Lecture 3

Question 1

What is sensitisation?

Answer 1

increased responsiveness of nociceptive neurons to their normal input and/or recruitment of a response to normally subthreshold inputs

Question 2

What is peripheral sensitisation?

Answer 2

Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields

Question 3

What are the peptides released by nociceptors at 2nd order neuron (dorsal horn)

Answer 3

Calcitonin gene-related peptide (CGRP)
Substance P
Glutamate

Question 4

Effect of inflammatory mediators

Answer 4

• Stimulates nociceptors directly (depolarise)
• Lowers the threshold for activation of nociceptors (sensitising) e.g. prostaglandin, bradykinin
• Activates silent nociceptors (primarily C fibres)

Question 5

Describe peripheral sensitisation

Answer 5

• Damage to tissue
• Inflammatory soup (bradykinin, histamine, chemokines, cytokines, nerve growth factor, Adenosine triphosphate, prostaglandin) creates acidic environment
• Release of these substances lower activation threshold of nociceptors or trigger AP’s (binding to receptor opens ion channels) that activate nociceptors making area more sensitive
• continued activation causes transcriptional changes, which results in enhanced excitability of peripheral nerve (maintains peripheral sensitisation)
• some smudging: APs cause release of NT’s which elicit inflammatory mediator release from adjacent tissue, which spreads inflammatory response

Question 6

What are the cardinal signs of peripheral sensitisation

Answer 6

Heat
Swelling
Redness
Pain

Question 7

What are the pro-inflammatory mediators?

Answer 7

Bradykinin
Histamine
Chemokines
Cytokines
Nerve growth factor
Adenosine triphosphate
Prostaglandin E2

Question 8

What is central sensitisation?

Answer 8

Increased responsiveness of nociceptive neurons in the CNS to their normal or subthreshold afferent inputs

Question 9

What are the changes in the spinal cord from central sensitisation

Answer 9

Increased efficacy of synapses
- increased receptors
- increased presynaptic release of glutamate
- increased calcium influx through NMDA receptor
- expansion of the receptive fields of the spinal cord

Disinhibition
- decrease in GABA

Question 10

Central sensitisation results in:

Answer 10

increased outputs from primary afferent terminals increases the excitability of the post synaptic neurons, directly and through activation of secondary mechanisms

• Development of or increases in spontaneous activity
• A reduction in the threshold for activation by peripheral stimuli
• Increased responses to suprathreshold stimulation
• An enlargement of receptive fields

Question 11

Other mechanisms to consider for central sensitisation

Answer 11

Epigenetics
Immune system
Individual variation

Question 12

What is hyperalgesia

Answer 12

Painful stimuli that was painful to begin with becomes more painful

Question 13

What is allodynia

Answer 13

Non-painful stimuli previously now becomes painful

Question 14

What is neuropathic pain

Answer 14

Pain caused by a lesion or disease of the peripheral somatosensory nervous system

Question 15

Positive signs of neuropathic pain

Answer 15

Paresthesia (numb, P&Ns)
Dysesthesia (abnormal physical touch sensation without outside cause)
Paroxysmal pain (skin redness/warmth and attacks of pain)

Question 16

Negative signs and symptoms of neuropathic pain

Answer 16

tactile hypoesthesia (abnormal sensory response, sensation reduced)
Pinprick hypoalgesia
Loss of vibration sensation

Question 17

What are the peripheral and central mechanisms of neuropathic pain?

Answer 17

Peripheral
- Peripheral sensitisation mechanisms
- Ectopic impulse generation

Central
- increased glutamate levels
- synaptic efficacy
- axonal sprouting
Disinhibition (+apoptosis of interneurons)

Question 18

What is ectopic impulse and which type of pain does it occur in?

Answer 18

Spontaneous firing of AP’s resulting in pain in absence of identifiable stimulus
Neuropathic pain

Question 19

What is nociplastic pain?

Answer 19

Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain

Question 20

Describe Wind Up

Answer 20

State of hyperexcitability in CNS
- Increased electrical activity from 1st order neuron means more synapsing with 2nd order neuron so depolarisation occurs easier

Question 21

In peripheral sensitisation activation of nociceptors as well as retrograde transport of NGF bound to its receptor causes what?

Answer 21

transcriptional changes, resulting in increased production of sodium channels, CGRP and SP which results in enhanced excitability of peripheral nerve which maintains state of peripheral sensitisation