L05 - Pain

Question 1

What is pain?

Answer 1

• An unpleasant sensory and emotional experience associated with actual or potential tissue damage
• It is a combination of sensory (discriminative) and affective (emotional) components

Question 2

What is nociception?

Answer 2

The sensory component of pain alone, distinct from its emotional component - i.e. pain signal from periphery to cerebral cortex

Question 3

What are nociceptors and where are they found?

Answer 3

• Free nerve endings that respond to pain

- They are found in skin, muscle and viscera

Question 4

What are the two types of nociceptors and how do they differ?

Answer 4

1 - Mechanical nociceptors - respond to shearing forces in the skin - produce a sharp pain - innervated by Aδ fibres

2 - Polymodal nociceptors - respond to many stimuli, including shearing forces, heat and substances released by damaged tissue - produce a dull, burning pain - innervated by C fibres

Question 5

List 5 substances released by damaged tissue that stimulate polymodal nociceptors.

Answer 5

1 - K+

2 - H+

3 - Histamine

4 - Prostaglandins

5 - Bradykinin

Question 6

Where do nociceptors synapse?

Answer 6

Directly or indirectly with secondary neurones in the substantia gelatinosa of the grey matter dorsal horn

Question 7

What are the differences between Aβ fibres, Aδ fibres and C fibres with regards to myelination, conduction velocity, and information?

Answer 7

Aβ:

• Very myelinated
• 20 – 100 ms-1 conduction velocity
• Innocuous information

Aδ:

• Some myelination
• 4 – 30 ms-1 conduction velocity
• Noxious + innocuous information

C:

• No myelination
• <2.5 ms-1 conduction velocity
• Noxious information

Question 8

On which laminae do different fibres synapse?

Answer 8

• Aβ fibres synapse in laminae III-V

- Aδ & C fibres from cutaneous regions synapse in laminae I-II, and from viscera synapse diffusely at lamina I, V, & X

Question 9

Describe the gate theory of pain.

How does this work?

Answer 9

• Non-painful input closes the nerve ‘gates’ to painful input, which prevents pain sensation from travelling to the CNS
• The majority of interneurones between primary sensory neurones and secondary sensory neurones are inhibitory
• Fibres that do not convey pain information such as Aβ fibres will excite both the secondary sensory pain neurone (leading to the brain) and the inhibitory interneurone. The excitatory signal from the Aβ fibre is cancelled out by the inhibitory interneurone
• Only pain signals that overcome this inhibition reach the brain:
• Aδ and C fibres excite both secondary sensory pain neurones and inhibitory interneurones which inhibit the inhibitory interneurones that synapse with Aβ fibres. This diminishes the inhibition to the secondary sensory neurone caused by the Aβ fibre interneurone, reopening the gate

Question 10

Why does rubbing a wound reduce the intensity of pain?

Answer 10

• Rubbing the wound excites Aβ fibres

- According to the gate theory of pain, Aβ fibres excite an interneurone which inhibits the secondary sensory neurone

Question 11

Through which tract do secondary neurones conveying pain signals ascend to the brain?

Answer 11

The spinothalamic tract

Question 12

What is the functional difference between the cortex and subcortical areas of the brain with regards to the processing of pain information?

Answer 12

• The cortex is responsible for localising pain

- The subcortical areas are responsible for perceiving pain

Question 13

Which system of the brain is responsible for the generation of an emotional response to pain?

Answer 13

The limbic system

Question 14

What is the intrinsic analgesic system?

Answer 14

• Descending pathways from brainstem nuclei (e.g. periaqueductal grey, nucleus raphe magnus, & locus coereleus) make up the intrinsic analgesic system
• They cause the release of 5-HT, NAd, & encephalin in the spinal cord
• These close the gate at the level of the dorsal horn & thus inhibit the sensation of pain

Question 15

How does normal physiological pain differ physiologically from persistent / chronic states of pain?

Answer 15

• In normal physiological pain the sensation of pain is equal to the afferent input in terms of duration and sensitivity (i.e. the rate of action potential firing directly causes the level of pain felt)
• However the processes of peripheral and central sensitisation lead to a modification of neurotransmission
• This is referred to as plasticity in nociceptive pathways, and occurs at all levels
• Persistent/chronic pain states increase sensitivity to pain

Question 16

What is hyperalgesia?

Answer 16

An enhanced painful response to a normally painful stimulus - something previously painful generates more pain than before

Question 17

What is allodynia?

Answer 17

• A painful response to a normally non-painful stimulus

- This is due to a shift in the pain threshold in which action potentials are generated at a lower level of stimulation

Question 18

Describe the mechanism that underlies primary hyperalgesia.

Answer 18

• Noxious stimulation activates nociceptor directly & causes release of various factors in damaged skin/underlying tissue
• Antidromic AP propagation (‘axon reflex’) can occur along primary afferent branches that innervate injured tissue
• Stimulates substance P & CGRP release from peripheral nerve endings, which act on vasculature causing redness, swelling, plasma extravasation, & immune cell migration into tissue
• Immune cells release pro-inflammatory PGs, H+, bradykinin, NGF, cytokines, which act on polymodal nociceptor to lower threshold for AP generation (= neurogenic inflammation)
• Lower threshold causes peripheral sensitisation
• Peripheral sensitisation -> enhanced pain sensitivity that occurs directly in damaged tissue = primary hyperalgesia

Question 19

What change occurs in a neurone to become sensitised?

Answer 19

The threshold for action potential generation is lowered

Question 20

What is secondary hyperalgesia?

Answer 20

Increased pain sensitivity distant from the site of injury

Question 21

Describe the peripheral mechanism for secondary hyperalgesia.

Answer 21

• Antidromic action potentials propagate along fibre branches that innervate injured and neighbouring uninjured tissue
• This results in sensitisation of the neurone branches that innervate the neighbouring uninjured tissue, as well as the neurones direct to the injury site

Question 22

Describe the central mechanism for secondary hyperalgesia.

Answer 22

• A high frequency afferent input invades the pre-synaptic terminal; this stimulates substance P release as well as increasing glutamate release
• Substance P and extra glutamate are only released in high frequency situations, and therefore are not involved in acute pain signalling
• The combination of substance P acting at the NK1 receptor, and glutamate acting at the AMPA receptor, produces sufficient depolarisation of the post synaptic membrane to relieve voltage-dependent Mg2+ block of the NMDA receptor
• Glutamate is therefore able to bind to the NMDA receptor, resulting in Ca2+ entry to the secondary neurone
• This activates second messengers within the neurone that increase its responsiveness and amplify the rate of action potential efferent firing along the ascending nociceptive pathway