Neurology of Pain Flashcards
What is congenital insensitivity to pain? what are the causes?
Condition with ↓/absent pain sensation
Causes: Na+ channel mutations/other conditions (usually genetic)
Multiple MSK problems, ↓Life expectancy
What is the definition of chronic pain?
Pain that persists beyond normal healing - Clinically: >3-6 months
Pathological process +/- biopsychosocial element
What is dysathesia?
Abnormal, unpleasant sensation (but not pain itself)
What is Hyperalgesia?
Increased pain response to noxious sitmuli
What is allodynia?
Pain response to non-noxious stimuli
What is paraesthesia?
Nerve sensations in absence of any stimulus - pain, crawling, tingling, burning, itching
What are paroxysms?
Spontaneous shooting pains - may also occur as recurrent pains after a single stimulus
What is hyperpathia?
Pain threshold increased - but also increased response when threshold passed (e.g. exponential growth in pain response compared to magnitude of stimulus)
What is involved in the reflex arc?
Stimulus → Nociceptive (afferent) fibre → Interneuron (in CNS: Substantia Gelatinosa of Dorsal Horn):
→ Ascending pathways to brain
→ Motor neuron of Ventral Horn → Effector muscles
What are nociceptors?
Free nerve endings - not special structures
What are the different types of nociceptors?
TRPV1 (Capsaicin Receptor) - ↑Temperature Receptor (>43oC → burning sensation)
Chemical Receptors - Inflammation receptors (Inflammatory cytokines - histamine, bradykinin, prostaglandins)
Mechanical Receptors - Stretch receptors (excesssive stretch)
What are the two main types of nociceptive fibres?
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
How does rubbing a sore area provide pain relief?
Aβ fibres (type II) transmit crude touch signals
Inhibit pain signals at dorsal horn cells - rubbing area provides pain relief
What is the substantia gelatinosa?
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
What are the second order nociceptive fibres? and where do they go?
Ascending pathways
Cross at level of entry
Ascend in spinothalamic tract
Synapse in the ventral postero-lateral (VPL) nucleus of the thalamus
What happens in the VPL and where does information from it go in the nociceptive pathway?
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
What does the descending opioid/serotinergic pathway do?
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
What does the descendng noradrenergic pathway do?
Locus Coeruleus (Pons) → Noradrenergic projections → Dorsal horns of spinal cord → Interneurons
How does down regulation occur in the spinal cord?
Release of enkephalins (endogenous opioids) into synapse:
Inhibit pre-synaptic neurotransmitter release
Hyperpolarise post-synaptic membrane
What is the mechanism of stress-induced analgesia?
Stress → Amygdala → stimulate PAG → Opioid release → NRM
How does inflammation affect nociceptors? and what inflammatory mediators are involved?
Nociceptors are sensitised by inflammation
Inflammatory mediators act on nociceptors:
Prostaglandins
Substance P
Bradykinin
Histamine
What inflammatory mediator is released by nociceptors and what is the action of this?
Substance P - further inflammation
Mast-cell degranulation: Release histamine, contributing to further inflammation and cytokine release
Vasodilates blood vessels: contributing to further inflammation
What is the wind up theory?
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
What are the secondary Wind up mechanisms?
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
What is the mechanism of referred pain?
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
What are the basic analgesic mechanisms of the following?
Local Anaesthetics
NSAIDs
Opioids
General Anaesthetics
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
What type of receptor are opioid receptors? and what are the three subtypes?
Metabotropic - slow acting
μ - potent analgesic effects, addictive
? - potent analgesic effects
ϰ
Which subtype/s of opioid receptor are affected by endorphins and what are they important for?
Agonist to all, but highest affinity to μ
Important for learning behavious (palability to foods etc.)
What subtype of opioid receptors do enkephalins affect and what are they important for?
Primarily ?
Released by interneurons in spinal cord to down-regulate nociceptive signal transmission
What subtype of opioid receptors do dynorphins act on?
ϰ
What are the effects of opioids?
Analgesia
Euphoria
Sedation
Cough supression
Constipation
Respiratory depression - Naloxone antidote
N&V
Miosis - pupil constriction
What is neuropathic pain?
Pain caused by neuronal damage - anatomical or functional abnormaliites of pain pathways
neuropathies, nerve avulsions, cancers, infections, MS etc.
What are the mechanisms of neuropathic pain?
Inflammation
↑ Sympathetic activity
Sensitisation of dorsal horn neurons
Central sensitisation and re-organisation
What is trigeminal neuralgia and how is it treated?
Compression of trigeminal nerve
Intense episodic pain - triggered by stimulation of nerve
Treated with anticonvulsants - Carbamazepine, Baclofen, Gabapentin/Pregabalin
