2014B05 Describe the physiology of pain pathways and how drugs may modulate the perception of pain.

 

List:

·       Nociceptive receptor

·       Primary afferent

·       Secondary afferent and tracts

·       Tertiary afferent and above

·       Descending modulation

 

Nociceptive receptor:

Physiology

·  Free nerve ending on 1° afferent in periphery

·  Activated by mechanical, thermal, chemical insults

·  Sensitised by inflammation

·  Ionotropic and metabotropic

Pharmacology

·  Local anaesthetic (LA): inhibits VDNaC

·  NSAID: inhibits prostaglandin-induced receptor sensitisation and activation

 

Primary afferent (nociceptor):

Physiology

·  From periphery -> dorsal horn, with cell body in dorsal root ganglion

·  Ascent or descent 1-2 levels via Lissauer’s tract

Aδ fibre:

·  Releases glutamate

·  Synapse at superficial layers.

·  Sharp, fast, well localized (i.e. somatic pain)

C fibre:

·  Releases glutamate, substance P

·  Synapse at deeper layers.

·  Dull, slow, poorly localized (i.e. visceral pain)

Silent nociceptor:

Conveys pain only when sensitized

Pharmacology

Pre-synaptic inhibition:

·  Neuraxial LA: VdNaC at dorsal root ganglion, spinal nerve root

·  Opioid

·  Noradrenaline and serotonin reuptake inihbitors

·  Gabapentinoids: antagonists at synaptic VdCC α2δ subunit

·  Cannabinoids: at own receptor

Other:

·  Paracetamol: inhibits bradykinin-sensitive nociceptors

·  Regional LA (nerve, plexus): inhibits axonal VDNaC

 

Secondary afferent and tracts:

Physiology: cell

·  Nociceptive-specific: superficial layers, variable threshold

·  Wide dynamic range: deeper layers, high threshold, only when sensitized

·  Note also interneurons: excitatory and inhibitory

·  Note inhibitory afferents: e.g. Aβ conveying light touch

Physiology: tracts

·  Decussation in anterior commissure

·  Ascent in spinothalamic tracts

o Neo-STT: to thalamus (VPL nucleus)

o Paleo-/archi-STT: to brainstem

Pharmacology

·  Post-synaptic inhibition:

o NMDA antagonist: ketamine, N2O, Xe, Mg2+, tramadol, methadone

 

Tertiary afferents and above

Physiology:

·  VPL thalamus -> primary somatosensory cortex (localisation)

·  Brainstem -> medial thalamus, hypothalamus, amygdala (affective, autonomic)

Pharmacology

·  NMDA antagonist (as above) -> thalamocortical dissociation

·  Paracetamol: COX-3 inhibition

·  General anaesthetics: inhibit brainstem ARAS -> no perception

 

Descending modulation:

Physiology

·  Pathway: PAG or RVM -> dorsal horn via Lissauer’s tract

·  Mediators: noradrenaline -> serotonin

·  Effect: inhibit 1° afferent (pre-synaptic) and 2° afferent (post-synaptic)

Pharmacology

·  Opioids: ↓activity of OFF cell -> ↓Inhibition of ON cell

·  Noradrenaline reuptake inhibition: ketamine, tramadol, tapentadol, NRI

·  Serotonin reuptake inhibition: tramadol, SSRI

·  Dorsal horn α2 agonism: clonidine, dexmedetomidine

 

 

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