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



·        Nociceptive receptor

·        Primary afferent

·        Secondary afferent and tracts

·        Tertiary afferent and above

·        Descending modulation


Nociceptive receptor:


·   Free nerve ending on 1° afferent in periphery

·   Activated by mechanical, thermal, chemical insults

·   Sensitised by inflammation

·   Ionotropic and metabotropic


·   Local anaesthetic (LA): inhibits VDNaC

·   NSAID: inhibits prostaglandin-induced receptor sensitisation and activation


Primary afferent (nociceptor):


·   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


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


·   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


·   Post-synaptic inhibition:

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


Tertiary afferents and above


·   VPL thalamus -> primary somatosensory cortex (localisation)

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


·   NMDA antagonist (as above) -> thalamocortical dissociation

·   Paracetamol: COX-3 inhibition

·   General anaesthetics: inhibit brainstem ARAS -> no perception


Descending modulation:


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

·   Mediators: noradrenaline -> serotonin

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


·   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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