Neurology of Pain

Question 1

What is congenital insensitivity to pain? what are the causes?

Answer 1

Condition with ↓/absent pain sensation

Causes: Na+ channel mutations/other conditions (usually genetic)

Multiple MSK problems, ↓Life expectancy

Question 2

What is the definition of chronic pain?

Answer 2

Pain that persists beyond normal healing - Clinically: >3-6 months

Pathological process +/- biopsychosocial element

Question 3

What is dysathesia?

Answer 3

Abnormal, unpleasant sensation (but not pain itself)

Question 4

What is Hyperalgesia?

Answer 4

Increased pain response to noxious sitmuli

Question 5

What is allodynia?

Answer 5

Pain response to non-noxious stimuli

Question 6

What is paraesthesia?

Answer 6

Nerve sensations in absence of any stimulus - pain, crawling, tingling, burning, itching

Question 7

What are paroxysms?

Answer 7

Spontaneous shooting pains - may also occur as recurrent pains after a single stimulus

Question 8

What is hyperpathia?

Answer 8

Pain threshold increased - but also increased response when threshold passed (e.g. exponential growth in pain response compared to magnitude of stimulus)

Question 9

What is involved in the reflex arc?

Answer 9

Stimulus → Nociceptive (afferent) fibre → Interneuron (in CNS: Substantia Gelatinosa of Dorsal Horn):

→ Ascending pathways to brain

→ Motor neuron of Ventral Horn → Effector muscles

Question 10

What are nociceptors?

Answer 10

Free nerve endings - not special structures

Question 11

What are the different types of nociceptors?

Answer 11

TRPV1 (Capsaicin Receptor) - ↑Temperature Receptor (>43^oC → burning sensation)

Chemical Receptors - Inflammation receptors (Inflammatory cytokines - histamine, bradykinin, prostaglandins)

Mechanical Receptors - Stretch receptors (excesssive stretch)

Question 12

What are the two main types of nociceptive fibres?

Answer 12

A? fibres (type III) - Fast

• Myelinated and large diameter
• “First pain” after noxious stimulus
• Unimodal - only one type of pain - sharp, localised

C fibres (type IV) - Slow

• Unmyelinated and small diameter
• Polymodal - transmite distinguishable types of pain e.g. temp/stretch/inflammation
• Dull ache of distinguishable type

Question 13

How does rubbing a sore area provide pain relief?

Answer 13

Aβ fibres (type II) transmit crude touch signals

Inhibit pain signals at dorsal horn cells - rubbing area provides pain relief

Question 14

What is the substantia gelatinosa?

Answer 14

Region of dorsal horn of spinal cord - gelatinous (lack of myelin)

Nociceptive fibres → Interneuron synapse

Synapse at level of entry or ascend 1-2 segments via Lissaer’s Tract

A? - laminae 1/4

C - lamina 2

Question 15

What are the second order nociceptive fibres? and where do they go?

Answer 15

Ascending pathways

Cross at level of entry

Ascend in spinothalamic tract

Synapse in the ventral postero-lateral (VPL) nucleus of the thalamus

Question 16

What happens in the VPL and where does information from it go in the nociceptive pathway?

Answer 16

Receives inputs from other regions, filtering/processing work

Send projections to cerebral cortex

Insula/cinculate cortices - unpleasant sensation associated with pain

Primary somatosensory cortex - localisation of pain

Question 17

What does the descending opioid/serotinergic pathway do?

Answer 17

Higher brain opioidergic projections → PAG → Nucleus Raphe Magnus (medulla)

This pathway is upregulated by exogenous opioids

NRM → Serotinergic projections → Dorsal horns of spinal cord via reticulospinal tracts → Interneurons

Question 18

What does the descendng noradrenergic pathway do?

Answer 18

Locus Coeruleus (Pons) → Noradrenergic projections → Dorsal horns of spinal cord → Interneurons

Question 19

How does down regulation occur in the spinal cord?

Answer 19

Release of enkephalins (endogenous opioids) into synapse:

Inhibit pre-synaptic neurotransmitter release

Hyperpolarise post-synaptic membrane

Question 20

What is the mechanism of stress-induced analgesia?

Answer 20

Stress → Amygdala → stimulate PAG → Opioid release → NRM

Question 21

How does inflammation affect nociceptors? and what inflammatory mediators are involved?

Answer 21

Nociceptors are sensitised by inflammation

Inflammatory mediators act on nociceptors:

Prostaglandins

Substance P

Bradykinin

Histamine

Question 22

What inflammatory mediator is released by nociceptors and what is the action of this?

Answer 22

Substance P - further inflammation

Mast-cell degranulation: Release histamine, contributing to further inflammation and cytokine release

Vasodilates blood vessels: contributing to further inflammation

Question 23

What is the wind up theory?

Answer 23

Repeated stimuli → amplification of pain (hyperalgesia) = Hypersensitisation of dorsal horn interneurons

Repeat C fibre stimulation → ↑Glutamate release by presynaptic 1st order nociceptive fibre → Open NMDARs (AMPA normal receptor when sensitisation hasn’t occurred)

Increased Ca²⁺ entry via NMDA → depolarisation of dorsal horn neuron → interneuron/2nd order fibre more likely to depolarise = hyperalgesia

Question 24

What are the secondary Wind up mechanisms?

Answer 24

NO-induced opioid resistance

Ca²⁺ influx into post-synaptic fibres → NO release

NO stimulates K⁺ channel closure on pre-synaptic membrane

• Opioids open K⁺ to inhibit depolarisation, so NO = opioid resistacnce

NO triggers Substance P release → c-fos → ↑Na⁺ channel expression, ↑Interneural connectivity

Question 25

What is the mechanism of referred pain?

Answer 25

Internal organs have 1st order nociceptive fibres They have **no dedicated 2nd order nociceptive fibres** 1st order nociceptive fibres synapse with 2nd order fibres from skin etc. - so brain interprets signals coming from skin

Question 26

What are the basic analgesic mechanisms of the following? Local Anaesthetics NSAIDs Opioids General Anaesthetics

Answer 26

Local anaesthetics - tend to block transmission of noxious stimulants to spinal cord NSAIDs - reduce inflammation → reduce impulses from certain nociceptors Opioids - act on descending pain pathways - upregulate NRM and its projections. Direct inhibition of nociceptive signals at 1st order nociceptor/dorsal horn neuron synapse. **Blunt emotional aspects of pain.** GA - unknown

Question 27

What type of receptor are opioid receptors? and what are the three subtypes?

Answer 27

Metabotropic - slow acting μ - potent analgesic effects, addictive ? - potent analgesic effects ϰ

Question 28

Which subtype/s of opioid receptor are affected by **endorphins** and what are they important for?

Answer 28

Agonist to all, but highest affinity to **μ** Important for learning behavious (palability to foods etc.)

Question 29

What subtype of opioid receptors do enkephalins affect and what are they important for?

Answer 29

Primarily **?** Released by interneurons in spinal cord to down-regulate nociceptive signal transmission

Question 30

What subtype of opioid receptors do dynorphins act on?

Answer 30

**ϰ**

Question 31

What are the effects of opioids?

Answer 31

Analgesia Euphoria Sedation Cough supression Constipation Respiratory depression - Naloxone antidote N&V Miosis - pupil constriction

Question 32

What is neuropathic pain?

Answer 32

Pain caused by neuronal damage - anatomical or functional abnormaliites of pain pathways neuropathies, nerve avulsions, cancers, infections, MS etc.

Question 33

What are the mechanisms of neuropathic pain?

Answer 33

Inflammation ↑ Sympathetic activity **Sensitisation of dorsal horn** neurons Central sensitisation and re-organisation

Question 34

What is trigeminal neuralgia and how is it treated?

Answer 34

Compression of trigeminal nerve Intense episodic pain - triggered by stimulation of nerve Treated with **anticonvulsants - Carbamazepine, Baclofen, Gabapentin/Pregabalin**