S3: The Physiology of Pain

Question 1

What is Pain?

Answer 1

• Pain is all in the mind
• Pain is a warning system
• Pain is essential
• Pain is an sensory experience
• Pain is a trigger for emotional and behavioural responses
• Pain doesn’t simply correlate with receptor activation

Question 2

Describe how pain is all in the mind (and nociception isn’t)

Answer 2

Pain is all in the mind and the pain pathways in our nervous system (nociceptors in periphery) plug into the emotional parts of the brain via spinal cord. We also have modulatory systems which can wipe out the feeling of pain completely.
- Pain is not properly measurable as it is in the mind so people often experience chronic pain (for no apparent reason).

Question 3

What are nociceptors?

Answer 3

They are somatosensory primary afferents that terminate in the spinal cord and synapse in the laminae I, II and V. They are known as pain receptors.

• Nociceptors also detect noxious stimuli that are or about to damage the body. This means that pain is our brains way of representing damage or impending damage to the body.
• They are present in all tissues except the brain itself.

Question 4

How do nociceptors differ from touch receptors?

Answer 4

Nociceptor primary afferents terminate in the spinal cord, their axons do not project to the brain stem.

Question 5

How pain is a warning system?

Answer 5

We have nociceptors that help use detect and avoid harm. The role of = A-delta fibres and C fibres are important.

Question 6

What are the two broad classes of nociceptors?

Answer 6

1) A- delta receptors/fibres

2) C-fibres

Question 7

Describe A-delta fibres

Answer 7

A delta receptors/fibres are thin (but thicker than C fibres) and myelinated which make them fast, These fibres respond to many things but primarily to mechanical trauma (stab) or noxious heat.

• These fibres travel up the spinal cord where they synapse with secondary afferents. They then cross over the midline and travel up up the anterolateral spinal tract white matter. They then get up to the thalamus and are relayed into the cortex.
• When this pathways is activated, people feel a sharp stabbing pain (1st pain - usually the first pain we feel).
• Neurotransmitter at synapse is glutamate only.

Question 8

Describe C-fibres

Answer 8

These are thin, non myelinated axons that are slow. They are not good at sending a warning signal, instead they report ongoing situations. These fibres respond to many things including mechanical pressure (especially long intense pressure) and noxious cold/heat. They are most well known for responding to inflammation.

• If inflammation is hot, tender and red it is c-fibres causing the long throbbing dull aching pain until the injuy has healed.
• C fibres release a wide range of neurotransmitters and its most famous is substance P.

Question 9

Why is pain essential?

Answer 9

Without pain it is impossible to live a normal healthy life (those who are congenitally insensitive to pain). Being unable to feel pain actually shortens an individuals life.
- Individuals who do not perceive pain will get many injuries when they are young and repeat them because they haven’t felt any pain and thus haven’t learnt to avoid harmful behaviour. When they grow up they may become extremely overcautious but still get injured. They are also less likely to recognise symptoms of pathology e.g. Appendicitis and they often suffer from joint degeneration e.g. Opening door, our body tells us to adjust movement if it hurts but they don’t get it.

Question 10

Describe the a nociceptor pathway of pain using treading on glass as an example

Answer 10

• Stepping on glass is the noxious (mechanical) stimuli that will damage tissue and activate a-delta fibres.
• The fibres are fast and will quickly send impulses to the spinal cord to generate protective reflexes by activating projection cell and interneurones.
• In this case, the protective reflex is the withdrawal reflex where flexors will be activated and the other leg will extend to support the weight.
• While the reflex has been occuring, the signal will have reached our brain via the anterolateral spinal tract so we feel the sharp stabbing pain.

Question 11

Describe the c nociceptor pathway of pain using treading on glass as an example

Answer 11

• While the a-fibre pathway is occurring, our c-fibres get activated by either the mechanical stimulus or by the tissue damage (release of potassium and inflammation).
• These fibres are slow so they release protective reflex that immobilises and protects against exacerbating the injury.
• In this case, the heel may go stiff (muscles here tense)
  .- Eventually signals reach the brain and we feel the aching pain.

Question 12

What is the consequence of the perception of pain from nociceptors? Give examples in context with glass in feet

Answer 12

• It will force us into remedial action as pain is unpleasant. This is to treat the injury. If we don’t take appropriate remedial action we may get an infection which makes things worse and more painful, which we will also learn from.
• We will also learn from the injury to avoid the pain e.g. to not walk barefoot in sand.

Question 13

What is the problem with pain?

Answer 13

Once pain has served its purpose, it becomes part of the problem. Pain also doesn’t always have a clear purpose.

Question 14

How is pain a function of the somatosensory system?

Answer 14

The pathways carrying and interpreting pain stimuli are closely associated with other somatosensory pathways so pain would fit into the sensation and perception part of the CNS function.

• Sensation is the awareness that an event has occurred.
• Perception is the processing of the sensation.

Question 15

Describe the somatosensory pathway for gently touch

Answer 15

• Touch receptor afferent goes back to the spinal column and goes up the dorsal columns in the medulla.
• At the top, it synapses with the secondary afferent and crosses over at the dorsal column nuclei.
• From here it goes up to its specific area in the thalamus, the ventral posterior nuclei which is the somatosensory relay of the brain.
• It then synapses with a third afferent and is relayed up to the cortex.

Question 16

What is the equivalent pain pathway to the somatosensory pathway for gentle touch?

Answer 16

The lateral pain pathway. The first synapse with the secondary afferents in the dorsal horn, but then the axon secondary aferent crosses the midline and ascends mainly in the anterolateral tract. This bypasses the brainstem and heads straight to the nucleus in the thalamus via internal capsule.

Question 17

What is the primary SS cortex role?

Answer 17

It is associated with consicous perception.

Question 18

What is the role of the lateral pain pathway?

Answer 18

1. Causes electrical stimulation of the somatosensory cortex e.g. localised sensation.
2. Electrical stimulation in the VPN.

Question 19

What is the homunculus?

Answer 19

All the afferents from vibration, hair, touch sensory and nociceptors etc will terminate in the relevant part of this map that is the primary SS homunculus.
- People with primary SS lesions may lose part of brain involved in conscious sensation.

Question 20

How is pain a trigger for emotional and behavioural responses?

Answer 20

The emotional response to pain comes about through a different set of pathways and is associated with the subconscious part of the CNS. Nociceptive input can lead to withdrawal reflexes that are unconsciously done. As well as this nociceptor input can cause sympathetic activation (fight or flight!). Pain can also cause the emotional responses, such as fear, anxiety, aversion and recuperative behaviour (ability to not repeat an action that was harmful). This occurs because the pain pathways (medial pain pathway) directly plug into the emotional pathways.

Question 21

What are the subconscious responses from the CNS triggered by pain?

Answer 21

1. Control of movement
2. Autonomic responses
3. Emotional and Behavioural responses

Question 22

Describe the medial pain pathway

Answer 22

• The same nociceptors as the lateral pain pathway activate secondary afferents (of a different sort) that have branches in various levels of the brainstem that terminate in the non specific thalamic nuclei (not the nuclei associated with SS pathway like VPN).
• Non specific nuclei are the ones that project to places like the insula of the cortex and anterior cingulate. These brain stem centre are areas of modulatory and autonomic control so nociceptor pathway are directly plugging into these centres.

Question 23

What is the role of the insula and anterior cingulate?

Answer 23

• The insula are receiving inputs from all of the interreceptor from all over body. It is hypothesised that they have a role in homeostasis and awareness of cell.
• The anterior cingulate connects to hypothalamus, amygdala, frontal cortex that are associated with processing of emotional stimuli, processing emotional stimuli and working out what’s good and bad for us and how to respond appropriately. They also connect down to the autonomic control centres.

Question 24

Evidence for the medial pain pathway

Answer 24

1. Electrical stimulation in medial thalamus - Evidence from people who have had activation in non specific thalamic nuclei and they can’t say what had happened, and point to area of body that hurts but they don’t like the sensation and don’t want it to be repeated.
2. Patient with primary SS lesions can’t feel noxious stimuli but they don’t like the sensation but they cannot explain why.

Question 25

What are the two sets of pain pathways that we have?

Answer 25

1. Straightforward sensory pathway -allows us to consciously perceive where and what has happened.
2. Complex set of interconnected pathway - responsible for the distress, avoidance and emotional content of a painful stimulus.
   Both pathways can be separated.

Question 26

Describe where the visceral are in the primary SS map and their role

Answer 26

They aren’t represented on the homunculus as they represent referred pain.

• Visceral afferents project to spinal cord but don’t have own pathways to cerebral cortex so they travel with secondary afferents that belong to nociceptors on the body surface. These secondary afferent go up to activate part of the somatosensory cortex that belong to the specific part of the body. The sensation that is produced from the afferents produce localised pain to the area of the body that belong to the pathway. E.g. Heart afferents are activating part of the cerebral cortex that is part of the chest and usually the left arm and sometimes the jaw.
• These afferents include the ones that activate the medial pain pathway e.g. Why people having heart attack will be sweaty, anxious and unpleasant etc. As not only the SS cortex in lateral pain pathways is activated but the ones in medial pain pathways are.

Question 27

Explain how pain doesn’t simply correlate with receptor activation

Answer 27

• People with serious injuries that are pain free.
• People with no physical injury with severe pain.
• As pain is something that is generated inside the brain, it can’t be measured so we have to take people’s word for it.

Question 28

Explain our pain killing system

Answer 28

This explains why pain does’t correlate with receptor activation as people with severe injuries can not feel their pain due to shock.

• Information is processed in orbital frontal or anterior cingulate cortex which activates the brainstem and activates the descending systems.
• Our pain killing system (nucleus raphe magnus and locus coeruleus) are origins of axons that run back down spinal cord and innervate inhibitory interneurons that switch off the pain pathway right at their first synapse.
• Switching off transmission of nociceptor information to these pathways, then there is depression of emotional and memory response (medial and lateral pain pathway).
• This cannot occur whenever we feel pain. So we’ve developed a system that only switches these off during survival injuries.

Question 29

How does opioids affect our pain killing systems?

Answer 29

• Opioids can be used to switch on the descending axons artificially.
• Opioids are also used by inhibitory inter-neurones as there are opioids receptors in the spinal cord.

Question 30

Explain the link between mental state and pain

Answer 30

Pathologically reduced activity in the inhibitory pathway which will increase transmission of any painful stimulus in through the spinal cord (both emotional and sensory aspect of pain).
- We think this why if you treat a patient incorrectly, this can make them anxious and increase the level of pain that they actually feel.
- So anxiety, poor coping skills and poor expectations can make someone hyperalgesic (probably by down regulating the inhibitory pathways).
- Chronic pain is often associated with depression, and treatment with antidepressants is often said to reduce pain by improving mood and coping ability.
but these agents will also increase transmission of serotonin and noradrenaline in the descending anti-nociceptive pathways.

Question 31

What is nociceptive pain?

Answer 31

‘Normal’ pain due to tissue damage, which stimulates nociceptor nerve endings.

Question 32

What is neurogenic pain?

Answer 32

Neurogenic painis defined aspaindue to dysfunction of the peripheral or central nervous system, in the absence of nociceptor (nerve terminal) stimulation by trauma or disease. This is when pain pathways themselves go wrong.

Question 33

Describe inflammatory pain

Answer 33

Inflammation and neural ‘sensitisation’ may lead to hyperalgesia (nociceptor activation becomes more painful) and allodynia where tissue becomes hypersensitive (touch becomes painful).

Question 34

Describe how nociceptors respond and contribute to inflammation

Answer 34

• Injury releases inflammatory soup which depolarises and hypersensitises C fibres.
• The depolarised C fibres will release inflammatory mediators of their won including substance P.
• This causes self-sensitisation of C fibres due to positive feedback. This also causes initial zone of inflammation to spread throughout the territory of C fibres and throughout the territory of overlapping c-fibres. This can cause gentle touch to be painful.

Question 35

Do nociceptive and inflammatory pain fade as the tissue heals?

Answer 35

Yes

Question 36

Give an example on how pain can result from nociceptor response to pathological condition

Answer 36

Eg. Diabetic neuropathy
High glucose levels doing microdamage to tissues and nociceptors. The C fibres therefore depolarise and fire AP and respond inflammatory mediators from nearby tissue. This is neuropathic condition produced by chronic pathology. Hyperalgesia and allodynia can then occur.

Question 37

Describe how pain can result from abnormal processing of normal signals

Answer 37

This is neurogenic pain generated by CNS.
Neurogenic pain is often started by tissue injury but after the tissue heals, the pain can continue and built up and this is due to abnormal processing of normal signals.

Question 38

Describe how

pathological pain is associated with abnormal brain activity

Answer 38

• Cortical responses to mildly painful stimuli, detected via fMRI.
• The greater the brain activity, the greater the pain felt.
• Activity was stronger and more widespread in patients with pathological pain (neurogenic pain).

Question 39

Describe the cells in the spinal cord activity from nociceptors

Answer 39

Activity in cells in spinal cord is down to balance of excitation from afferents and inhibition from inhibitory inter-neurones.

• The cells in the superficial layers are nociceptor specific cells that only receive innervation from the nociceptors. When these cells fire AP, the brain only interprets them as being painful.
• The other cells get input from nociceptors and touch receptors. They respond to gently touch with low frequency of AP firing which brain interprets as gentle touch. They respond to nociceptor input with high frequency of AP firing which the brain interprets as painful. This can go wrong in many ways.

Question 40

How can loss of inhibition to spinal card increase nociceptor signals which will exaggerate responses? Drug treatment targeting this?

Answer 40

Secondary afferents respond much more strongly to their cell input - ordinary signally from nociceptors and cause much higher firing rate from nociceptor specific cells.
- People in chronic pain are sometimes treated with benzodiazepines which act as anxiolytics but they also reduce activity in the pain pathways by enhancing spinal cord inhibition.

Question 41

How can potentiation of synapses increases nociceptor signals? Drug treatment targeting this?

Answer 41

Synapses are strengthened from C-fibres which create plasticity.
- Chronic pain is often treated with anticonvulsants which are normally used to block high frequency AP firing during seizures and reduce transmitter release, specifically at potentiated synapses.