Week 5- Pain (and temperature & itch)

Question 1

Transient Receptor Potential (TRP) channels

Answer 1

-Family of ion channels that pass Na+ and Ca2+ ions
-Many different kinds
-Channel opens at particular temperature (some activated by cold, some by cool, some by warm or hot) = Na+ and Ca2+ ions flow into sensory nerve cell
(depolarisation)
-Enough depol. = triggers action potential in sensory
nerve cell

Question 2

What does overlapping sensitivity of different TRP channels suggest?

Answer 2

Population coding scheme

Question 3

Thermoreceptors

Answer 3

-Thermoreceptors are on the tips of free nerve endings
-Different thermoreceptors have different activation thresholds
-Encode subtle differences in temp from cold → hot

Question 4

Do TRP channels usually respond to only 1 type of energy?

Answer 4

-Many TRP channels are also thermosensitive and chemosensitive (i.e. they respond to 2 kinds of energy and thus perform 2 kinds of signal transduction)

Question 5

Are chemaethesis and chemosensation the same thing?

Answer 5

-No, do not get them confused!

-Chemosensation= is an old term for the chemical senses (olfaction + gustation)

-Chemaethesis= the sensitivity of mucosal surfaces or skin to environmental chemicals. Activation of this system elicits thermal, nociceptive and tactile sensations. In simple terms it is the ‘feel’ of tastants.

Note: when talk about the chemosensory system talking about chemaethesis

Question 6

What are some examples of chemaethesis?

Answer 6

E.g. in oral cavity, pungency, coolness
E.g. in nasal cavity, tingle of fizzy drinks
E.g. on skin, coolness of eucalyptus, heat of camphor
E.g. on eyes, burn/tearing-up after cutting onions

Question 7

What does chemaethesis activate? What does this technically mean about the chemicals that cause chemaethesis?

Answer 7

-Activate thermoreceptors and/or nociceptors on free nerve endings
-Chemicals that activate chemaethesis are technically therefore classed as irritants or poisons but in modern day eating drinking and eating often utilizes chemaethesis (e.g. chili, wasabi, pepper, ginger, mint, carbonation etc.)

Question 8

Does chemaethesis occur only for facial skin?

Answer 8

No chemaethesis/ the chemosensory system is activate all over the skin

Question 9

Chemaethesis for the face (what nerves/ branches are invovled)?

Answer 9

-Cranial Nerve V (Trigeminal Nerve) innervates the skin of the face, the nasal cavity, mouth, cornea and conjunctiva of the eye
-Innervation around eye is very sensitive to chemical stimuli (low threshold)
-Other branches of nerve require higher concentrations of stimuli (skin’s protective layer makes it less sensitive)
-Cranial nerve IX (glossopharyngeal) and X (vagal) also carry some chemosensory information that is non-tastant induced [and more pharyngeal+bronchial]

Question 10

What innervates cranial nerve V?

Answer 10

-Mechanoreceptors
-Thermoreceptors
-Chemoreceptors
-All on or associated with free nerve endings

Question 11

What is the purpose of the chemosensory system (chemaethesis)?

Answer 11

-Serves as a safety surveillance system: initiates protective mechanisms: tearing, mucus, salivation, coughing, sneezing, vasodilation/flushing

Question 12

How is adaptation a problem from the chemosensory system?

Answer 12

Adaptation means that when you present a stimuli repeatedly sensation decreases.

Problem for the purpose of the chemosensory system which is to initiate protective mechanisms: will stop doing this.

Question 13

Green (1996)

Answer 13

-Repeated exposure to capsaicin
-Rapid adaptation from 1st to 2nd block……
-But perceived iritation rapidly returns to almost baseline levels i.e. rapid re-sentitization instead
of lasting adaptation

Question 14

Baumann et al. (1991)

Answer 14

-Repeated capsaicin application sensitizes Cfibers
-Triggers hyperalgesia (increased sensitivity/response to pain)
-Triggers allodynia (pain due to a typically non-painful stimulus, such as heat or touch)

Question 15

Gold & Gebhardt (2010)

Answer 15

-Repeated exposure of chemaesthetic stimuli
causes inflammation
-This converts chemaesthetic stimuli to nociceptive stimuli

Question 16

A-delta fibers

Answer 16

-Smallest diameter of the ‘A’ group of fibers (1-6 µm)
-Partially myelinated, slow conduction velocity (9-11 m/s)
-Carry nociceptive + thermoreceptive signals (respond to intense pressure & noxious temperature)

-‘first pain’ / ’fast pain’ (stabbing, cutting, sharp)

-endings cluster in small spots (small receptive field)

Question 17

C-fibers

Answer 17

-Very small diameter (< 1 µm)
-Unmyelinated
-Slowest conduction velocity (<1 m/s)
-Mechano, noci and thermo signals (respond to firm, but not too intense, pressure, noxious chemicals and noxious temperature)

• ‘second pain’/ slow pain’ (burning, aching, dull)

-endings broader (larger receptive field)

Question 18

Are pain fibers fast or slow?

Answer 18

-Slow (C-fibers)
-They are unmyelinated and have a very small diameter so conduction velocity is slow
-Doesn’t make any sense you would expect that pain signals would need to be fast

Question 19

What tract/ ascending pathway does temperature and nociception use? What divisions occur within it?

Answer 19

The spinothalamic tract:
-Lateral spinothalamic tract for thermoception and nociception
-Anterior spinothalamic tract for crude mechanoreception

Question 20

Spinothalamic tract

Answer 20

-Thermoreceptors on sensory nerve free endings
-1st order (afferent) neuron projects to spinal cord
-Decussate (cross over) in the spinal cord
-Synapses with second order neuron, which travels
to thalamus
-Synapses with 3rd order neuron which travels to
primary somatosensory cortex (SI)

Question 21

What is the difference between the spinothalamic tract and other sensory tracts?

Answer 21

-The fact that crossing over occurs in the spinal cord!
-For other sensory tracts information travels up ipsilaterally and crosses over (decussates) in the brain stem

Question 22

What is pain?

Answer 22

“An unpleasant sensory or emotional experience
associated with actual or potential tissue damage, or
described in terms of such damage”

3 Types of Pain:
-Abrupt/strong cutaneous sensation, tissue damage
-Damage to neural structures, neural supersensitivity
-Physical pain of psychological origin

Question 23

What is nociception? What are the four types of noxious stimuli that produce nociception?

Answer 23

-Nociception= ‘to hurt’

Four types of noxious stimuli:
-Mechanical pressure
-Temperature
-External chemicals
-Internal chemicals

Note: the top three are all external stimuli

Question 24

How are the four types of noxious stimuli linked in how they result in nociception?

Answer 24

-External stimuli (external chemicals, mechanical pressure, temperature) if strong enough can trigger release of internal chemicals

-It’s these internal chemicals that act on nociceptors

Question 25

Nociceptors

Answer 25

-There are many kinds of nociceptor
-Some TRP channels are also nociceptors (noxious cold/heat)
-They sit on the free nerve endings of peripheral sensory neurons (A-delta and C fibers)
-No need to remember them all – just appreciate that there are many kinds of nociceptor and they all bind different chemicals (mainly related to inflammation, low pH, noxious heat or mechanical damage)

Question 26

What are the three ways nociceptive fibers can differ?

Answer 26

1) Threshold
2) Range
3) Stimulus specificity (some responding to noxious temperature, some to noxious mechanical pressure and some to both i.e. polymodal)

Question 27

What kind of encoding scheme is at play with nociceptors?

Answer 27

Rate coding

Question 28

Process of nociception

Answer 28

-Nociceptive stimuli activate nociceptors on free nerve endings, this causes signal transduction

-Resultant neural signal travels along nociceptive fibre into spinal cord (Recall A-delta fibres partially
myelinated, C fibres unmyelinated)

(spinothalamic tract from here until thalamus)
-synapse onto second order neuron in spinal cord

-second order neuron crosses midline (decussates) and ascends all the way to thalamus

-synapse onto third order neuron in thalamus.

-Lateral thalamus projects to SI and SII somatosensory cortex. Medial thalamus projects to the frontal cortex (exp. ACC & insula)

Question 29

Pain Matrix

Answer 29

-The ‘pain matrix’: a set of brain areas including SI & SII, prefrontal cortex, anterior cingulate cortex, thalamus, insula that consistently respond to
painful stimuli.

-Some would add limbic system also (hippocampus, amygdala)

Question 30

Does it have to be you yourself that is in pain for the pain matrix to be activated? What questions does this raise?

Answer 30

-No, the non-sensory parts of the pain matrix can become activate even from just seeing someone else in pain
-This begs the question: how much of the ‘pain matrix’ is actually specific to pain? Could the areas instead be related to empathy, aversion, planning, learning??

Question 31

Mouraux et al. (2011)

Answer 31

-‘pain matrix’ brain regions respond to nociceptive
somatosensory, non-nociceptive somatosensory, auditory and visual stimuli.

-Not just pain!

Question 32

Salomons et al. (2016)

Answer 32

-Noxious mechanical stimuli given to healthy
individuals and individuals with a genetic mutation (don’t have calcium receptors in nerves) that makes them unable to sense pain.
-Similar activity in ‘pain matrix’ brain regions (thalamus, insula, S2, and anterior cingulate cortex) of both groups

Question 33

What is an alternative hypothesis for the ‘pain’ matrix?

Answer 33

-More likely scenario: we’re talking about a group of brain regions that respond to salience, not necessarily pain
-If it’s attention grabbing, the ‘pain matrix’ will probably light up
-Our best guest is still that pain involves processing in the ‘pain matrix’ we just don’t know exactly how

Question 34

What does fMRI rely on? What is the issue of this?

Answer 34

-fMRI relies on ‘reverse inference’ : using brain activity to deduce that a cognitive event (e.g. pain perception) is happening.

-But a brain region like the ACC is involved in pain, attention, working memory, conflict processing, effort….
-Which process are you recording???

Question 35

What areas of the brain are activated by itch?

Answer 35

-Thalamus, SI, SII, ACC, Prefrontal cortex, Insula, motor cortex & basal ganglia
-The first 5 are also the ones invovled in pain!

Important…!
-Sensory areas (itch)
-Motor (scratch)
-Dopamine circuits (urge)

Question 36

What is itch?

Answer 36

-An unpleasant sensation which triggers the urge to scratch

Question 37

Is itch considered separate from pain and why/ why not?

Answer 37

-Previously considered not to be a true submodality: just a less severe version of pain
-Now recognised as independent of pain

Question 38

What things are the same about itch and pain? What is the fundamental difference that results in them as being classed as separate submodailities?

Answer 38

Same:
-Many of the same cortical processing areas
-Same sensory tract (spinothalamic)
-Same fiber types (A-delta fibers, C fibers)
-Both require free nerve endings

Different:
-Itch is triggered by irritants, pathogens or allergens on skin (unless the itch is neurological/ psychological in origin, which can happen)

Question 39

What do Pruritogens trigger?

Answer 39

-Release of chemicals from skin cells or immune cells
-Chemicals bind to receptors or ion channels on free nerve endings
E.g. in response to mosquito bite, local immune
cells release histamine, which binds to receptors on free nerve ending

Question 40

What are pruritogens? (courtesy of chat gtp :)

Answer 40

Pruritogens are substances that can cause itching or a sensation of itchiness. These substances can activate sensory nerve fibers that transmit signals to the brain, leading to the perception of itch. Examples of pruritogens include histamine, proteases, and certain opioids.

Question 41

Are all fibers selective for pain over itch?

Answer 41

-Evidence that some fibers are selective for itch over pain!
-They express MrgprA3 and Histamine receptors

Question 42

Is itch purely pruriceptive?

Answer 42

-No, there are other kids of itch
-Resulting from changes in neural activity in the spinal cord or brain: neuropathic, psychogenic
-Resulting from changes to the whole body as a result of illness such as liver or kidney disease: systemic

Question 43

What problems arise because of itch not being soley pruriceptive? And then what question does this raise about pain treatment?

Answer 43

-How would you treat these different kinds of itch? Antagonists of certain receptors/channels could work as anti-pruritics (e.g. antihistamines), but what about itch that doesn’t seem to involve pruriception?

• Could you also treat pain in different ways? Would there be a benefit to targeting psychogenic aspects of pain over nociception?

Question 44

Why do we scratch an itch or rub a bump? Why does this alleviate the unwanted sensation?

Answer 44

• Melzack & Wall (1965): Gate control theory of pain put forward to answer these very questions

-Basic idea = non-nociceptive (or non-pruritive) signaling such as touch, pressure, vibration can ‘cancel out’ noxious signaling associated with pain/itch

-Still the dominant model of pain signaling today

Question 45

Two ‘somatosensory highways’

Answer 45

-Noxious and non-noxious signaling travel up opposite sides of the spinal cord
-Noxious (e.g. pain) = decussates in spinal cord at
level of sensory nerve innervation then ascends contralaterally
-Non-noxious = ascends immediately (i.e. ipsilaterally) then decussates at brainstem

This has big implications!

Question 46

Dissociated Sensory Loss

Answer 46

-If you damage the spinal cord, you may differentially affect mechanoreception and nociception, at different sites of the body (this is what dissociated sensory loss means)

This happens because of two reasons:
-Each level of spinal cord receives info only for a
specific dermatome
-And there is a difference in how the ‘type’ of information ascends. Non-painful info ascends ipsilaterally immediately. Painful info crosses over, then ascends contralaterally.

Question 47

What sensory loss would you expect to see from Bilateral damage at T3?

Answer 47

No sensory info gets to brain from either side of body below level of lesion

Question 48

What sensory loss would you expect to see from unilateral damage at T3?

Answer 48

-No nociceptive info from contralateral side of body below lesion level

-AND! No mech info from ipsilateral side of body below lesion level

Question 49

How does activity in one highway ‘cancel out’ the other highway?
(the gate control theory of pain but in more detail)

Answer 49

Existence of 2 cell types in spinal cord:
-Transmission (T) cells: transmit pain signals up, to
brain
-Gate cells: inhibitory cells that work to ‘gate’ (i.e.
suppress) the T cells

-Essentially there is a competition between these two populations
-Brake on T cell firing = no pain
-Release brake on T cell firing = pain

Question 50

What is meant by the phrase:
“the gate cell is tonically active”

What does this mean in terms of gate control theory?

Answer 50

-Keeps firing even without any stimulation and thus keeps the gate closed when no nociceptive stimuli is present

-Signals from mechanoreceptors boost the activity
of the gate cell, so even greater brake on T-cell

-Signals from nociceptive fibers do 2 things:
excite the T-cell directly AND suppress the activity
of the gate cell (i.e. inhibit the inhibitory neuron –
“disinhibition” of the T-cell)

Question 51

What revision of the gate control theory has been made according to recent evidence by Sun et al. 2017?

Answer 51

• Sun et al, 2017 has made a revision to the gate control theory of pain by proposing a ‘leaky gate’ i.e. after a certain level of itch/nociceptive activation the gate will close again. In other words if pain is strong enough this will trigger release of enkephalin (an endogenous opioid) which closes the gate and decreases the transmission of pain signals.

Question 52

In what ways can influencing the gate influence pain perception?

Answer 52

• bottom-up modification (increase cutaneous sensation to try and ‘shut the gate’)
• top-down modification (send a message from the brain to ‘shut the gate’) e.g. attention

-Exogenous control (use an exogenous drug to help ‘shut the gate’)

Question 53

Top down modification of pain

Answer 53

Descending pathways modulate the transmission of ascending nociceptive signals:
- descending neurons release enkephalin, endorphin and dynorphins [endogenous opioids]
- electrical stimulation of descending path has been shown to inhibit spinal T-cells and produce analgesia
-descending pathway responds to opiate drugs [exogenous opioids]

Question 54

Top down modulation of pain: via descending pathway

Answer 54

-Strong incoming nociceptive information will automatically (subconsciously) activate the descending pathway (e.g. via enkephalin release as per Sun et al., 2017)

-Some people seem to be good at activating descending pathways consciously

-Which has lead to the thinking that we could do surgery without anesthesia if we controlled this process (hypnosis). Kind of sketch though.

Question 55

Functions of pain

Answer 55

-A warning signal that tissue damage has occurred or is about to occur

-Very difficult to ignore that signal

Initiates an immediate behavioural response:
- in you: hyperalgesia
- in you: allodynia
- in others: physical help, attention, empathy

Question 56

Why do we all perceive pain differently (different pain thresholds)?

Answer 56

Partly due to physiology, e.g.
- degree of free nerve ending innervation
- numbers and types of TRP channels, NaV1 (sodium) channels, etc.
- skin properties (thick/ thin)

Partly due to Psychology, e.g.
- selected attention
- conforming to social norms / social referencing
- emotional state
- personality traits

Question 57

What is a standard experiment used to measure pain?

Answer 57

-Use Von Frey Filaments which are a way to provide standardized mechanical compression that is not painful (ethics wouldn’t allow for an experiment where individual’s are in great degrees of pain so instead use a method for cutaneous detection)

-When the filament flexes (will happen at different pressures for each filament) ask can you feel that?- if no move to next filament until the participant can

-Similar to Fechner’s method of limits from week 1

-Interestingly gender of the experimenter administering this test has an effect

Question 58

What is phenomenology?

Answer 58

-Study of conscious experience. We need to have descriptions of what people are experiencing (qualia)

-Subjective experience is hard to gain through scientific data. This is why self-report measures can be good to quantify pain and the variation in perception between individuals

Question 59

How can you ethically source participants for an experiment looking at pain?

Answer 59

Recruit those already in chronic pain

Question 60

What is the McGill pain questionnaire?

Answer 60

-Developed by Ron Melzack

-Can be used to monitor pain over time and to determine the effectiveness of any intervention

-3 sections:
(1) What does your pain feel like?
(2) How does you pain change with time?
(3) How strong is your pain?

Question 61

Prevalence of Pain

Answer 61

-The world is in pain – 80% of people will experience chronic pain at some point

-Pain is the #1 cause of disability, time off work

-Pain is the #1 money maker for the pharmaceutical industry

-But inactivity & painkillers have their drawbacks, how do you deal with pain?

Question 62

Catastrophizing Chronic Pain

Answer 62

-Intensification of the emotional & cognitive components of pain perception (overwhelmed, judging tasks unachievable)

-A very typical response in many (more often when stressed, depressed)

-May elicit social support (reward - positive feedback, conditioning) but counterproductive….increases distress and fosters disability (again through conditioning & reward mechanisms)

Question 63

Pain when there is no clear cause?

Answer 63

-This means there is no bottom up factor

-For example 30-40% of chronic back pain is discogenic but typically outlasts disc pathology (and in many cases disc pathology is present when pain is not- very poor correlation)

-Cause of pain could be sensitization of pain pathways in spinal cord – role for inflammatory molecules?