Week 1-Peripheral and Central Mechanisms of Pain

Question 1

What is involved in Pain Receptors?

Answer 1

-free nerve endings

-TRP channels

-afferent fibres (connects tissues to the spinal cord)

Question 2

What is involved in Pain Pathways?

Answer 2

-spinal cord processing

-spinothalamic tract

Question 3

What is involved in Pain Mechanisms?

Answer 3

-gate control theory (outdated theory)

-sensitisation

-temporal summation

-referred pain

Question 4

What is involved in Pain Hyperalgesia?

Answer 4

primary (peripheral nerves) and secondary (spinal cord) hyperalgesia

Question 5

Define Pain (International Association for the Study of Pain, 2020)

Answer 5

An unpleasant sensory and emotional experience associated or resembling actual
or potential tissue damage.

Question 6

Name the 3 basic types of pain

Answer 6

1.Nociceptive

2. Neuropathic
3. Nociplastic

Question 7

What’s Nociceptive Pain?

Answer 7

Day-to-day pains e.g., bruises caused by the stimulation of nociceptors in the tissues

Question 8

What regions of the body lack nociceptors?

Answer 8

 brain tissue (however, the meninges i.e., the brain blood vessels do have nociceptors)

 bone (however, the periosteal membrane i.e., membrane surrounding the spinal cord has nociceptors)

 interstitial tissue of the kidney (however,
the capsula has nociceptors)

 liver (however, the liver capsula has nociceptors)

 lungs (however, pleura has nociceptors)

-Therefore, these regions cannot detect pain, BUT those mentioned around it can

Question 9

What is the Basic Pain Scheme?

Answer 9

1. Free nerve endings in the tissues
2. Peripheral nerves
3. Dorsal horns of the spinal cord
4. Spinal cord pathways
5. Brain centres

-Rene’s first attempt to explain pain as a physical mechanism was through burning his foot=animal spirits passing this pain message to the brain in the pineal gland

Question 10

The cell body of axons of peripheral nerve fibres are located where?

Answer 10

In the dorsal root ganglia located a few
millimeters away from the spinal cord

The skin:
-C5 can penetrate the dermis in the skin

-no pain receptors in the epidermis meaning no pain if peeled off

-nociceptor refers to the entire afferent neuron going from the tissue/the free nerve endings/the molecules sitting on the free nerve endings in the iron channels

Question 11

How does the body respond to touch and pain?

Answer 11

Touch:
-MS mechano-sensitive channels on their nerve endings to detect touch sensations

Pain:
-Channels such as MS, TRPV1 etc., can sense touch and temperature (hence polymodal)

-So their job is to detect when the stimuli is noxious (i.e., Painful: will cause damage to tissues and nerves)

Question 12

Where does the name Transient Receptor Potential channels (TRP) originate from with examples of these channels (McMahon & Koltzenburg, 2006)

Answer 12

-Modern theory of nociception suggests there are different types of TRPs where some are noci-sensors

-name of TRP comes from the fact it causes slight depolarisation of the membrane but is transient (over small amount of time) and won’t trigger an action potential, but makes it more likely to occur by another event

-TRPV1 (V = valoid) most common with capsaicin (aka chilli) mouth becomes more susceptible to heat and activates this channel reminisicing an inflammatory response. Channel becomes more temperature sensitive (decreases threshold from 43 degrees)

-TRPM8 (malastatin) the receptor menthol binds in cooler temperatures (i.e., mentol cools it). senses noxious (painful) cold e.g., 8 degrees

-TRPA1 is sensitive to mustard oil which is more sensitive to cold temperatures (detects pain at colder temps)

Question 13

True or false: TRPM8 - cold/pain, TRPV1 - capsaicin receptor increase the permeability to cations, including Ca2+ (McKemy, 2005)

Answer 13

True!

-Additionally, combining more spicy food = greater noxious heat perception

Question 14

How did Caterina et al. (2000) test the role of TPRV1 in recognising pain?

Answer 14

-Selectively bred mice until they no longer showed TRP receptors

-Injected capsaicin into skin at different doses (higher doses didn’t have big difference)

-The more they licked their paws the more they were in pain/inflammatory response but those without TRP showed less pain response (TRP can’t be only receptor for detecting chemical pain)

-Knock-out mice lacking the capsaicin
receptor-reduced pain induced by
capsaicin or heat.

Question 15

How did Vriens & Voets (2019) prove that a triplet of TRPs fully explains heat pain in mice?

Answer 15

-Gene editing techniques to remove channels as selective breeding would be too hard

-Tail burned on and no response

-Knocking out all 3 channels eliminated heat pain response

-Sensitivity to mechanical and cold pain was maintained

-Demonstrates how these receptors (as a combination) are specific to heat pain

Question 16

True or False: The spinal dorsal root ganglion hosts the cell bodies of neurons in afferent peripheral fibres

Answer 16

True

-Chronic pain can cause the Dorsal Root Ganglion to squeeze by adding pressure or stimulating it, causing neuropathic pain (e.g., nerve pressure)

Question 17

Name the 3 main Peripheral Nerve Fibres which transmit information from the tissues to the spinal cord

Answer 17

1. A-fibres
2. B-fibres
3. C-fibres

-These nerve fibres are in the DRG

Question 18

What are C Fibres aka C mechano-heat nociceptors (CMH)?

Answer 18

• thin, non-myelinated fibers, located under the epidermis
• depth 20-560um
• velocity: 0.5-2.0 m/s
• burning, long-lasting pain, responsible for most types of chronic pain of peripheral origin (e.g., inflammation or rheumatoid arthritis) (takes a while to detect pain (half a second) and has a slow offset hence burning)
• large receptive field (check what means) (100 mm2), comparatively poor spatial localisation (i.e., hard to locate where the stimuli was)
• sensitive to mechanical and heat stimuli

Question 19

What did McMahon & Koltzenburg (2006) find about C-fibres?

Answer 19

-C fibers fire in parallel to stimulus intensity

-Responses of CMH to a 3-s heat stimulation of the glabrous skin of the monkey

-Apply noxious heat stimulus

-43 c-fibres get more excited and increasing temperatures increases this meaning more action potentials

-A tight relationship between pain and the level noxious heat in human and monkey i.e., perfect correlation of c-fibres and the objective identification of heat pain.

Question 20

What are the characteristics for type 1 and type 2 A-delta fibres?

Answer 20

Type 1:
-High threshold to short stimuli
-Slowly increasing response to heat
-Long response latency to intense heat
-Late peak latency to intense heat
-Located on hairy and glabrous skin

Type 2:
-Low threshold to short stimuli
-Adapting response to heat
-Short response latency to intense heat
-Early peak latency to intense heat
-Located on hairy skin

-Low threshold to heat stimuli (i.e., sensitive to heat)

Question 21

How did fibres Treede et al., (1998) investigate the two types of A-delta fibres?

Answer 21

Type 1: Slow response, long adaptation,
hairy and glabrous skin

Type 2: Rapid response, rapid adaptation,
hairy skin

-AP rate = rate of action potentials

-Slow response = slow build-up

-Type II not necessarily about how hot it is but rather acknowledging that there is pain

Question 22

What is first and second pain?

Answer 22

-first is A-fibres

-second is C-fibres

-Blocking a-delta fibre only brings c-fibre pain

-right picture take with a pinch of salt (hasn’t been widely replicated) but stimuli that selectively activates a-delta fibres shows different activations in the brain (somatosensory cortex) where c-fibres (anterior cingulate cortex)

Question 23

What’s Hyperalgesia (HA)?

Answer 23

-HA = shift in stimulus-response function to the left (e.g. stimulus of 41°C is as painful as 49°C)

-HA occurs after burn injury or inflammation, or after repetitive nociceptive stimulation

• painful swallowing in pharyngitis (sore throat)
• pain produced by touching sun burned skin
• painful micturition in urinary infection

-HA = more pain

-nociceptive stimulation = can include electrical stimulation

-Primary HA = peripheral mechanism entirely mediated by chemical mediators within primary afferents (i.e., peripheral effect) (limited to that area of noxious input/tissue damage)

-Secondary HA = a CNS mechanism (sensitised to a wider area of skin due to the fact of spinal mechanisms)

Question 24

What’s the link between hyperalgesia and allodynia?

Answer 24

-As you increase stimulus intensity you increase pain intensity

-43 degrees acts as a 0 in normal conditions but the leftward shift causes the pain to suddenly become a 5/10

-Allodynia is the lower pain intensity before HA

Question 25

What is Primary Hyperalgesia and what are its features?

Answer 25

-Primary HA manifests in increased painfulness within the injured region of the skin to both mechanical and heat stimuli.

Features of primary HA:
* Decreased threshold of CMH and AMH (peripheral) nociceptors
* Increased response to the suprathreshold stimuli
* Expansion of the receptive field
* Spontaneous pain

-Suprathreshold stimuli = above the pain threshold

-Spontaneous pain is in that area

Question 26

What are the three basic mechanisms of primary hyperalgesia?

Answer 26

1. Chemical sensitisation: If you had damaged tissues and an inflammatory response, they would both release mediators and interact with receptors on the nerve ends to stimulate TRP channels
2. Upregulation of TRP receptors: TRP channels are proteins and these proteins are synthesised in the soma (body) of the
   nociceptive neuron and travel to the free nerve ending in the axonal cytoplasm. Trophic factors, e.g. NGF (nerve growth factor), are released from injured cells and cause synthesis of new TRPs and their transport to the periphery (nerve growth factors get released from damaged tissues = more receptors and proteins like TRP).
3. Silent nociceptors = neurons that cannot
   be excited by even very strong stimuli in healthy tissues. However, silent nociceptors would respond to mechanical stimuli in the presence of inflammation (becomes polymodal as a result)

Question 27

What Chemical Agents cause Primary HA?

Answer 27

Bradykinin – present in inflammatory exudates (fluids); sensitises TRPV1 in particular; bradykinin causes pain when injected into skin (makes TRPV1 more conductive).

Histamine - from the mast cells in tissues; excites visceral nociceptors; causes itch rather than pain when injected into skin.

Serotonin - from blood platelets; activates nociceptors; enhances response to bradykinin; causes pain when injected into skin.

Substance P - from peripheral nerves; also causes pain when injected into the skin (SP potentiates excitatory NTs like glutamate, explaining why it causes pain)

Leukotrienes - from immunocompetent cells (lymphocytes, macrophages).

Prostaglandins – e.g., PE2 formed from arachidonic acid that has been released
from damaged cell membranes (P sensitises nerve endings).

Question 28

How is Primary HA modulated?

Answer 28

-Blood and cell fluids contain chemical substances which bind to nociceptors and can modulate primary hyperalgesia

Opioid substances are contained in inflammatory cells (macrophages, lymphocytes): action to reduce excitatory
neurotransmitters; open potassium channels to hyperpolarise neurons.

Cannabinoids: CB1 and CB2 receptors are distributed along the pain axis starting from nociceptors. CBs modulate ion flow across TRPs, and also modulate afferent nerves.

Somatostatin (SST) is contained in immuno-competent cells (e.g., lymphocytes, macrophages). Acts on TRPV1 primarily. SST suppresses inflow of calcium and opens potassium channels.

-These are essentially pain killers

Question 29

What are 4 main features of the spinal cord?

Answer 29

1. Thin, elongated tubular structure
   running in the spinal canal, in the
   openings of individual vertebrae.
2. Spinal cord comprises bodies of
   neurons and long axons (connecting
   with the brain) and short axons
   (interneurons).
3. Spinal cord sends a pair of spinal
   nerves through the openings on sides
   of vertebrae; these nerves comprise
   both sensory and motor neurons.
4. There are 31 pairs of spinal nerves.

Question 30

The Spinal Cord: What are the Zones of Rexed? (1952)

Answer 30

They are Major nociceptive zones in the grey matter of the spinal cord called:
1. Lamina I
2. Lamina II
3. Lamina V

Question 31

What is Lamina I?

Answer 31

Zona marginalis: Primary entry zone for the C and small diameter A-delta fibres. Mainly, nociceptive specific (NS) interneurons (i.e., only respond to nociceptive stimuli).

Question 32

What is Lamina II?

Answer 32

Substantia gelatinosa: Large number of nociceptive specific (NS) interneurons capable of post-synaptic inhibition. Entry of A-delta fibres and C fibres.

Question 33

What is Lamina III-IV?

Answer 33

The entry zone for the tactile A-beta fibres.

Question 34

What are the 3 main dimensions of pain? (Melzack and Casey, 1968)

Answer 34

1. sensory-discriminative: physical stimuli + their processing (i.e., off-set and on-set and where the pain is, brief or sustained over time)
2. affective: unpleasantness, emotions
3. cognitive-evaluative: situation, context (internal and external environment too), memory, cognition

-you can’t separate the sensory and emotional aspects of pain, it is inherently unpleasant

Question 35

What’s Neuropathic Pain?

Answer 35

Pain directly caused through a lesion or
disease affecting the somatosensory system (i.e., one of the nerves is injured = pain through various mechanisms)

Question 36

What’s Nociplastic Pain?

Answer 36

-Pain that arises from altered nociception (ask lecturer what AN means)

-No clear evidence of actual or threatened tissue damage, i.e. no activation of peripheral nociceptors + evidence for disease or lesion of the somatosensory system causing the pain (i.e., change in the somatosensory system function not associated with actual tissue/nerve damage)

-Nociplastic pain more associated with chronic types of pain

Question 37

How does the body respond to temperature?

Answer 37

-Channels such as TRPV3, TRPV4 and TRPM8 detect and respond to temperature

-There can be combinations of the stimuli and nerve fibres e.g., hit hand with hammer (pain and touch), thermal stimuli (temp and pain)

Question 38

What are the different types of A-fibres?

Answer 38

Alpha: proprioception 12-20 um (diameter) 70-120 m/s (velocity)

Beta: touch, pressure 5-12 um 30-70 m/s

y: muscle spindles 3- 6 um 15-30 m/s

Delta: pain (any), cold 2- 5 um 15-30 m/s

-A-fibres a-delta are most important regarding pain

-A-beta fibres non-noxious touch sensations relevant in gate control theory and can get involved in causing greater pain

Question 39

What are the different types of B-fibres?

Answer 39

-preganglionic fibres < 3 um (diameter) 3-15 m/s (velocity)

-autonomic system

Question 40

What type of nerve fibres are C-fibres?

Answer 40

-Pain (any), warmth, affective touch < 0.4-1.2 um (diameter) 0.5-2 m/s (velocity)

-C-fibres are unmyelinated hence small diameter meaning they are slow-conducting, sensitive to chemical irritants and inflammation

-Bundle of nerves/neurons not just one

Question 41

What is Lamina V?

Answer 41

Contains a large number of WDR cells; converging inputs from visceral nociceptors (in internal organs) and cutaneous and muscle afferents; the site of origin of the spinoreticular tract.

Question 42

What is Lamina VII-VIII?

Answer 42

Contains motor neurons. Receives pain information from interneurons rather
than directly from afferent fibres; responds to noxious stimuli from either the left or right side of the body.

Question 43

What are the differences between Wide-dynamic-range vs. Nociceptive-specific neurons?

Answer 43

WDR:
1. Activated by a variety of stimuli (even by strong tactile stimuli)

2. Long after-discharges (i.e., you get a train of APs following stimulation)
3. Large receptive fields
4. Located in Lamina V (and I)
5. Large number
6. Subject to plasticity effects (partly due to long after-discharges)

NS:
1. Activated only by noxious stimuli

2. Rather abrupt termination of discharges (i.e., brief number of APs)
3. Small, circumscribed receptive fields
4. Located predominantly in Lamina I and II
5. Small number
6. Limited plasticity

Question 44

WDR and NS: Give functional examples (Cervero & Laird, 1996)

Answer 44

-Electrically stimulated in the spine

-Evidence of long-train of APs seen in the WDR whereas few APs limited to a small amount of time in the NS

-Evidence NS are sensitive to noxious stimuli e.g., pinpricks & WDR sensitive to all types but also non-noxious stimuli (therefore WDR receiving a-delta/a-beta/C fibre inputs)

Question 45

What are some Mediators of spinal nociception/plasticity? (all NTs)

Answer 45

1. Glutamate is the main excitatory mediator in nociceptive afferent fibers and in dorsal horn neurons.
2. Substance P (peptide), excitatory mediator which also amplifies the effects of glutamate.
3. GABA (gamma-amino-butyric acid) and glycine are the main inhibitory mediators.
4. Many other mediators: neuropeptide Y, serotonin, cholecystokinin, orexin…(about 30).

Question 46

Phenomenon resembling plasticity: What is the temporal summation of pain? - Wind Up (Staud et al., 2006)

Answer 46

-Temporal summation of repeatedly presented warm (innocuous) stimuli
stimulating > 0.33 Hz (starts to become more painful than originally believed)

-Involvement of C fibres, WDR cells (overlapping of APs causing a build up of pain), and glutamatergic NMDA and NK1 receptors (for substance P) (these NTs as its causing excitation).

-Entirely a spinal process

Question 47

What did Cervero and Laird (1996) find regarding Wind Ups?

Answer 47

That Wind-up works with C fibres only

Question 48

Plasticity Phenomenon: What is Central Sensitisation? (Torebjork et al., 1992)

Answer 48

-A long lasting change in plasticity of the spinal cord or very strong stimuli which will cause the dorsal horn neurons to fire more strongly, respond to subthreshold (non-painful) stimuli, and expand their receptive fields

-Example: Capsaicin-induced sensitisation (secondary hyperalgesia)

-Stimulation on non-painful level = tactile sensation, feeling it in the nerve ending

-Stimulation on painful level + injection of capsaicin adjacent to TS = local inflammatory response (PA) + SA which encompasses tactile sensation (previously non-painful now painful). Once it dies down it becomes a TS again

Question 49

What’s Secondary Hyperalgesia including its features?

Answer 49

-A symptom of pain during mechanical stimulation outside the primary zone

Features:
* Caused by central sensitisation
* Decreased sensitivity to heat stimuli
* Increased sensitivity to mechanical stimuli
* Spontaneous pain

Secondary HA – two main types:
1. Dynamic-mechanical HA = allodynia (something non-painful like brushing the skin becomes painful: activates a-beta and c fibres)
2. Punctate HA (poking the skin with something sharp: activates a-delta fibres)

Question 50

What’s Dynamic-mechanical hyperalgesia = allodynia?

Answer 50

• Brushing, gentle touch of the skin within the secondary zone (allodynia)
• Allodynia varies from minor sensations (tingling) to unbearable pain (e.g., during clothes dressing, shaving)

Question 51

What is a Possible mechanism of dynamic-mechanical HA (allodynia)?

Answer 51

• Sensitisation of WDR neurons (Lamina V),
  such that when receiving tactile input (from non-nociceptive A-beta fibres), they transmit nociceptive information to the
  brain (i.e., go from being perceived as non-painful to painful)
• Sensitisation is mostly due to the greater efficiency of the glutamatergic NMDA receptors (due to greater upregulation of these receptors and good conduction)

Question 52

What is Punctate hyperalgesia?

Answer 52

• It is produced by stiff, sharp probes
• The area of skin showing HA is larger
• After a capsaicin injection, HA lasts much longer (12 hours, vs. 1-2 hours in D-M HA)
• Local cooling of the skin does not reduce hyperalgesia (unlike in D-M HA) – less dependent on peripheral signals

Question 53

What is Gate control theory: Melzack & Wall (1965)

Answer 53

T = transmission cells in the spinal cord (WDR cells, Lamina V)

SG (subst. gelat.), the site of synaptic inhibition, Lamina II

L = large, myelinated fibres conveying touch and pressure (A-delta, A-beta)

S = small, non-myelinated fibers for pain (C)

-Mediators in SG are essential for the development of chronic pain and for its treatment

1. Gate at the spinal cord that opens and closes based of cognitive emotional states (modulated through the brain)
2. Neurons projected to the brain which is stimulated by L or by S
3. Somewhere in the spinal cord, there will be inhibitory neurons (aka SG) which can be modulated by L (excitatory and minimises pain)/S (inhibits and increases pain)

Question 54

What are the 3 main problems with the Gate Control Theory?

Answer 54

1. Oversimplification: One of the primary criticisms is that the model may be too simplistic to explain the complexities of pain modulation. Pain perception involves multiple pathways, neurotransmitters, and brain regions, many of which are not accounted for in the Gate Control Theory.
2. Plasticity / Temporal Factors: The theory doesn’t account for the influence of temporal summation and other time-related factors on pain perception. The theory also does not explain the long-lasting neurophysiological changes occurring in chronic pain patients (plasticity).
3. Presynaptic inhibition in WDR cells from SG cells has not always been shown to occur in all contexts.

Question 55

Pain Pathways: What is the spinothalamic tract? (Craig, 2002) LOOK AT NOTES FROM LAST YEAR

Answer 55

3rd neuron:
From thalamus (ventrobasal complex) to
the cerebral cortex

2nd neuron: grey matter to thalamus,
crossing in anterior part of spinal cord
= commissura alba anterior

1st neuron: from spinal ganglion to
the grey matter of the spinal cord

Question 56

What are some other pain pathways?

Answer 56

Spino-thalamic axons also project to the brain stem (collaterals of the spinothalamic tract)
* Nucleus tractus solitarius
* Ventral medulla oblongata (both cardiorespiratory control)

• Parabrachial nucleus – sends to amygdala (fear)
• Periaqueductal gray matter – role in antinociception
• Hypothalamus – defensive or aggressive behaviour

Further tracts parallel the spinothalamic tract, and are known as e.g., spino-reticular, spino-mesencephalic, or spino-hypothalamic tracts (i.e., alternative names)

Question 57

Explain Descending nociceptive control:
endogenous opioids (Tracey & Mantyh, 2007)

Answer 57

 How much analgesia to apply?
Periaqueductal gray matter (PAG)

 Execution: Rostroventromedial
medulla (RVM), dorsolateral pontine
tegmentum (DLPT)

Evidence:
 Electrical stimulation of PAG/RVM
causes suppression of behavioural
response to pain (Reynolds, 1969)
 Microinjections of morphine – -
opioid receptor agonist has the same
antinociceptive effec

Question 58

What is Visceral Pain?

Answer 58

• Pain resulting from noxious events in internal organs
• Chemical (e.g. inflammation) and mechanical (distention, irritation) stimuli (rather than heat or cold)
• Visceral pain often has a quality of burning pain (C fibres involved)

Two components:
1. nociceptive afferent information from the organ (poorly localised, dull)
2. nociceptive information from the tissues
covering the organ (sharp and strong)

Giamberardino et al., 2006:
-Referred pain: visceral pain is felt elsewhere in the body (e.g., heart attack felt in arm)

Question 59

Referred pain: What is the convergence-projection theory?

Answer 59

-Convergence of afferent visceral nociceptive fibres and cutaneous fibres in Lamina V

-Skin/muscle area (dermatome)

-Viscus

-There is a corresponding area of the body which sends signals to WDR similar to another area