Pain 1

Question 1

What are examples of healthy pain and pathological pain?

Answer 1

healthy pain:

• escape from danger
• awareness of harm
• treatment of tissue damage
• learning about harmful environment

pathological pain:

• migraine
• neuropathic pain
• back pain
• joint pain (arthritis)
• toothache

Question 2

In general, what pathway does pain travel in?

Answer 2

1. pain is detected by sensory receptors in the skin
2. these travel via the somatic sensory neurones to the spinal cord
3. neurones ascend through the medulla oblongata to the sensory cortex

Question 3

Which part of the brain perceives pain?

Answer 3

the pain signal first goes to the thalamus

the thalamus sends the signal to a few different areas for interpretations

it also sends signals to the limbic system, which is the emotional centre of the brain

Question 4

What are the 5 different sensory receptors in the skin?

Answer 4

1. Meissner corpuscle
2. Pacinian corpuscle
3. Ruffini’s corpuscle
4. Merkel’s disks
5. free nerve endings

Question 5

Which sensory receptors are found just beneath the epidermis?

Answer 5

Meissner corpuscles and Merkel’s disks

Meissners corpuscles sit between the dermal pupillae

Merkel’s disks are aligned with the dermal pupillae

Question 6

Where are pacinian corpuscles located?

Answer 6

they are large encapsulated endings located in the subcutaneous tissue

Question 7

Where are Ruffini’s corpuscles located?

Answer 7

they are located deep in the dermis

the long axis of the corpuscle is orientated parallel to the skin

they form 20% of receptors in the skin

Question 8

How is conduction velocity associated with axon diameter?

Answer 8

conduction velocity is positively correlated with axon diameter

(larger diameter axons have faster conduction velocity)

Question 9

What types of axons of sensory afferents innervating somatosensory receptors have a large diameter?

Answer 9

large diameter, rapidly conducting afferents (I / II) are associated with low threshold mechanoreceptors

e.g. proprioceptors of skeletal muscle, mechnoreceptors of skin

Question 10

what types of axons of sensory afferents innervating somatosensory receptors have a small diameter?

Answer 10

small diameter, slow conducting afferents (III / IV) are associated with nociceptors and thermoreceptors

both type III and IV fibres are involved in conducting pain sensation

Question 11

What are the two categories of pain perception?

Which fibres do they travel in?

Answer 11

different fibres convey different aspects of pain sensation

first pain:

• conveyed through fast Ad fibres

second pain:

• conveyed through slow C-fibres

Question 12

What is the difference in sensation between first and second pain?

Answer 12

a single painful stimulus yields two successive and distinct sensations

first pain:

• brief, pricking and well localised

second pain:

• longer-lasting, burning and less well localised

Question 13

What are the characteristics of first pain?

What types of receptors produce this kind of pain?

What is the duration like?

Answer 13

conducted via fast Ad fibres

• sharp or prickling
• easily localised
• occurs rapidly
• short duration

mechanical or thermal nociceptors

Question 14

What are the characteristics of second pain?

What types of receptors detect this pain?

Answer 14

carried by slow C-fibres

• dull ache, burning
• poorly localised
• slow onset
• persistent

sensory receptors are polymodal nociceptors

Question 15

What are the spinal connections of the nociceptive axon terminals?

Answer 15

• afferent terminals enter the dorsal horn and project into the zone of lissauer
• afferent terminals synapse onto neurones of lamina I and lamina II (substantia gelatinosa)

Question 16

What are the connections between the primary afferent pain fibres and the spinal cord?

Answer 16

AB myelinated fibres:

• synapse with PKCy⁺ neurones and lamina V

Peptidergic C fibres:

• synapse with lamina I

Ad myelinated fibres:

• synapse with outer lamina II and lamina V

nonpeptidergic C fibres:

• synapse with inner lamina II

Question 17

What are the 3 different neurones involved in the spinal pain pathway?

Answer 17

first order neurones:

• pseudounipolar neurones have a cell body in the DRG

second order neurones:

• cell body in Rexed lamina of spinal cord or cranial nerve nuclei in the brainstem
• decussate in anterior white commisure
• ascend cranially in the spinothalamic tract to the VPL of the thalamus

third order neurone:

• cell body in the VPL of the thalamus
• project via posterior limb of internal capsule to terminate in ipsilateral postcentral gyrus
• this is the primary somatosensory cortex

Question 18

What are the specialised receptors that some first order neurones have?

What type of receptors are these?

Answer 18

nociceptors which are activated through various noxious stimuli

nociceptors exist as the free nerve endings of the primary afferent neurone

as they are free nerve endings, they are unencapsulated receptors

Question 19

What are the 3 different types of nociceptors?

What type of stimulus do they detect?

Answer 19

mechanical nociceptors:

• detect sharp, prickling pain

thermal / mechano-thermal nociceptors:

• detect sensations which elicit pain which is slow and burning or cold and sharp in nature

polymodal nociceptors:

• detect mechanical, chemical and thermal stimuli

Question 20

How are signals from mechanical, thermal and mechano-thermal nociceptors transmitted?

Answer 20

they are transmitted to the dorsal horn via Ad fibres

these are myelinated and have a low threshold for firing and fast conduction speed

they are responsible for transmitting the first pain

they permit localisation of pain

Question 21

Where do Ad fibres terminate?

Answer 21

rexed lamina I

they mainly release the neurotransmitter glutamate

Question 22

How do polymodal nociceptors transmit their signals to the dorsal horn?

Answer 22

via C-fibres

these are unmyelinated and have a slow conduction speed

they have large receptive fields and poor localisation of pain

Question 23

Where do C fibres terminate?

Answer 23

in rexed laminae I and II

they release the neurotransmitter substance P

Question 24

What are the roles of the cingulate cortex and insular cortex in pain perception?

Answer 24

cingulate cortex:

• acute pain perception
• development of chronic pain after peripheral nerve injury

insular cortex:

• part of the limbic system
• subjective feeling of pain and induce learning about the pain in other brain areas

Question 25

What is meant by 'dissociated sensory loss'?

Answer 25

a pattern of neurological damage caused by a lesion to a single tract in the spinal cord it involves preservation of fine touch and proprioception and selective loss of pain and temperature

Question 26

In a unilateral spinal lesion, how would senses be affected?

Answer 26

* sensory loss of **touch, pressure, vibration** and **proprioception** **_BELOW**_ the lesion on the _**SAME_** side * diminished sensation of pain **_BELOW_** the lesion on the **_OPPOSITE_** side * this is dissociated sensory loss

Question 27

What are the 3 neurones involved in the trigeminal pathway for pain and temperature?

Answer 27

**1st order neurone:** * from the face * projects to pars interpolaris & pars caudalis of the medulla / upper cervical cord **2nd order neurone:** * ascends contralaterally to thalamus via trigeminothalamic tract **3rd order neurone:** * projects to cortex from VPM of thalamus this pathway innervates speicialised structures

Question 28

What is meant by the gate control theory of pain?

Answer 28

a gating mechanism that exists within the **dorsal horn** of the spinal cord small nerve fibres (pain receptors) and large nerve firbes (mechanoreceptors) synpase on **projection cells** and **inhibitory interneurones** projection neurones travel to the brain via the spinothalamic tract

Question 29

According to gate control theory, what happens when no input comes in?

Answer 29

the inhibitory interneurone prevents the projection neurone from sending signals to the thalamus the gate is closed

Question 30

According to gate control theory, what happens when there is normal somatosensory input? (more / only large fibre stimulation)

Answer 30

both the inhibitory interneurone and projection neurone are stimulated the inhibitory interneurone prevents the projection neurone from sending signals to the brain the gate is closed

Question 31

According to gate control theory, what happens when there is more/only small fibre stimulation? (nociception)

Answer 31

the inhibitory interneurone is inactivated the projection neurone sends signals to the thalamus informing it of pain the gate is open

Question 32

According to gate control theory, what is the role of the descending pathways from the brain?

Answer 32

descending pathways from the brain close the gate by inhibiting the projector neurones and dimishing pain perception

Question 33

What are the 2 different types of pain?

Answer 33

**physiological pain:** * this involves acute pain **pathological pain:** * this involves inflammatory and chronic pain

Question 34

What is the primary event in somatosensation?

Answer 34

the generation of an action potential in an afferent fibre ending

Question 35

What regulators of neuronal excitability are specific for nociceptive neurones?

Answer 35

**voltage-gated sodium channels:** * Nav1.7 * Nav1.8 * Nav1.9 **sensory TRP channels:** * TRPV1 * TRPM8 * TRPA1 **purinergic ligand-gated channels:** * P2X₂ * P2X₃

Question 36

What is meant by congenital insensitivity to pain?

Answer 36

a rare disease characterised by inability of experience to feel pain

Question 37

What tends to cause congenital insensitivity to pain?

Answer 37

mutations within nociceptor-specific voltage-gated sodium channel Nav1.7 population genetics can be used to pin-point pain-related genes

Question 38

What are the 4 different types of inflammatory mediators of pain?

Answer 38

1. act to directly activate ligand-gated ion channels 2. act via activation of G-protein coupled receptors 3. act via activation of receptor tyrosine kinases 4. gasotransmitters

Question 39

What types of inflammatory mediators act to directly activate ligand-gated ion channels?

Answer 39

* ATP activates P2X receptors * H⁺ activates TRPV1

Question 40

What inflammatory mediators act via activation of G-protein coupled receptors?

Answer 40

* prostaglandins * substance P * bradykinin * proteases * histamine

Question 41

What inflammatory mediators act via activation of receptor tyrosine kinases?

Answer 41

* NGF * BDNF

Question 42

What are examples of gasotransmitters?

Answer 42

these are gaseous signalling molecules * CO * NO * H₂S

Question 43

What are the 3 mechanisms involved in signalling cascades of inflammatory nociception?

Answer 43

1. activation / sensitisation of sensory channels 2. modulation of ion channels through intracellular signalling cascades 3. modulation of gene expression

Question 44

What is the role of central sensitisation?

Answer 44

central sensitisation contributes to **sustained pain states** it is a condition of the nervous system that is associated with the **development & maintenance of chronic pain** when it occurs, the nervous system goes through the process of **wind-up** and gets regulated in a persistent state of high reactivity

Question 45

What is the definition of central sensitisation?

Answer 45

the process through which a state of hyperexcitability is established in the central nervous system this leads to enhanced processing of nociceptive (pain) messages

Question 46

What are the 3 main mechanisms of central sensitisation?

Answer 46

1. NMDA-mediated signalling 2. disinhibition 3. microglia activation

Question 47

What is familial hemiplegic migraine (FHM)?

Answer 47

an autosomal dominant subtype of severe migraine accompanied by visual disturbances known as aura

Question 48

What causes the aura in familial hemiplegic migraine?

Answer 48

aura is caused by cortical spreading depression (CSD) this is a slowly advancing wave of tissue depolarisation in the cortex

Question 49

What is the cause of more than half of the cases of familial hemiplegic migraine?

Answer 49

gain-of-function mutations within neuronal Cav2.1 voltage-gated Ca²⁺ channel gene the mutation results in increased Ca²⁺ flow into dendrites and excessive release of the excitatory neurotransmitter glutamate

Question 50

What initiates cortical spreading depression (CSD)?

Answer 50

CSD is ignited by local elevation of **extracellular K⁺ levels** in pockets of intense excitatory transmission

Question 51

How is CSD threshold altered in FHM patients?

Answer 51

the threshold for CSD initiation is reduced in FHM patients with mutations in the Cav2.1 Ca²⁺ channel the higher Ca²⁺ level in dendrites facilitates glutamate release this increases the likelihood that K⁺ levels will reach the CSD threshold