W6: Pain

Question 1

What is pain?

Answer 1

A response to a sensory input that is potentially damaging to the tissues.

Question 2

What is nociception?

Answer 2

The sensory component of pain

Question 3

What are nociceptors?

Answer 3

Sensory receptors that respond to stimuli sufficient to cause damage to the body. Activated by noxious stimuli. The free nerve endings.

Question 4

What are the 2 types of nociceptor?

Answer 4

Mechanical and polymodal nociceptors

Question 5

What are mechanical nociceptors activated by?

Answer 5

Strong sheering force in skin e.g., cut, strong blow. Produces a sharp pain.

Question 6

What do polymodal nociceptors respond to?

Answer 6

Many stimuli, e.g., sharp blow, damaging heat (>46°C), chemicals released by damaged tissue like K+ histamine H+ PGs bradykinin. Causes a dull burning pain.

Question 7

What fibres do mechanical and polymodal nociceptors have?

Answer 7

Mechanical nociceptors have Adelta fibres = relatively fat and myelinated (sharp pain)
Polymodal nociceptors gave C fibres = thing and non-myelinated (dull pain)

Question 8

What property do all nociceptors have?

Answer 8

They are all primary afferent fibres and are all excitatory.

Question 9

How is pain transmitted?

Answer 9

• stimulus is propagated up the axon, causing neurotransmitter release to pass the signal onto the second order neurone
• dorsal horn of the spinal cord has many output neurones and if activated they can send signals up to the brain
• for many Abeta fibres the axon can also split before the second order neurone and go upto the brain via the dorsal column pathway - important for non-noxious information but some noxious can go this way

Question 10

Does sharp or dull pain reach the brain first and why?

Answer 10

Sharp pain is first pain and dull pain is second pain.
Both Adelta and C fibres are activated by the same stimulus at the same time, but Adelta fibres are myelinated and will carry it faster, getting to the end of the fibre more quickly than the action potential generated in the C fibres.

Question 11

What is the substantia gelatinosa?

Answer 11

Lamina II of the dorsal horn. A superficial layer of the dorsal horn where the cell bodies of the second order neurones are carrying the information upto the brain. Nociceptive/noxious information enters this part.

Question 12

Where do Abeta Adelta and C fibres synapse in the dorsal horn?

Answer 12

Abeta spill synapse in the deeper layers III-V

Adelta and C fibres will synapse in more superficial layers: cutaneous I-II (topographic) or viscera I, V, X (diffuse)

Question 13

Why is the location of where the neurone synapses in the periphery important?

Answer 13

It determines precision of the localisation of the synaptic input coming into the dorsal horn. E.g., for the skin, primary afferent fibres send information upto a very specific neurone in the dorsal horn, which synapses with a very specific neurone in the brain, to be sent to the somatosensory cortex, so information can be localised due to the precise topographic organisation of synapses.
However input from the viscera is not as precise, since not just one neurone is activated. Diffuse input and thus diffuse signalling to the brain, so it is much harder to localise the specific starting point.

Question 14

Describe the interneurons of the dorsal horn

Answer 14

Majority are inhibitory, dampening the activity of the output neurone.

• some are spontaneously active - constantly firing APs and inhibiting their targets
• some are stimulated by primary afferent inputs (which are always excitatory)

Question 15

What is the general principal of the gate theory of pain?

Answer 15

The pain signal must overcome inhibition to be sent to the brain.

Question 16

How do non-noxious stimuli not cause a pain signal to be transmitted?

Answer 16

• non-noxious stimuli comes in from Abeta mechanoreceptor primary afferent fibres
• these synapse with a projection neurone which can send a pain signal, which we do not want since it is non-noxious information
• it is excitatory information so would allow a signal to be sent to the brain
• it also gets inhibitory input. To make sure the projection neurone does not send an ascending pain signal it will get more inhibition from the Abeta fibre, which will also synapse with the inhibitory neurones, ensuring the projection neurone does not respond to excitatory input.
• hence the gate is kept closed

Question 17

How is the gate opened to overcome inhibition in the presence of a noxious stimuli?

Answer 17

• Adelta/C fibres carry nociceptive information
• this excites the projection neurone, which might not be enough to overcome inhibition
• it also makes synaptic contact with another population of inhibitory interneurones, exciting these which inhibits the other interneurone, thus switching inhibition off.

Question 18

When you hurt yourself you make a sound which activates the brain. What would a responsive behaviour to this be?

Answer 18

One would rub the affected area to activate sensory nerve endings. It is designed to respond to touch - non-noxious primary afferent fibres are activated with Abeta axons. This increases the amount of information going up these fibres, excoriating the inhibitory interneurones more, switching off the projection neurone and closing the spinal gate to relieve pain.

Question 19

How can transcutaneous electrical nerve stimulation (TENS) have analgesic effects?

Answer 19

Pads on skin pass electrical current through the skin which is controlled by the patient. A small amount of current will activate Abeta fibres because they are fat fibres and more easy to activate electrically than thin pain-carrying fibres. So stimulate these fibres to produce an analgesic effect.

Question 20

Where is information travelled to and from in the ascending spinothalamic pathway?

Answer 20

Out of the spinal cord and into the thalamus. Information can end up in the cortex or in subcortical areas.

Question 21

How is emotion added into pain?

Answer 21

Via spinothalamic pathway:

Emotion is added in via the activation of the limbic system - a subcortical area.

Question 22

What areas of the brain need to be activated to perceive pain?

Answer 22

Pain is only perceived when parts of the subcortical areas of the brain are active. But inputs are localised at the cortical level in the somatosensory cortex.

Question 23

How can the brain use descending pathways to stop pain?

Answer 23

Brainstem nuclei (rich in opioids) send axons down to the dorsal horn and cause internal action with the gate circuitry to potentially close the gate. Has the potential for release of substances (e.g., 5-HT and noradrenaline - endogenous opioids) in the dorsal horn from neurones which have cell bodies in the brainstem.

Question 24

What is the Intrinsic Analgesia System?

Answer 24

The brains involvement in inhibiting/closing the dorsal gate, thereby preventing the feeling of pain by preventing ascending signals.

Question 25

What is facilitated pain?

Answer 25

When we feel more pain than normal

Question 26

How do we feel facilitated pain?

Answer 26

Due to plasticity in neuronal systems - nociceptive neurones can change and amplify their signals to feel more pain

Question 27

What happens to pain as stimulus intensity increases?

Answer 27

As stimulus intensity increases, we feel more pain, after the threshold of the innocuous stimulus.

Question 28

What is an innocuous stimulus?

Answer 28

When we feel the stimulus but not as pain

Question 29

What happens to the normal pain/stimulus intensity relationship in injury?

Answer 29

If injury occurs to the same places now if a certain amount of weight is added that was previously not painful, it becomes painful. So a lower stimulus intensity will cause pain and a previously innocuous stimulus becomes noxious. A shift in the stimulus threshold on the graph.

Question 30

What is hyperalgesia?

Answer 30

More pain - enhanced painful response to a normally painful stimulus

Question 31

What is allodynia?

Answer 31

A pain response to a normally non-painful stimulus

Question 32

Describe the process of peripheral sensitisation

Answer 32

• a noxious stimulus occurs
• cells/tissues are damaged, releasing substances
• causes an ‘axon reflex’ - antidromic action potential conduction (AP branches down the axon branches)
• this causes release at the peripheral nerve ending of substance P or CGRP (peptide neurotransmitters)
• these can diffuse away from the nerve ending and interact with receptor on blood vessels causing many different effects

Question 33

What effects are produced on blood vessels by substance P and CGRP?

Answer 33

• vasodilation causing redness of damaged skin
• blood vessels becoming leakier, causing plasma extravasation, causing swelling of tissues
• immune cells can also migrate out of the vasculature and activation in the tissue, which can release lots of substances (inflammatory soup)

Question 34

What substances are part of the ‘inflammatory soup’?

Answer 34

PGs, H+, bradykinin, NGF, cytokines

Question 35

What does the inflammatory soup do?

Answer 35

In damaged tissues it can signal bad to the nerve ending. These substances lower the threshold at which the nerve ending will fire an action potential, thus become sensitised (usually have a high threshold).

Question 36

What receptors show sensitisation in response to the inflammatory soup?

Answer 36

Polymodal receptors

Question 37

What is neurogenic inflammation?

Answer 37

The process of peripheral desensitisation - started by the neurone, responds to the stimulus and then changes the behaviour of the neurone.

Question 38

What is primary hyperalgesia?

Answer 38

The increased pain sensitivity that occurs directly in the damaged tissue. As a result of the lowered threshold at the sensitised nerve ending, thus more action potentials fired, creating a bigger response and causing more pain.

Question 39

What is secondary hyperalgesia?

Answer 39

Increased pain sensitivity a distance from the site of injury.
Antidromic AP propagation along fibre branches that innervate injured and neighbouring uninsured tissue. Result is sensitisation of neurones that also innervate the neighbouring uninsured tissue.

Question 40

What does peripheral sensitisation promote?

Answer 40

Central sensitisation

Question 41

What is acute pain?

Answer 41

Pain that comes on and off very quickly. Normal and non-facilitated pain.

Question 42

What is the common neurotransmitter for primary sensory afferents (nociceptors)?

Answer 42

Glutamate and substance P in vesicles

Question 43

Describe the process of signalling of acute pain

Answer 43

• stimulus comes into the periphery and the nociceptive nerve ending responds to the stimulus and fires AP(s), which are propagates into the dorsal horn, carried by Adelta and C fibres.
• a single AP at low frequency will cause activation at the synapse, releasing glutamate (excitatory), which will bind to the AMPA receptor.
• substance P is not involved in low frequency firing
• second order neurone will send that signal on upto the brain. It will reproduce that signal (duplicates it) = high fidelity signalling. Ascending ‘pain’ signal.

Question 44

What is the resting state of the NMDA receptor in acute pain?

Answer 44

In acute pain, the NMDA receptor is blocked by a magnesium ion. (Glutamate receptor)

Question 45

What is the central sensitisation mechanism/ what happens when there is facilitated pain with high frequency AP firing?

Answer 45

• more enhanced glutamate release
• substance P released so the NK-1 receptor is activated, so more post-synaptic receptor stimulation occurring.
• the combination of AMPA and NK-1 activating allows NMDA to be activate too. This higher level of depolarisation causes the magnesium ion to unblock the channel, so glutamate can activate this receptor.
• this NMDA channel allows Ca2+ through (AMPA only allows Na+ through)
• the influx of Ca2+ triggers secondary messenger cascades - phosphorylation cascades make the postsynaptic cell much more responsive to the incoming signal
  So the incoming Adelta/C fibre ‘pain’ signal (which is big) has caused a change in the cell, making the cell send a bigger ascending signal. Facilitated signalling.