Pain

Question 1

How are the different types of pain categorised?

Answer 1

Usually by the area of the body the pain signals originate from

Question 2

Where does somatic pain originate?

Answer 2

Cutaneous, skeletal muscle/tissue or the peritoneal membrane

Question 3

When would somatic pain arise?

Answer 3

Post-operative
Post-exercise
Mild trauma

Question 4

Where does visceral pain originate from?

Answer 4

Thoracic or abdominal organs

Question 5

When would visceral pain arise?

Answer 5

Post-operative
Cancer
Traumatic injury

Question 6

Where does neuropathic pain originate from?

Answer 6

Specific damage to nerves

Question 7

When would visceral pain arise?

Answer 7

Amputation
Type 2 diabetes, hyperglycaemia induced damaged

Question 8

Where does sympathetically maintained pain originate from?

Answer 8

Sensitisation of the CNS causes neuropathic pain in distribution of a sympathetic nerves

Question 9

When would sympathetically maintained pain arise?

Answer 9

Complex regional pain syndromes

Question 10

Describe the differences between nociception and pain.

Answer 10

Nociception refers to the central nervous system (CNS) and peripheral nervous system (PNS) processing of noxious stimuli, such as tissue injury and temperature extremes, which activate nociceptors and their pathways.
Pain is the subjective experience one feels as a result of the activation of these pathways but is also influenced by psychological factors such as past experiences, beliefs about pain, fear or anxiety.

Question 11

What are nociceptors?

Answer 11

They are the specialised endings of primary afferent nerve endings of Alpha-delta and C fibres within the periphery. They detect noxious stimuli, transforming the stimuli into electrical signals, which are then conducted to the central nervous system.

Question 12

Where are nociceptors found?

Answer 12

In mammals, nociceptors are found in any area of the body that can sense noxious stimuli. External nociceptors are found in tissue such as the skin (cutaneous nociceptors), the corneas, and the mucosa. Internal nociceptors are found in a variety of organs, such as the muscles, the joints, the bladder, the visceral organs, and the digestive tract.

Question 13

Where are the cell bodies of nociceptors found?

Answer 13

Either in the dorsal root ganglia or the trigeminal ganglia. The trigeminal ganglia are specialized nerves for the face, whereas the dorsal root ganglia are associated with the rest of the body.

Question 14

What are the different types of noxious stimuli?

Answer 14

Mechanical
Thermal
Polymodal

Question 15

What are AB fibres responsible for?

Answer 15

They are primary afferent nerve fibres that respond to/transmit non-noxious stimuli. Essentially carry information related to touch.

Question 16

Describe the characteristics of AB fibres.

Answer 16

Aβ fibres are highly myelinated and of large diameter, therefore allowing rapid signal conduction. They have a low activation threshold and usually respond to light touch and transmit nonnoxious stimuli.

Question 17

Describe the characteristics of Aδ fibres.

Answer 17

Aδ fibres are lightly myelinated and smaller diameter, and hence conduct more slowly than Aβ fibres. They respond to mechanical and thermal stimuli. They carry rapid, sharp pain and are responsible for the initial reflex response to acute pain.

Question 18

Describe the characteristics of C-fibres.

Answer 18

C fibres are unmyelinated and are also the smallest type of primary afferent fibre. Hence they demonstrate the slowest conduction. C fibres are polymodal, responding to chemical, mechanical and thermal stimuli. C fibre activation leads to slow, burning pain.

Question 19

Describe the different types of pain that Aδ fibres and C-fibres are responsible for transmitting.

Answer 19

Both Aδ fibres and C-fibres are responsible for responding to noxious stimuli. Aδ fibres are found commonly in skin are respond to mechanical and thermal stimuli. They are responsible for sharp, pricking pain that is first experienced with an injury. Whereas C-fibres which have a slower transmission are associated with the longer lasting, aching dull pain which persists for longer.

Question 20

Describe how the first and second pain mediated by the different fibres gives rise to different behaviours?

Answer 20

The first pain experienced mediated by Aδ fibres is said to be very informative, as a reflex action it encourages us to move away from danger. Whereas the persisting, longer-lasting pain mediated by the C-fibre drives overall behaviour change.

Question 21

What are the four processes of nociception?

Answer 21

Detection - noxious stimuli activate nociceptive fibres
Transmission - how the signal transmits to the brain
Perception - how the brain perceives signals
Modulation - how can pain signals be changed

Question 22

How do nociceptors become activated?

Answer 22

Any tissue damage results in the initiation of an inflammatory response. Inflammatory mediators are released from damaged tissue and can stimulate nociceptors
directly. They can also act to reduce the activation threshold of nociceptors so
that the stimulation required to cause activation is less. This process is called
primary sensitisation.

Question 23

What are some examples of inflammatory mediators that can directly activate nociceptors?

Answer 23

Bradykinin, serotonin, prostaglandins, cytokines and H+

Question 24

When nociceptors become activated what can be released?

Answer 24

When activated nociceptor fibres can release substance P, neuropeptides, CGRP, NGF and Neuropeptide Y which can then act on surrounding cells including immune cells and blood vessels.

Question 25

What are the effects of these mediators in terms of peripheral modulation?

Answer 25

These then cause the release of inflammatory mediators (in a positive feedback loop) and nerve growth factor which then increases the sensitivity of the neurons.

Question 26

What is hyperalgesia?

Answer 26

Sustained release can therefore cause increased sensitivity to pain.

Question 27

How do nociceptor fibres become activated?

Answer 27

When these inflammatory mediators act either on the ion channels or on the GPCRs and the nociceptor fibres become sensitised, once the depolarisation becomes above the threshold firing of action potential occurs which is then transmitted to the spinal cord.

Question 28

State the ion channels present on the nociceptive afferent terminal and how they are stimulated?

Answer 28

ASIC ion channels which respond to high H+ concentrations PX2 ion channels which respond to high levels of ATP TRPV1 which respond to an acidic pH (below 5.5), noxious heat (become activated at 43 degrees), capsaicin, endogenous chemicals such as Endovanilloids Voltage gated sodium channels Voltage gated potassium channels

Question 29

What is the downstream effects of ASIC, PX2 and TRPV1 activation?

Answer 29

All are cation selective ion channels, which when activated cause influx of cations such as calcium and sodium which drives depolarisation. This leads to the opening of the voltage gated sodium channels also present inducing the firing of action potential when it reaches above the threshold.

Question 30

State the GPCRs present on the nociceptive afferent terminal and what are their ligands.

Answer 30

B2 receptor which respond to bradykinin, an inflammatory mediator Prostanoid or EP receptor which responds to prostaglandins An inhibitory GPCR which responds to opioids, cannabinoids and Noradrenaline

Question 31

Describe the downstream signalling pathway of B2 activation.

Answer 31

B2 activation upon binding to bradykinin activates PKC which then induces phosphorylation of TRPV1 - which induces its sensitisation and causing it to open and enhances depolarisation, by then causing calcium and sodium influx.

Question 32

Describe the downstream signalling pathway of Prostanoid/EP receptor activation.

Answer 32

Bradykinin induces release of prostaglandins which then act on the GPCR causing the stimulation of PKA and the phosphorylation of of many ion channels such as voltage gated sodium channels then causing depolarisation. EP receptor stimulation also prevent opening of the K+ channels which would cause hyperpolarisation and therefore allow it to more closely reach threshold for action potential firing.

Question 33

How do inhibitory GPCRs work?

Answer 33

Their downstream signalling pathway induces the opening of K+ ions which causes potassium efflux and hence hyperpolarisation meaning that a greater depolarisation is required to then reach threshold for firing of an action potential.

Question 34

Explain the downstream signalling pathway for TrkA.

Answer 34

Nerve growth factor acts on its receptor TrkA after being released from the nerve terminals themselves. Acting on TrkA has a long lasting effect on nociceptor sensitivity and affects the gene expression of ion channels. And also causes an increase activity of ion channels by phosphorylation.

Question 35

Describe where the ascending pathway and descending pathway travel and their purpose.

Answer 35

Ascending pathway is a neural pathway responsible for the transmission of somatosensory information including pain from the periphery to the cerebral cortex. The descending inhibitory pathway runs from the brain through to the spinal cord to modulate the amount of information received from the periphery to the brain.

Question 36

Where do the neurons synapse in the ascending pathway?

Answer 36

The peripheral nerve has a peripheral terminal within the target tissue, an extended axon that a cell body within the dorsal root ganglia. A second terminal known as the central terminal is found in the spinal cord.

Question 37

Which channels are essential for propagating the AP across the neurons?

Answer 37

Voltage gated sodium channels are expressed along the length of the axon and are responsible for propagating the action potential along to the spinal cord.

Question 38

What are some of the inhibitory receptors/ion channels expressed at the central terminal synapse?

Answer 38

CB1 GABA MOR DOR

Question 39

What are some of the inhibitory receptors/ion channels expressed at the central terminal synapse?

Answer 39

Voltage gated calcium channel 2.2 TRPV1 TRPA1 EP B2

Question 40

What are some of the substances released at the synapse of the central terminal?

Answer 40

Glutamate Substance P CGRP BDNF CCL3 NO

Question 41

How many sodium channels are found to be expressed along the axon?

Answer 41

9 types from Na 1.1 to Na 1.9

Question 42

What have mutations in Na 1.7 resulted in?

Answer 42

Erythromelalgia and paroxysmal extreme pain disorder

Question 43

What has defects/loss in activity in Na 1.7 resulted in?

Answer 43

Means people do not feel pain (congenital insensitivity to pain) Similar for Na 1.8 and 1.9

Question 44

Describe the structure of the voltage gated sodium channel.

Answer 44

Contains 24 transmembrane domains clustering around a central aqueous pore. Categorised from D1.1-D1.4 with 6 transmembrane domains each with an extracellular loop between 5 and 6.

Question 45

Where do the periphery afferent neurons enter the spinal cord?

Answer 45

At the dorsal horn, each type of fibre synapse with higher order neurons at one of the ten layers of the dorsal horn called Rexed laminae.

Question 46

Which layers of the dorsal horn do Alpha-delta fibres synapse with?

Answer 46

Alpha-delta fibres synapse with a higher order neuron with Laminae 1 the most superficial layer. This neuron axons then travels to the thalamus. Alpha-delta fibres also synapse with neurons in Laminae 5 which then travel to the brainstem and the thalamus.

Question 47

Which layers of the dorsal horn do C-fibres fibres synapse with?

Answer 47

C fibres enter and synapse with higher order neurons in Lamella 1 and 2 which then send their signal to the thalamus.

Question 48

Which layers of the dorsal horn do Alpha-delta fibres synapse with?

Question 49

What is found in Lamella 2?

Answer 49

It is a densley packed area of the doral horn, contains the presence of lots of short interneurons both inhibitory and excitatory which act as input/output modulators which controls what goes through the spinal cord.

Question 50

Where do Alpha-Beta fibres synpase?

Answer 50

As mechanoreceptors (responsible for detecting touch) they synapse at Lamella 3,4,5 and 6.

Question 51

Where do neurons present in Lamella 5 receive signals from?

Answer 51

They receive direct inputs from Alpha-delta and Alpha-beta fibres but also indirect inputs from C-fibres as they interact with their dendrites in Lamella 2. They also receive inputs from viseral nociceptors as well as cutaneous.

Question 52

Where are inhibitory interneurons found?

Answer 52

Present throughout the dorsal horn especially prevalent in the substantia gelatinosa (I-II).

Question 53

Explain the concept of referred pain.

Answer 53

Inputs of visceral interneurons into Lamella 5 may explain why referred pain occurs. This is where the location information associated with a noxious insult is misread/misinterpreted by the brain. This is due to nociceptors from visceral organs converging at the same lamella as cutaneous - visceral pain is rare compared to somatic pain so it associates it with another part of the body (e.g. heart attack patients experiencing shoulder pain).

Question 54

What are the ways that pain can be modulated?

Answer 54

Modulation of pain can be altered through changing the transmission of pain in the descending modulatory pain pathways. This can either be: Excitatory response which increases the pain transmission signalling (up modulation) Inhibitory response which reduces the pain transmission signalling (down modulation)

Question 55

Where is a site in the body that pain signals can be modulated?

Answer 55

Central synapse within the spinal cord

Question 56

Describe the role of inhibitory interneurons within the central synapse and how they can be activated and inactivated.

Answer 56

The central synapse in the dorsal horn of the spinal cord sees non-myelinated C-fibres and slightly myelinated alpha delta primary afferent neurons synapse with projection neuron to transmit their information to the brain. Inhibitory interneurons within the Substantia gelatinosa essentially modulate the amount of sensory information from the nociceptive fibres that can be sent to the brain, by decreasing the excitability of the projection neurons. These interneurons can inhibited by nociceptive afferent fibres, which leads to increased sensory transmission to the brain. But they are activated/stimulated by alpha-beta mechanoreceptors and the descending inhibitory pathway, therefore controlling pain transmission.

Question 57

Describe the gate control theory in application of the pain transmission modulation.

Answer 57

The gate control theory is an analogy for the control of pain transmission within the central synapse. When the gate is open this is when C-fibres and Alpha-beta fibres are firing and the gate is closed when inhibitory interneurons are stimulated modulating the transmission of sensory information from the primary afferent fibres to the brain.

Question 58

How do the descending inhibitory pathways interact with pain transmission from the central synapse?

Answer 58

Descending inhibitory pathways interact with the central synapse in two ways. They directly inhibit the transmission of the central synapse and the pathway also stimulates local inhibitory interneurons to do so.

Question 59

What are the effects if inhibitory interneurons are removed?

Answer 59

Enhanced pain transmission and sensation causing hyperalgesia. Also engagement of alpha-beta fibres without the presence of inhibitory interneurons can result in innocuous stimuli (from touch) to now be perceived as painful.

Question 60

Where do the descending inhibitory pathways originate from?

Answer 60

Two distinct areas of the brain: Periaqueductal grey Locus coeruleus

Question 61

Which neurotransmitters do the periaqueductal grey and locus coeruleus use?

Answer 61

The descending inhibitory pathway originating from periaqueductal grey area of the brain utilises serotonin as its primary neurotransmitter. Whereas the descending inhibitory pathway originating from locus coeruleus of the brain utilises noradrenaline as its primary neurotransmitter.

Question 62

How are Enkephalin involved in both pathways involving pain modulation?

Answer 62

Enkephalins which are endogenous opiates are involved in the neurotransmission of short inhibitory interneurons within the substantia gelatinosa and they are also involved in stimulation of the descending inhibitory pathway.

Question 63

What are some examples of excitatory central modulation?

Answer 63

Hyperalgesia - increased pain in response to a mild stimulus Allodynia - when a non-noxious stimuli causes pain Spontaneous pain - pain resulting from no specific stimuli

Question 64

How does neuropathic pain occur?

Answer 64

When damage to the nervous system occurs, which is a type of chronic pain. Thought to be due to increase in synaptic transmission through the spinal cord with a long lasting enhancement of synaptic transmission. Other cells surrounding could be contributing to an enhancement in firing.

Question 65

What does central sensitisation mean?

Answer 65

Central sensitisation is defined as an increased responsiveness of nociceptors in the central nervous system to either normal or sub-threshold afferent input.

Question 66

State the different areas within the central synapse where central sensitisation can occur.

Answer 66

1) It can either occur at the central synapse where there can be increased signalling. 2)When there is switching off of inhibitory interneurons - disinhibition. 3) Due to input from microglial cells.

Question 67

Explain the concept of how increased signalling at the central synapse can result in central sensitisation.

Answer 67

This usually involves increased glutaminergic transmission due to NMDA-mediated hypersensitivity which is similar to long term potentiation.

Question 68

Explain the concept of how disinhibition of inhibitory interneurons in the central synapse can result in central sensitisation.

Answer 68

Disinhibition of inhibitory interneurons can lead to a loss of tonic control, this usually occurs due to GABAergic/Glycinergic inhibitory interneurons loose control, which results in depolarisation and excitation of projections neurons leading to increased pain transmission.

Question 69

Describe the glial-neuron interaction which results in central sensitization.

Answer 69

Activation of microglial cells release cytokines, ATP etc. which enhance the signal across the synapse, however this effect is dependent upon the expression P2X4 on the microglial. Released ATP binds to these P2X4 receptors causing their activation and triggering the release of brain derived neurotropic factor. This then alters how GABA is interpretated by projection neurons , it is now seen as excitatory response rather than inhibitory due to changes in the threshold required for firing. This leads to increased signalling. Activated microglial cells in turn activate astrocytes causing neuro-inflammation, reducing GABA-ergic inhibition by changing the threshold potential for firing. This causes excitation of the excitatory neurons leading to an increase in synaptic transmission and ultimately resulting in central sensitisation.

Question 70

What are the four opioid receptors?

Answer 70

Delta opioid receptor (DOR) Mu opioid receptor (MOR) Kappa opioid receptor (KOR) Orphan receptor (ORL1)

Question 71

What type of receptors are opioid receptors?

Answer 71

All four are GPCRs and are all coupled to Gai/o and therefore when activated produce an inhibitory response.

Question 72

Describe the opioid receptor signalling pathway.

Answer 72

Upon activation of the opioid receptor this causes a reduction in adenylyl cyclase activation and therefore suppresses a production of cAMP. Gai through activation of the BY subunit inhibits the opening of the voltage gated calcium channel which can, if expressed pre-synaptically can prevent the release of neurotransmitters. Furthermore Gai can also open potassium channels specifically Kir3, resulting in potassium efflux, leading to hyperpolarisation and a decrease in excitation. Other opioid receptor signalling includes: Arrestin recruitment and internalisation of the GPCR and also MAPK signalling ERK, p38 and JNK.

Question 73

Which opioid receptor is involved in acute pain signalling?

Answer 73

The mu opioid receptor in which Morphine is a partial agonist at.

Question 74

What are the endogenous agonists at mu opioid receptor?

Answer 74

B-endorphin, Met-encephalin DAMGO is a synthetic peptide agonist CTOP is a synthetic peptide antagonist

Question 75

Do opioid analgesics only target the mu opioid receptor to provide an analgesic effect?

Answer 75

No acting on the KOR (periphery) and DOR (spinal) receptors can also provide some, but a lower analgesic effect, but activation of these receptors is associated with increased side effects.

Question 76

Which opioid receptors are associated with respiratory depression?

Answer 76

MOR and less so DOR

Question 77

Which opioid receptors are associated with euphoria?

Answer 77

MOR

Question 78

Which opioid receptors are associated with sedation?

Answer 78

MOR and KOR

Question 79

Which opioid receptors are associated with dependence?

Answer 79

MOR

Question 80

Which opioid receptors are associated with hallucinations?

Answer 80

KOR

Question 81

What is the endogenous opioid peptide and where is it found?

Answer 81

Enkephalin and it is found in many neurons within the spinal cord.

Question 82

Where are mu opioid receptors found?

Answer 82

In Lamella 1 of the dorsal horn

Question 83

Where do opioid react in the nociceptive pathway?

Answer 83

There are three places opioids can act to reduce nociceptive transmission: Spinal - can reduce nociceptive signalling through the dorsal horn by supressing transmission through the central synapse, both pre-synaptic and post-synaptic sites Periphery - reducing nociceptive firing, preventing detection of noxious stimuli Brain - regulating the descending inhibitory pathway

Question 84

What happens when naloxone is applied to the periaqueductal gray matter?

Answer 84

It shows the prevention of signalling through the opioid receptor, preventing the analgesic effect

Question 85

Explain the excitatory response of opioids.

Answer 85

Opioids can have an excitatory response of descending neuronal inhibition pathways, this is because opioid receptors are expressed on GABAergic inhibitory neurons which regulate the descending inhibitory pathway. Therefore by inhibiting the activity of the GABAergic neurons this allows firing down the descneidng inhibitory pathway from the periaqueductal gray, releasing the inhibitions of these neurons allowing them to fire, giving rise to an analgesic effect.

Question 86

What are the different types of opioid peptides?

Answer 86

Encephalins, dynorphin and endorphins with each having affinity for different opioid receptors.

Question 87

How does neuropathic pain arise?

Answer 87

Due to damage to nociceptive neurons themselves.

Question 88

What are some of the disorders that could cause neuropathic pain?

Answer 88

CNS disorders: – Stroke – Multiple sclerosis - Parkinson's - Some types of tumours Peripheral nerve damage: – Diabetic neuropathy – Herpes zoster infection (shingles) – Traumatic/surgical amputation (phantom limb pain)

Question 89

What is the pharmacological target for Gabapentin and Pregabalin?

Answer 89

They bind to the voltage gated calcium channels alpha-2 delta subunit which regulates the activity of the channel, which inhibits neurotransmitter release.

Question 90

Which anti-depressants are effective at treating neuropathic pain?

Answer 90

TCAs and SNRIs such as Amitriptyline and Desipramine, Duloxetine which potentiate descending inhibition pathway by modulating synaptic levels of noradrenaline and serotonin. By preventing the reuptake of these neurotransmitters this increases the synaptic levels and therefore enhancing descending inhibition.

Question 91

What are some of the other pharmacological interventions for neuropathic pain?

Answer 91

* Capsaicin patches - these are useful for peripheral neuropathic pain, Capsaicin is an agonist for TRPV1 which causes desensitization of the ion channel, preventing nociceptive firing * Lidocaine – local anesthetic again preventing nociceptive firing * Ziconotide – inhibits calcium channels – CaV2.2 preventing neurotransmitter release (similar to Gabapentin and Pregabalin) * Ketamine – NMDA receptor blocker therefore suppressing neurotransmission through the central synapse.