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BIOM30001 - Frontiers in Biomedicine > Lecture 24 - Introduction to Pain > Flashcards

Lecture 24 - Introduction to Pain Flashcards

1
Q

Outline the various types of pain

A
  1. Nociceptive
    • Triggered by brief injury
    • Results in brief pain
    • Nociceptors carry message to CNS where ‘pain’ is generated
  2. Inflammatory
    • Mediators in inflamed tissue activate nociceptors
    • Results in persisting pain
  3. Neuropathic
    • Abnormal circuits in the CNS
    • Can be triggered by non-noxious stimuli, e.g. feather
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2
Q

Give the IASP definition of ‘Pain’

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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3
Q

What is nociception?

A

Neural encoding and processing of noxious (painful) stimuli

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4
Q

What are nociceptors?

A

Free nerve endings in tissue (skin, bone) that are activated by noxious stimuli

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5
Q

List ways that nociceptors can become activated

A
  1. Mechanical stimuli
  2. Thermal stimuli
    • Heat
    • Cold
3. Chemical stimuli
 • H+
 • ATP
 • Prostaglandin
 • Bradykinin
 • Caspaicin
 • Histamine
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6
Q

Describe nociception following tissue injury

A 
1. Tissue injury results in release of:
 • Bradykinin
 • Prostaglandin (through inflammation and activation of COX2)
 • ATP
 • Acid
  1. These chemical activate receptors on nociceptors in damaged tissue
  2. Activated nociceptors release:
    • Substance P
    • CGRP
  3. Substance P causes mast cell degranulation, releasing histamine, as well as increased vascular permeability (along with CGRP), resulting in tissue oedema
  4. Nociceptor conducts message to dorsal horn of spinal cord, where ‘pain’ experience is generated
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7
Q

How can prostaglandin synthesis be pharmacologically targeted?

A

NSAIDs, such as aspirin and ibuprofen

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8
Q

What is the effect of CGRP?

Where does it come from?

A

Released by activated nociceptors

Results in increased vascular permeability → tissue oedema

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9
Q

Define the following terms:
• Hyperalgesia
• Allodynia

A

Hyperalgesia:
• Increased sensation of pain to a stimulus of a given noxious intensity
• i.e. Less intense stimuli can result in pain that would normally be elicited by a very intense stimulus
e.g. pain of showering when sunburnt

Allodynia:
• Pathological response to non-noxious stimuli
• e.g. excruciating pain upon light touch

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10
Q

When does pain hypersensitivity occur?

Describe the mechanism

A

This occurs after tissue injury

Early inflammation:
• Amplification of chemical mediators that activate nocicpetors

Long terms changes:
• Transcription of ‘pain’ receptors, ion channels and neurotransmitters
• This is driven by cytokines and GFs

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11
Q

Define dermatome

A

Area of skin supplied by a given spinal nerve

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12
Q

Describe the axonal transport of somatic pain signals from the tissue to the CNS

A
  1. Nociceptor activated in tissue
  2. Action potential travels up axon
    • Cell body in dorsal root ganglion
  3. Synapse on neuron in dorsal horn of spinal cord
  4. Pain pathway projects to:
    • Superior colliculus
    • Periacqueductal grey (PAG)
  5. Further projections to many areas in the brain
    • Dopaminergic system
    • Cardiovascular centre
    etc.
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13
Q

Outline the different neuron types

A

Aα - motor and proprioception, heavily myelinated
Aβ - touch and pressure
Aγ - motor to muscle
Aδ - pain, temp., touch

B - preganglionic autonomic

C - pain, reflex, postganglionic autonomic

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14
Q

Which neurons detect pain?

Differentiate between them

A

Aδ:
• Sharp, prickling, acute pain

C:
• Slow, aching, throbbing, burning pain

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15
Q

Describe what happens to the sensation of pain in the spinal cord

A
  • Modulation of the signal being transmitted by nociceptors
  • Dampening aspects
  • Interneurons, afferents etc. are interconnected
  1. Primary nociceptor neuron release glutamate
  2. Glutamate moves across synaptic cleft and acts on receptor on the post-synaptic neuron:
    • NMDA
    • AMPA

Attenuation of pain:
• Other neurons inhibit nociceptor neurons in the spinal cord - ‘gate control theory’
• Descending signals form the brain can inhibit nociception in the spinal cord (think about the soldiers tuning out the pain)

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16
Q

Describe Gate Control Theory

A

a. Interneurons in the spinal cord can release endorphins, which inhibit the neurons that are conducting the ‘pain’ signals
b. Furthermore, vibration stimuli detected by Aβ neurons, can inhibit ‘nociceptor’ neurons in the spinal cord and activate the inhibitory interneurons, thus attenuating pain

Nociceptors, on the other hand, activate neurons in the spinal cord that synapse with the pain centres

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17
Q

What effect do endorphins have on nociception?

A

Endorphins inhibit pain

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18
Q

Compare the neurotransmitters release by excitatory and inhibitory neurons

A

Excitatory:
• Glutamate
• Aspartate

Inhibitory:
• GABA

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19
Q

Which receptors does glutamate act on on the post-synaptic neuron?

Compare them

A

AMPA:
• Low activation threshold

NMDA:
• High activation threshold

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20
Q

Describe the NMDA receptor

A

Transmembrane pore plugged with Mg2+ in inactive state

Protracted nociceptor results in the displacement of the Mg2+

The receptor is now resistant to opioids

→ “Wind-up”

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21
Q

Describe the effects of opioids

Where do they predominantly act?

A

Pre-synaptically:
• Decrease neurotransmitter release

Post-synaptically:
• Hyperpolarisation of post synaptic neuron

Predominantly act in the spinal cord

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22
Q

What type of receptor is the opioid receptor?

A

GPCR

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23
Q

Where are nociceptors (ascending to the brain) located in the spinal cord?

A

Dorsal horn

24
Q

Describe how descending pathways attenuate pain

How could this be exploited pharmacologically?

A

(think about the wounded soldiers)

Descending neural projections from the brain can inhibit Adelta and C fibres that are conducting pain signals through the spinal cord

Descending neurons release:
• Adrenaline
• Serotonin

Since these pain attenuating descending neurons are adrenergic and serotonergic, by mimicking this pharmacologically, one could block pain impulses

25
Q

Describe the experiments with Amitryptyline

What is amitryptyline?

A

Amitryptyline:
• NA and serotonin reuptake inhibitor
• Tricyclic antidepressant

  1. Mice administered with Amitryptyline
  2. Mice subjected to pain protocol
    • Tail placed in front of a heat source
    • Frequency of moving the tail away from the heat recorded
  3. Amitryptyline resulted in analgesia
    • 70x more potent than aspirin
    • Not as potent as morphine
26
Q

Describe the TPRV1 receptor

What activates it?

A

This is a receptor on nocicpetors that is activated by noxious stimuli

Ligands:
• Heat
• Capsaicin
• H+

27
Q

Describe the role of tricyclics antidepressants in central analgesia

A

Amitryptilline is a tricyclic antidepressant

Showed experimentally to produce a potent analgesic effect by actin on the spinal cord

28
Q

List ways that transmission in the spinal cord can be pharmacological targeted

A
  1. Amitryptilline
    • Inhibition of NA and serotonin reuptake
    • Mimics the activity of the inhibitory neural projections from the brain
  2. Gabapentin
    • Inhibits subunit of Ca channel in spinal neurons
29
Q

Describe the role of the ‘Periacquaductal grey’ area in the brain

How can this be therapeutically exploited?

A

PAG:
• Target of pain pathway projections from the spinal cord

Murine model:
• Stimulation of this area results in analgesia

Opioids stimulate this area

Therapy:
• Deep brain stimulation of this area for relief of chronic pain

30
Q

Describe the effect of pain on the cardiovascular system

A

Pain pathways to the brain then project further to the cardiovascular centre in the brain

Results in:
• Tachycardia
• Hypertension
• Vasoconstriction

31
Q

List the ‘levels’ upon which pain can be pharmacologically targeted

A
  1. Noxious stimuli
    • e.g. Aspirin and Ibuprofen inhibit prostaglandin production
  2. Nociceptor
    • Ketamine inhibits NMDA receptor
  3. Spinal cord
    • Activation of descending neural projections that normally inhibit pain pathways in spinal cord:
    - Amitryptilline (NA and serotonin reuptake inhibitor)
    • Gabapentin: Ca2+ channel inhibitor
    • Opioid: inhibition of neuronal transmission
    • Lignocaine: inhibits neuronal transmission
  4. Brain
    • Deep brain stimulation of PAG
    • Naraptriptan: serotonin agonist
32
Q

Describe how imaging technology can investigate the effect of drugs on the brain

A

e.g. fMRI
• Measure brain activity during experience of noxious stimulus (e.g. heat on hand)
• Look at the areas that light up during pain

Testing the effect of the analgesic:
• Administer the patient a drug, and see if there is diminished activity of the pain centres in the brain

33
Q

List ways that genetics can affect experience of pain

A
  1. Metabolism
    • Neurotransmitter metabolism (COMT: dopamine metabolism)
    • Drug metabolism (e.g. codeine metabolism)
  2. Receptor genes
    • ‘Stargazer’ gene
34
Q

Describe the role of the COMT gene in pain

A

COMT: enzyme that metabolises pain

If the enzyme is under active, there is increased dopamine in the system

Endorphins have less time to act on receptors

The individual has an increased susceptibility to pain

35
Q

What is the gold standard analgesic?

A

Morphine

36
Q

What is the definition of chronic pain?

How does chronic pain occur?

In which situations does it occur?

A

Chronic pain:
Pain that continues to be present more than three months after surgery or an injury or from various disease or other causes

Mechanism:
Structural remodelling leading to abnormal hyper-excitability of pain responses

The pain signal becomes embedded in the system (i.e. not triggered by external events)

When?
• 15-20% develop chronic pain after traumatic injury
• Conditions such as shingles
• Limb amputation (phantom limb syndrome)

37
Q

Describe the effect of sodium channel mutations in chronic pain

A

Sodium channel (Nav1.7) is key in the transmission of neural impulses in pain pathways

WT: no pain

PE disorder:
• Increased channel function mutation
• Painful hands and feet
• Autosomal dominant

PEPD disorder:
• Increased channel function mutation
• Ocular, mandibular and rectal pain
• Autosomal dominant

CIP disorder:
• Absent channel
• Absence of pain
• Autosomal recessive

38
Q

List some genetic pain syndromes

A
  • Familial hemiplegic syndrome
  • Primary erythermyalgia (PE)
  • Paroxysmal extreme pain disorder (PEPD)
  • Channelopathy-associated Insensitivity to Pain (CIP)
39
Q

Describe the ‘Stargazer’ mutation

A

‘Stargazer’ gene encodes ‘Stargazin’ protein
• A subunit of the AMPA receptor
• aka CACNG2

In this mutation, the protein is absent

Stargazer mice exhibit:
• Absence of seizures and ataxia
• Susceptible to neuropathic pain

Polymorphism of this gene in humans is associated with chronic pain

40
Q

Describe the role of codeine metabolism in chronic pain

A

Codeine metabolism:
• Codeine → Morpheine or Norcodeine
• Metabolised in the liver by CYP2D6

CYP2D6 mutation:
• Can’t metabolise codeine into morphine
• Codeine is ineffective in bringing about analgesia

41
Q

List analgesic medications

A
  1. Opioids
    • Mainstay for severe to moderate pain
  2. Paracetemol
  3. Aspirin
  4. NSAIDs
    • e.g. Ibuprofen
  5. Adjuvants
    • Antidepressants
    • NMDA antagonists
    etc.
42
Q

List side effects of morphine

A 
• Ventilatory depression
 • Drowsiness
 • Sedation
 • Urinary retention 
etc.
43
Q

Outline the strategies for pain management

A 
1. Multimodal analgesia
 • Small doses of opioids + non-opioids
 • Targets pain transmission at multiple sites (receptors)
 • Synergistic analgesic effect
 • Reduces opioid requirement
  1. Pre-emptive analgesia
    • Analgesia prior to injury (i.e. surgery)
    • Theorectically: attenuates injury and neuroplastic response
    • In practice, has little effect
  2. Regional anaesthesia
    • Targets nerve transmission
    • ‘Nerve block’
  3. General anaesthesia
    • Removes cognition: pain perception and transmission
    • Enables surgical procedures
44
Q

Define anaesthesia

A

Loss of sensation

45
Q

Define analgesia

A

Reduction in pain

46
Q

List limitations of analgesic drugs

A
  • Individual response
  • Inadequate pain control
  • Administration
  • Dependence, addiction
  • Multiple adverse effects (e.g. Bex, phenacetin, chronic renal failure)
47
Q

Describe pain and intervention in MI

A

Experienced pain:
• Crushing visceral pain
• Referred pain to arm and neck

Intervention:
• Aspirin in ambulance
• Morphine to relieve distress
• Glyceryl nitrate, thrombolysis

48
Q

Describe pain and intervention with a child with a broken leg

A

Pain:
• Distressed child

Intervention:
• Intranasal opioid delivers rapid analgesia

49
Q

Describe pain intervention with sports injury (e.g. shoulder reconstruction)

A
  • Paracetamol
  • NSAIDs
  • Synthetic codeine
  • Local anaesthetic
  • Morphine if required
50
Q

Describe pain intervention with migraine

What is the pathogenesis of migraine?

A

Pathogenesis:
• Cerebral vasodilation

Combined therapy:
1. Analgesics
• Aspirin
• Ibuprofen

  1. Vasoconstrictors
    • Ergotamine
    • Serotonin (5-HT) agonist
    • CGRP antagonists
51
Q

What drug is used for labour pain?

A

Inhalational NO

Morphine:
• Can not be used
• Crosses the placenta and harms to baby:
• Respiratory depression

52
Q

Describe spinal anaesthesia

A

Injection into spinal canal (dorsal horn) delivers anaesthesia to lower body

53
Q

Describe epidurals

A

Administer:
• Local anaesthetic
• Opioids

Into epidural space

Blocks nerves to uterus

54
Q

Describe an instance where pain is not triggered by physical stimuli

A

Emotional pain: e.g. rejection by friend induces experience of pain

55
Q

How do aspirin and ibuprofen act?

A

Inhibit production of prostaglandins

Prostaglandins activate receptors on nociceptor neurons
These neurons synapse on other neurons in the brain, generating the perception of pain

56
Q

Describe the action of ketamine

A

Analgesic

Acts on the NMDA receptor to inhibit pain

57
Q

Describe the action of cocaine

A

Local anaesthetic

Blocks neuronal transmission

BIOM30001 - Frontiers in Biomedicine (35 decks)

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