

Thermal tests include

A
  • noxious heat (<49°C), cold (>4°C)

- innocuous warm/cool

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19
Q

Mechanical tests include

A
  • punctate stimulation (von Frey Hairs)

- pressure

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20
Q

Chemical tests include

A
  • capsaicin, mustard oil (both activate ‘heat’)
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21
Q

“Hargreaves test” measures (what modality)

A

Thermal sensitivity

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22
Q

“Hargreaves test”–how

A

Radiant heat briefly applied to surface of the hindpaw
Measure latency to withdraw from heat source
Several trials for each paw
Calculate average withdrawal latency

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23
Q

“Hargreaves test”–baseline; manipulation and expected result

A

Baseline: threshold latency: ~12s
Manipulate: hindpaw inflammation
Re-assess: 3hrs after inflammation
latency to withdraw ~4s. = heat hyperalgesia

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24
Q

Acetone test measures (what modality)

A

sensitivity to cold/cool stimuli

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25
Q

Acetone test process

A

A small drop of acetone onto surface of hindpaw (normally innocuous)
Measure duration of response
Allodynia reflected by prolonged lifting and guarding of the paw

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26
Q

Acetone test–baseline; manipulation and expected result

A

Baseline: threshold duration of response: ~1s
Manipulate: animal model of MS
Re-assess: duration of response increases in mice with disease =Cold Allodynia

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27
Q

Von frey hairs measures

A

sensitivity to punctate mechanical stimuli

28
Q

Von frey hairs: How

A

Hairs are calibrated to deliver specific
amount of force when applied to the surface of the skin
Hairs are applied in ascending order of bending force (to hind paw)
Determine threshold force that elicits nociceptive withdrawal reflexes

29
Q

Von frey hairs–baseline; manipulation and expected result

A

Baseline: threshold 14g bending force
Manipulate: hindpaw inflammation
Re-assess: 3hrs after inflammation, force required to elicit nociceptive behaviour is ~3g =Tactile allodynia

30
Q

Issues with measuring treatments that relieve pain

A

It could be a true analgesic/anti-allodynic effect OR just sedation OR motor impairment (to explain lack of response)

31
Q

How to test if it is a true analgesic

A

Have to run other experiments to control for altered locomotion or sedation (assess motor function)

32
Q

How do we assess locomotor function as a control for treatments

A
“Open-field” activity OR
Rotorod assay (Assesses gross locomotor ability, co-ordination, balance)
33
Q

Rotorod assay

A

put animal on a rotating beam and monitor latency to falling off the beam–compare treatment to control

34
Q

Inflammatory pain cause

A

pain that arises as a result of cutaneous tissue injury

35
Q

How to model inflammatory pain

A

Inject small volumes of mediators that stimulate immune/inflammatory reactions (ex. carrageenan, CFA)

36
Q

How long do inflammatory pain models last

A

Affect sensory function (allodynia, hyperalgesia) for hours to days

37
Q

Neuropathic pain cause

A

pain that arises as a result of injury to the nervous system (peripheral or central).

38
Q

How long do Neuropathic pain model last

A

Sensory function affected (allodynia, hyperalgesia) for days to weeks

39
Q

“Seltzer Model” aka

A

Partial Nerve Injury

40
Q

Partial Nerve Injury/“Seltzer Model” HOW

A

Ligate (tie off) 1/3-1/2 of sciatic nerve

41
Q

Advantages of Partial Nerve Injury/“Seltzer Model”

A

relative ease of procedure

42
Q

Diadvanatages of Partial Nerve Injury/“Seltzer Model”

A
  • variability of injury from subject to subject; - variability between experimenters
  • nerves are rarely fully severed in real life (more often crushed–this doesn’t match that)
43
Q

“Bennett Model” aka

A

Chronic Constriction Injury

44
Q

Chronic Constriction Injury/ “Bennett Model” Process

A

4 chromic cat gut sutures loosely ligate sciatic nerve –> Leads to a gradual but progressive axonal injury AND Generates local inflammatory reaction

45
Q

Chronic Constriction Injury/ “Bennett Model” Advantages

A

closely resembles human pathology (i.e. crushed nerves)

46
Q

Chronic Constriction Injury/ “Bennett Model” Disadvantages

A
  • difficult surgery

- high variability between subjects & experimenters (even more variable than the seltzer model)

47
Q

Chung model aka

A

Spinal Nerve Ligation Injury

48
Q

Spinal Nerve Ligation Injury /“Chung Model” Process

A

Tightly ligate and cut L5 spinal nerve close to DRG (before it emerges and joins the schiatic nerve)–leave L3, L4, L6 uninjured
= mixing of injured and uninjured

49
Q

Spinal Nerve Ligation Injury /“Chung Model” Advantages

A

Consistent injury across all subjects (not variable)

50
Q

Spinal Nerve Ligation Injury /“Chung Model” Disadvantages

A

Very complicated surgery (have to remove spinal lamina to access spinal nerve–MEGA invasive)

51
Q

Spared Nerve Injury: process

A

Fully transect (cut) 2 of 3 terminal branches of the sciatic nerve (tibial & common peroneal) leave sural nerve intact (also mixing of injured and uninjured –> generates chronic and persistent change in pain sensitivity)

52
Q

Spared Nerve Injury: Advantages

A
  • consistency of injury across subjects

- ease vs. “Chung” model.

53
Q

Neuropathic Pain-Peripheral Nerve Injury produces

A
  • long term tactile allodynia
  • thermal hyperalgesia
  • cold allodynia
    AS intended then can use this pain to look at treatment modalities
54
Q

How to asess changes in sensory threshold AND how aversive (emotional aspect) the stimuli is with escape avoidance paradigm

A
  • more true to pain
    2 steps:
    1) Nerve injury or CFA inflammation + von Frey Hair stimulation (changes in threshold)
    2) Run testing in the context of an “Escape/Avoidance” paradigm (affective changes)
55
Q

“Escape/Avoidance” paradigm

A

Allowing an animal to choose b/t:
1 compartment that is dark and cozy (preferred) but has von frey hair stim
VS
Other compartment that is bright (scary to rats as they are prey) BUT no tactile stim

56
Q

“Escape/Avoidance” paradigm expected results

A

If allodynia occurs they will prefer (i.e. spend more time in) the brightly lit; if not they will prefer the cozy (as the mechanical stim isn’t off putting)

57
Q

“Escape/Avoidance” paradigm expected results

A

Measure time spent in “light” side of testing environment
Controls: spend only 30% of the time in light side
Nerve Injury/CFA: spend up to 90% of time in the light side (choose scary side over pain)

58
Q

“Conditioned Place Preference Paradigm”

A

Teach animal to associate one area with something (usually rewarding substances) and measuring time spent b/t the areas associated vs. not-associated with this substance

59
Q

“Conditioned Place Preference Paradigm” in Pain

A

Associate chamber with drug that removes pain

If there is an ongoing spont pain (as seen in humans) the animal should prefer the side that relieves the pain

60
Q

“Conditioned Place Preference Paradigm” : Clonidine OR. omega-conotoxin (vs. saline)

A

Both signal relief
Pre-conditioning–equal time in both
in Sham: equal time in both
with SNL (damage)–prefer drug side over saline (b/c it removes pain)

61
Q

Adenosine

A

In humans-spinal adenosine reduces ‘evoked’ pain. Ineffective for ongoing pain

62
Q

adenosine in animal studies of CPP

A

adenosine reverses mechanical thresholds BUT

No preference for adenosine over saline after SNL (measure of spont pain)

63
Q

Open field test measures…

A

anxiety state (affective component of pain)

64
Q

Open field test in pain studies

A

NO injury–most of time spent against wall but curiosity brings them to explore the centre
HIV-neuropathy (PAIN)–large amount of time against the wall, less curious, not exploring center = ANXIETY

65
Q

How to test pain vs noicieption

A

Incorporate assays that examine psychological learned associations to get additional insight into ‘qualitative’ aspects of the pain experience in rodents