Week 4 - finished

Question 1

What is nociception?

Answer 1

Nociception is information transmitted about noxious stimuli (current or predicted tissue damage)

Question 2

What is pain?

Answer 2

Pain is the brain’s perception of an adverse or unpleasant sensation
It is an unpleasant sensory and emotional experience associated with actual or potential tissue damage

Question 3

What are nociceptors?

Answer 3

Are free nerve endings without specialised receptor cells

Question 4

How do nociceptors receive stimuli?

Answer 4

Stimuli are received via noxious stimuli receptors that are built into C fibre endings at a molecular level. These noxious stimuli receptors are g-protien coupled receptors rather than specialised receptors e.g. merkle receptors or ruffini’s corpuscles.

Question 5

Do nociceptors have a specialised receptor?

Answer 5

No, they have a g protein receptor

Question 6

Where do nociceptor free nerve endings terminate?

Answer 6

In the tissues

Question 7

Where do nociceptor free nerve endings extend into?

Answer 7

The most superficial layers of the dermis

Question 8

Where so nociceptor cell bodies sit?

Answer 8

In the dorsal root ganglion

Question 9

What are the 2 fibre types of nociceptors?

Answer 9

A fibres or C fibres

Question 10

What % of DRG cells are nociceptive?

Answer 10

70%

Question 11

What are the 4 different ways that we can classify nociceptor cells?

Answer 11

The type of noxious stimuli they respond preferentially to

Their degree of sensitivity and therefore the intensity of the stimuli they detect

Their fibre type

Their inflammatory capability

Question 12

If we are to classify nociceptors by stimulus, what are the 3 classifications nociceptors can fall under? Briefly describe each of them.

Answer 12

Mechanical nociceptors: activated by strong mechanical forces on tissues and have a fairly high threshold, requiring a high input to fire. They are particularly sensitive to sharp stimuli

Thermal nociceptors: Either hot or cold, and can react to extremes in temperature.

Polymodal nociceptors: found through the skin and the deeper tissues. They can be activated by mechanical, thermal and chemical stimuli (esp acids).

Question 13

If we are to classify nociceptors by degree of sensitivity, what can we say about them

Answer 13

Most nociceptors have a high threshold, meaning they require a must higher intensity of stimulus to evoke a neuronal response.

Some nociceptors have a very high threshold to mechanical stimuli and do not transmit mechanical information unless inflamed or sensitised, but do tend to be highly sensitive to chemical stimuli e.g. inflammatory mediators.

Question 14

What % of DRG fibres are A beta?

Answer 14

20%

Question 15

What kind of information do A beta fibres transmit?

Answer 15

Mostly tactile and proprioceptive

Question 16

What % of DRG fibres are A delta fibres? What % of these fibres transmit nociceptive information? What information does the remaining A delta fibres transmit?

Answer 16

20%

50-70% of these fibres transmit nociceptive information. The rest transmit tactile information from hair cells

Question 17

20% of DRG fibres are A beta, and 20% are A delta. What type of fibres is the remaining 60% and what kind of information do they transmit?

Answer 17

C fibres.

They transmit mostly nociceptive information.

Question 18

Where do A fibres relay sensory information to in the cortex?

Answer 18

So S1 where they have localised or discriminant perception.

Question 19

What fibres relay fast and slow pain to S2?

Answer 19

A and C fibres

Question 20

What speed of information do C fibres transmit and where do they get relayed to? Why do they get relayed here?

Answer 20

C fibres relay poorly localised, indiscriminant pain to the cingulate cortex, a highly emotional area of the cortex which is thought to add emotional colouring and prior experience to our pain experience and drive motivation to act on pain and decide on behavioural responses.

Question 21

What % of DRG cells are peptidergic? What does this mean?

Answer 21

40%

This means that they produce neuropeptides (substance P and CGRP) and release them at their peripheral terminals to produce neurogenic inflammation.

Question 22

What does peptidergic mean?

Answer 22

If a cell is peptidergic it means that they produce neuropeptides (substance P and CGRP) and release them at their peripheral terminals to produce neurogenic inflammation.

Question 23

How large are nociceptor fields?

Answer 23

2-10mm in diameter

Question 24

What does the overlap of nociceptor fields protect us from?

Answer 24

Hyposensitivity, but not hypersensitivity

Question 25

Do primary afferents have a fixed receptive field?

Answer 25

Yes

Question 26

General info on primary and secondary afferents and their receptive fields:

Answer 26

Much overlap which protects from hyposensitivity but not hypersensitivity
Primary afferents have a fixed receptive field
Primary afferents converge on the secondaries making their receptive field much larger

By the time we reach the thalamic neurons we start to see whole body receptive fields being generated by this convergence

This is also true of the somatosensory cortex

At a cortical level we’re then able to adjust the degree of sensitivity and discrimination by switching between neurons with differing receptive fields

You might consider that we have fast, generalised screening operations that are highly sensitised but poorly localised to allow us to detect changes to our environment or we have slower, more highly processed operational systems that allow for fine, discriminant examination of our environment

The switch between these is more like a dimmer switch than an on/off button and thought to be mediated by inhibitory interneurons

Question 27

What does ALS stand for? Describe the ALS (terminations, decussation level, what info does it transmit?

Answer 27

Anterolateral system

Transmits crude touch, pain and temp

It decussates in the cord at the level it enters the cord at

It has brain stem terminations

It also has cortical and subcortical terminations

Question 28

General pain information

Answer 28

Put simply the nervous system has mechanisms for amplification and attenuation of nociceptive transmissions

This allows for a heightened response to aid tissue repair and remove ourselves from threat; or a reduction in perceived pain while tissues heal from minor injury that poses minimal threat

Nociception is relayed via peripheral and central pathways and can be modulated at several points including at tissue, cord and cortical levels

Question 29

List some of the inflammatory chemicals that chemoreceptors on nociceptors respond to

Answer 29

Histamine, prostaglandins and serotonin (mast cells)
ATP, glutamate and adenosine (tissue/ platelets)
Bradykinins, interleukins and nerve growth factors (various immune cells)

Question 30

Describe the basis of nociceptor sensitisation

Answer 30

A positive feedback loop involving inflammatory mediators released upon tissue damage. This sensitises or activates local nociceptors (A 2nd messenger (G protein cascade sensitises their associated ion channel meaning they open in response to a lesser stimuli) . Activation causes substance P and CGRP to be released. This increases vascular permeability in order to accelerate healing.

Question 31

Describe the axon reflex to pain:

Answer 31

Antidromic responce to peptidergic neurons

Substance P and CGRP get dumped into peripheral tissue

Acts on local capillaries, mast cells, smooth muscle and the terminals of the same nociceptor

This helps to enhance immune response and healing.

Question 32

What does secondary hyperalgesia suggest?

Answer 32

Central sensitisation

Question 33

What is hyperalgesia?

Answer 33

Increased pain from a stimulus that normally provokes pain

Question 34

What is allodynia?

Answer 34

Pain due to a stimulus that does not normally provoke pain

Question 35

What are the 2 types of hyperalgesia and describe them

Answer 35

Primary hyperalgesia is local to tissue damage and likely to be mediated by peripheral sensitisation mechanisms

Secondary hyperalgesia is sensitisation of distant tissues and may be mediated by either peripheral or central mechanisms

Question 36

What is nociceptive pain?

Answer 36

Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors

Question 37

What is peripheral sensitisation?

Answer 37

Peripheral sensitization is the increased responsiveness and reduced threshold of peripheral nociceptive neurons to the stimulation of their receptive fields.

Question 38

What is the dorsal horn wind up?

Answer 38

Continued or repeated intense nociceptive stimuli leads to an increased rate of nociceptive relay firing when delivered closely together. Peptidergic c fibres dump substance P and CGRP centrally leading to short term central sensitisation.

In addition to the up-regulation of existing receptors at the peripheral and central nociceptive terminals; inflammation also drives up-regulation of the production of these receptors

More membrane receptors are produced and transported to both the neuron’s central and peripheral terminals via the cells normal axonal transport mechanisms.This is driven by mediators such as NGF.

This reinforces both peripheral and central sensitisation at the dorsal horn.

With significant enough tissue insult and an intense enough peripheral nociceptive response we start to see larger magnesium plugged ion channels open up. This not only allows for a greater influx of sodium but also allows larger ions such as calcium into the cell.

These are all normal mechanisms by which we amplify nociceptive input for protection and preservation of the organism by preventing further tissue damage.

These changes are all fairly transient and presumed reversible with cessation of tissue damage and peripheral nociceptor stimulation

Question 39

Is central sensitisation normally a chronic or acute pain response?

Answer 39

Adaptive pain response.

Question 40

What can a maladaptation of central sensitisation lead to?

Answer 40

Chronic pain

Question 41

Is all central sensitisation associated with chronic pain and maladaptation?

Answer 41

No

Question 42

Long term maladaptations or change to pain information:

Answer 42

Much more likely to occur where there is a prolonged injury or insult or their is prior central sensitisation.

It involves changes that are not just metabolic but more structural or hard wired.

Up-regulation of existing receptors and up-regulation of the production of new receptors can occur in the second order neurone just as it did in the first.

Antidromic prostaglandin dumping may produce a positive feedback loop across the synapse.

These factors lead to the hypersensitivity of the second order neurone.

The second order neuron receives terminals from many DRG primaries and this can lead to an increased pain response to stimulus well outside of the initial injury site.

Prolonged relay sensitisation can then be further amplified by disinhibition of the relay neuron.

This involves pruning back or loss of the inhibitory interneurons and is thought to relate to excessive calcium uptake by the interneuron.

The death of neurone is a much more ‘concrete’ change in cord structure and function and is very difficult and slow to reverse

These interneurons are a critical part of the brain’s nociceptive down regulation mechanisms

They are in part regulated by opioids and their loss can go some way to explaining opioid insensitivity in CP patients

These changes have been demonstrated in the cord but are likely being mirrored up the chain at the brainstem and thalamus

We have some evidence of these types of changes in the cortex in the form of homunculus smudging

Question 43

How are microglia activated in the dorsal horn?

Answer 43

By the local release of substance P

Question 44

What is the function of microglia in the dorsal horn in relation to sensitisation?

Answer 44

Activated microglia dump cytokines that diffuse back to act on the primary neuron, further stimulating it. This leads to further stimulation of the secondary neuron and drives functor inhibition of local inhibitory interneurons.

Question 45

What is the mechanism behind neuropathic pain?

Answer 45

Axonal damage leads to a constant influx of ions and continuous, spontaneous depolarisation that is perceived as constant, intense pain.

NGF (neuron growth factor) stimulates the growth of axons back towards the DRG and collateral sprouting between axons, however this is not specific to somatic fibres and drives sympathetic fibre growth into the DRG and abnormal sympathetic coupling.

In stress, these sympathetic fibres with fire, secreting noradrenalin and activating local nociceptors within the DRG

This means that a stress response leads to the activation of nociceptors and pain transmission.

This means that stress, sleep deprivation and anger can all be triggers for a pain episode.

Question 46

What is the spinal pain modulation mechanism called?

Answer 46

The gate control hypothesis

Question 47

Describe the gate control hypothesis

Answer 47

This is a mechanism for the modulation and down regulation of pain as driven by the spine.

Increased input from the A alpha and A beta fibres on to the inhibitory interneurons reduces the output of nociceptive information by the projection neurons of the ALS.

In the absence of this input the C fibres not only stimulate the projection neurons but also inhibit the inhibitory interneurons. In the absence of these inhibitory interneurons we start to get allodynia.

This is why the stimulation of A fibres helps to decrease pain signals being sent, e.g. rubbing your leg when it hurts.

Question 48

How does the brainstem and cortex influence the transmission of pain?

Answer 48

There are descending systems that arise in the brainstem that send fibres down through the dorsolateral fasciculus to terminate in the dorsal horn. There terminations can directly act on the second order neurons or they can act on the inhibitory interneurons to directly modulate the second order neuron.

The reciprocative loop (spino-bulbao-spinal) of nociceptive modulation and transmission pathways is usually referred to as DNICS

Question 49

What does DNICS stand for?

Answer 49

Diffuse noxious inhibitory control system

Question 50

What does DNICS do?

Answer 50

It allows for the down regulation of pain transmission and also allows for the shifting of focus of nociceptive attention.

Question 51

What type of neuron is DNICS heavily reliant on?

Answer 51

Inhibitory interneurons.

Question 52

What is generally missing in chronic pain states?

Answer 52

Inhibitory interneurons.

Question 53

What are the 2 key descending pain inhibitory pathways?

Answer 53

1) Originates in the peri-aqueductal grey
- synapses at the Raphe nuclei of the medulla
- from here serotonergic neurons project to the dorsal horn.
- they either excite the inhibitory interneurons (opioid-enkephalins and endorphins) or directly inhibit the transmission of nociceptive information.

2) A second descending pathway arises from the lateral medullary reticular formation
- This is a nor-andronergic pathway
- Directly inhibits the transmission of nociceptive information
- Direct stimulation of these areas appears to activate these descending pathways, including analgesia.

Question 54

At what levels do opiates play a role in pain modulation?

Answer 54

Brain, brainstem and spinal cord levels

Question 55

What is stress induced analgesia? How does this mechanism work?

Answer 55

Analgesia caused by behavioural stress. The periaqueductal grey in particular has strong reciprocal connections to the limbic system via the hypothalamus.

Noradrenalin is secreted as part of the stress response and this may influence nor-androngeric pathways.

Question 56

Where is the primary somatosensory cortex located?

Answer 56

In the post central gyrus

Question 57

Where is the secondary somatosensory cortex located?

Answer 57

In the lateral sulcus of the parietal lobe and the posterior parietal cortex.

Question 58

What is the function of the posterior parietal cortex?

Answer 58

Sensory information from the different areas of the primary somatosensory cortex, visual and other cortices are brought together here to allow the different sensory systems to function as an overall unit.

This allows of the identification or recognition of familiar objects with very little thought.

It may also play a role in the recognition of danger or s threat with very little thought.

Question 59

What is the connection between the limbic system and pain?

Answer 59

The anterior cingulate cortex has been particularly impacted in the emotional colouring of pain and works very closely with the prefrontal cortex for the planning of motivated behaviours.

These areas appear highly connected to the descending pain modulation pathways of the brainstem, largely via the hippocampus

• distraction and attention
• attenuation and amplification