Physiology of Pain

Question 1

What is Lidocaine/ ligocaine?

Answer 1

• Local anesthetic that acts in the periphery (topically applied to skin)
• prevents nociceptor firing by blocking Na+ channels

Question 2

What are the three classifications of Pain?

Answer 2

• Nociceptive
  
  • normal functioning of nociceptors
  • in response to tissue injury that then subsides
  • Somatic vs Visceral
• Inflammatory Pain
• Neuropathic
  
  • pain response to injury to the nervous system

Question 3

What is Inflammatory pain?

Answer 3

Response of the somatosensory nervous system to tissue damage and inflammation.

• In the periphery, increased inflammatory mediators (cytokines and chemokines) sensitize local nociceptors:
• Lowers threshold for responsiveness (peripheral sensitization).
• Results in activation of pathways (substance p and calcitonin gene-related peptide CGRP) after innocuous input and in exaggerated responses to noxious stimulation. (erythema, heat and sensitisation)
• The plasticity that underpins these changes is rapid (occurring in minutes).
• The inevitable consequence of surgery and tissue trauma.
• Upregulation of nociception normally resolves as wound healing occurs.

Question 4

What is the difference between the two types of nociceptive pain - Somatic and visceral nociception?

Answer 4

Somatic nociception

• Activation of nociceptors in skin, muscles, bones, joints, and connective tissues
• Transmitted along A-delta and C fibres
• Somatic pain – sharp or dull pain. Exacerbated by movement.

Visceral nociception

• Activation of nociceptors in internal organs
• Transmitted along autonomic fibres
• Visceral pain – poorly localised, deep, squeezing, cramping pain, dull, sickening.
• Associated autonomic symptoms – nausea, vomiting, sweating

Question 5

Which nerve fibres are involved in pain transmission?

Answer 5

• A-theta fibre: thinly myelinated, medium diameter
  
  • light touch, temperature, nociception
  • sharp pricking pain
• C fibre: unmyelinated, small diameter
  
  • temperature. nociception
  • slow dull ache/ burning pain

Question 6

Label the afferent nerve endings in this diagram

Answer 6

Question 7

Explain nociceptor response to inflammation and tissue injury

Answer 7

• chemicals released as part of tissue injury and inflammation have excitatory effects on nociceptors
  
  • ATP, H+, Serotonin/ 5-HT,
    
    • these activate nociceptors: Purinergic receptors, acid-sensing ion channels, 5-HT₃ receptors
  • Histamine, Bradykinin, Prostglanding, Nerve growth factor

Question 8

Give an overview of the action of nociceptors during neurogenic inflammation

Answer 8

• Activation of one branch of a nociceptor by inflammation triggers the release of substance P and calcitonin gene-related peptide (CGRP) from another
• This causes:
  
  • Vasodilation
  • Activation of mast cells –> release of histamine = more inflammation

contributes to the pathophysiology of inflammatory diseases

Question 9

What is the effect of inflammation on nociceptors?

Answer 9

Exhibit modulatory effects on nociceptors and cause hypersensitivity

• Hyperalgesia: Noxious stimuli producing an exaggerated pain response
• Allodynia: Non-noxious stimuli produce a painful response

Question 10

Explain the mechanism behind pain hypersensitivity

Answer 10

peripheral and central sensitisation leads to hypersensitivity

Peripheral Sensitization:

• increase in the responsiveness of the peripheral ends of nociceptors
  
  • this is driven by tissue injury
• Bradykinin & NGF: reduce threshold heat-activated channels TRPV1
• Prostaglandins: reduce the threshold of sodium channels

Question 11

Explain the mechanism of action of bradykinin

Answer 11

Bradykinin indirectly acts on TRPV1

• Bradykinin binds to receptor
  
  • (metabotropic G protein-coupled)
• Activation of protein kinase
• Phosphorylation of TRPV1

Phosphorylation of channel reduces its threshold –> it fires more easily

Question 12

What is the difference between the fibre classification A-C

Answer 12

• Group A - heavily myelinated
• Group B - moderately myelinated
• Group C - unmyelinated

Question 13

Where do A-delta fibres synapse?

Answer 13

In the grey matter of the dorsal horn in the Rexed Laminae

→ terminate in Lamina 1 and 5

→ Synapse directly with 2nd order neurones that make up the ascending tracts

Question 14

Where do C-fibres synapse?

Answer 14

In the grey matter of the dorsal horn in the Rexed Laminae

→ mainly synapse with neurons in Lamina 2 (substantial gelatinosa)

→ synapse indirectly via interneurons (which can be varied)

Question 15

Explain the role of the Spinothalamic tract with transmission of pain/nociceptors

Answer 15

• pain information ascends the spinothalamic tract
• First-order neurons (nociceptors)
  
  • enter dorsal horn –> form tract of Lissauer –> synapse in substantial gelatinosa
• glutamate and substance P from nociceptors excite second-order neurons
• the A-delta or C nerves synapse with second-order neurons
• the second-order neurone then takes this signal up to the thalamus (via the spinothalamic or spinoreticular tracts).
• third-order neurones project from the thalamus to higher centres.
• descending pathways modulate the signals coming form the ascending pathways

Question 16

Explain the pathway of second-order neurons

Answer 16

second-order neurons: cross in the dorsal horn at each level and ascend the anterolateral column to the thalamus

Question 17

What is the role of the Lateral spinothalamic tract?

Answer 17

(new)

• terminates at the thalamus
• ascends anterolaterally in the white matter directly t_o the ventral posterior lateral (VPL) nucleus in the thalamus_
• important in the sensory-discriminative aspect of pain perception

Question 18

What is the role of the Medial spinothalamic tract?

Answer 18

(old)

• terminates at the thalamus
• this is a polysynaptic pathway that sends projections to the periaqueductal (PAG) grey matter, hypothalamus and reticular system in the midbrain before reaching the medial thalamus
• important in generating the autonomic and unpleasant emotional component of the pain experience

Question 19

Explain why/ how referred pain occurs

Answer 19

• Convergence of visceral and cutaneous nociceptors on same second-order neurons in the spinal cord
• Brain perceives visceral pain as cutaneous

Question 20

What is stress-induced analgesia?

Answer 20

• the necessary suppression of pain in order for survival
  
  • battle victims
  • endurance athletes
  • parturition

Question 21

Explain the descending regulation of pain

Answer 21

• the Periaqueductal gray matter (PAG) and Rostral ventromedial medulla (RVM) modulate the activity of the spinothalamic tract
  
  • Cortical regions project to PAG –> PAG projects to RVM –> RVM projects to dorsal horn

Question 22

Explain how pain is inhibited

Answer 22

• Periaqueductal grey matter neurons excite serotonergic neurons, which excite inhibitory interneurons
• Inhibitory interneurons inhibit spinothalamic tract neurons
• inhibit the excitatory effects of nociceptors

Question 23

What is the role/journey/action of the spinoreticular tract?

Answer 23

• it terminates in the reticular formation of the medulla and pons
• the information then sent to the thalamus
• the thalamus nuclei project diffusely to the entire cerebral cortex where pain reaches the conscious level and promotes behavioural arousal
• spinoreticular tract projects to neurona having a large receptive field that t can cover wide areas of the body and play a role in the memory and emotion component of pain neurons (global overview of your pain experience)

Question 24

How does the brain create the perception of pain?

Answer 24

• third-order neurons project from the thalamus to the somatosensory cortex
  
  • Primary somatosensory projections: mediate localisation of the pain stimulus
  • Secondary somatosensory projections: involved in sensing stimulus intensity
• third-order neurons also project from the thalamus to the limbic system: also the insula and anterior cingulate cortex (ACC)
  
  • Insula (major hub for visceral nociceptive inputs): assessment of nociceptive stimulus intensity
  • ACC: attention and response, also has connections to the Amygdala, hippocampus and hypothalamus
    
    • involved in the creation of emotion, behaviour and memory

Question 25

Give an overview of the endogenous opioid system

Answer 25

* Opioids play an important role in the inhibition of pain * E.g. Endorphins, enkephalins * Opioids are inhibitory * Act on inhibitory metabotropic receptors * Released from interneurons at multiple sites

Question 26

What are NSAID's? - examples - mechanism of action

Answer 26

* these are non-steroidal anti-inflammatory drugs that act in the periphery * e.g Aspirin and Ibuprofen * they reduce inflammation by inhibiting prostaglandin synthesis, which reduces peripheral sensitisation * COX inhibited --\> prostaglandin synthesis reduced --\> prevents decrease in Na+ channel threshold

Question 27

Explain the action/ mechanism of Paracetamol

Answer 27

* not an NSAID as it has no anti-inflammatory properties * acts centrally to reduce clinical pain * inhibits COX (cyclooxygenase) enzyme in the CNS * Acts on the descending serotonergic pathway

Question 28

Explain the action/treatment of Topical capsaicin treatment

Answer 28

* acts in the periphery and is topically applied to the skin * Acts as a TRPV1 agonist * persistent opening of TRPV1--\> calcium overload --\> nociceptor stops working

Question 29

What are Opioids? - example - mechanism of action

Answer 29

* very effective pain relief that acts centrally and peripherally (numerous side-effects) * morphine, codeine, tramadol * Acts as an agonist of the endogenous opioid system * disinhibition in the brainstem * inhibits channels on nociceptors in the periphery

Question 30

What is the Gate Control theory?

Answer 30

* Pain evoked by nociceptors can be reduced by the simultaneous activation of low threshold mechanoreceptors (Aβ fibres) * rubbing or blowing on a painful area can reduce the pain * Stimulation of Aβ fibres at injury site activates interneurons in the dorsal horn which inhibit spinothalamic neurons * C fibres inhibit inhibitory interneurons: opens gate * Aβ fibres activate inhibitory interneurons- closes gate

Question 31

What is Chronic pain? - give some examples

Answer 31

* Pain that persists for greater than 3 months * can be nociceptive or neuropathic * Chronic back pain, cancer, carpal tunnel syndrome, arthritis, * fibromyalgia, diabetes, migraine, post-surgery, postherpetic neuralgia (shingles), * phantom limb pain, multiple sclerosis, trigeminal neuralgia

Question 32

What is neuropathic pain?

Answer 32

* _A lesion or disease of the somatosensory nervous system._ * Impacts on function and causes structure changes in the somatosensory nervous system. * The result is a combination of sensory loss and increased responsiveness to both _noxious and innocuous stimuli._ * Positive phenomena can be described as: * *allodynia (pain after non-painful stimuli)* * *hyperalgesia (heightened pain after painful stimuli)* * *hyperpathia (an eruptive pain extending beyond the duration of a stimulus)*

Question 33

Give causes of chronic neuropathic pain

Answer 33

* Nerve injury may be a * compression, traction, * sever, hypoxia, demyelination, * tumour or neuroinflammation * affects 8% of the population

Question 34

What are the symptoms of neuropathic pain?

Answer 34

* stabbing * cramping * burning * aching * electricity/ shooting * hypersensitivity * constant fleeting and procoked * in anatomical distribution of nerve supply

Question 35

Explain the mechanisms of Peripheral Neuropathic pain

Answer 35

* _Peripheral sensitization_ * **_Increased firing of primary afferents_** * at nerve injury sites, the damaged tips of nociceptors fire spontaneously - *due to the accumulation of transported ion channels at the injury site* * responsible for spontaneous pain and also phantom limb pain (underlies central neuropathic pain mechanisms)

Question 36

What are two main mechanisms of Central Neuropathic pain?

Answer 36

* **_Central sensitization_** (within the spinal cord) * increase in the responsiveness of nociceptive neurons within the CNS - due to a reduced threshold for activation * **_Change in activation patterns/ cortical remapping_** (within the brain)

Question 37

Explain the mechanism behind reduced threshold for activation and how that causes neurological pain

Answer 37

* Constant firing of axons from the periphery (following injury) --\> * Sustained release of glutamate --\> * Prolonged depolarization of the postsynaptic membrane --\> * Massive influx of Ca2+ through NMDA receptors --\> * Activation of kinases --\> * Phosphorylation of NMDA/AMPA receptors * Channel protein synthesis

Question 38

What is Hyperalgesia and Allodynia

Answer 38

* **Hyperalgesia**: when activation of nociceptors results in amplified spinal cord activation * sensations are more painful than they ough to be * **Allodynia**: when non-noxious afferents activate sensitised 2nd order neurons * non-noxious A-beta fibres also synapse onto 2nd order spinothalamic neurons

Question 39

What are the key things to consider when managing/ treating chronic pain

Answer 39

* need to treat the patient as individually as possible * important to manage the primary condition as well as other associated symptoms * depression * sleep disturbances * fatigue

Question 40

What current neuropathic pain treatment is available - types of drugs

Answer 40

* Drugs: * Tricyclic antidepressants (analgesic) * Anticonvulsants (analgesic) * Topical capsaicin or lidocaine * Acupuncture * Physical therapies – e.g. manipulation of tissues, pacing * Psychological therapies – e.g. cognitive behaviour therapy * Surgery – e.g. spinal cord stimulator

Question 41

What is the action/mechanism of Tricyclic antidepressants - examples

Answer 41

* they act centrally to reduce neuropathic pain * Amitriptyline * Duloxetine * They act on descending inhibitory pathways to inhibit the reuptake of serotonin and noradrenalin

Question 42

What is the action/ mechanism of anticonvulsants in treating neuropathic pain - examples

Answer 42

* act centrally to treat neuropathic pain * Pregabalin * Gabapentin * Carbamazepine * they work in the spinal cord to reduce excitability by blocking calcium (pregabalin) and sodium (carbamazepine) channels * Pregabalin blocks nociceptor presynaptic voltage-gated Ca2+ channels * this prevents the release of glutamate * pain signal isn't continued along the spinothalamic tract

Question 43

What are the NICE guidelines on treating neuropathic pain?

Answer 43

* First-line of treatment: * Amitriptyline, duloxetine, pregabalin or gabapentin * Second-line of treatment: * Switch drugs or combine * Third-line of treatment: * Refer patient to a specialist pain service and consider oral tramadol (opioid) or in combination with the second-line treatment consider topical lidocaine

Question 44

What are the different areas of the nervous system that can cause of chronic pain?

Answer 44

* Peripheral terminals * Peripheral sensitization * Axon * Increased firing of primary afferents * Dorsal root ganglia * Changes in protein synthesis * Dorsal horn/spinal cord * Central sensitization * Brain * Changes in brain activation patterns

Question 45

Explain Melzack and Wall's gate control theory

Answer 45

* low- threshold myelinated afferents e.g A-beta fibres (rubbing on the skin) can reduce the response from C-fibre inputs by activating inhibitory interneurons * non-painful input closes the nerve ‘gates’ to nociceptive input which prevents the AP from travelling up the CNS

Question 46

What happens in descending inhibitory pathways for pain?

Answer 46

* Originate from supra-spinal structures: * periaqueductal gray * reticular formation * nucleus raphe magnus * Endogenous opioid receptors are heavily expressed here. * **Serotonin** and **NA** are key neurotransmitters in this pathway. * Inhibit transmission of nociception at the level of the Dorsal Horn