Pain/Sensory Pathway Anatomy

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  • Pain: an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
  • Acute pain: pain of recent onset and probable limited duration. It usually has an identifiable temporal and causal relationship to injury or disease
  • Chronic pain: commonly persists beyond the time of healing of an injury and frequently there may not be any clearly identifiable cause
  • Acute and chronic pain exist on a continuum (rather than being distinct entities)


  • Detect noxious stimuli and transduce this stimuli into action potentials for conduction
  • Nociceptive afferents include:
  • Medium-diameter lightly myelinated A-delta fibres
  • Slow-conducting unmyelinated C-fibres
  • Most common nociceptor class is the C-fibre polymodal nociceptor:
  • Responds to physical (heat, cold, pressure) and chemical stimuli
  • Thermal sensation is mediated by a range of transient receptor potential (TRP) channels
  • Noxious mechanical stimuli is detected by acid-sensing ion channels (ASICs), TRPs and potassium channels
  • Tissue damage in infection, inflammation, ischaemia and trauma causes:
  • Disruption of cells, mast cell degranulation, inflammatory cell secretion and induction of enzymes like COX-2
  • Chemical mediators act via ligand-gated ion channels or via metabotropic receptors to activate/sensitise nociceptors
  • Following activation, intracellular kinase cascades cause phosphorylation of channels, changing cell kinetics and threshold therefore sensitizing the nociceptor
  • Neuropeptides including substance P and calcitonin gene-related peptide (CGRP) contribute to recruitment of serum factors and inflammatory cells at the site of injury - neurogenic oedema - which causes peripheral sensitisation, which may result in primary hyperalgesia
  • NSAIDs - modulate peripheral pain by reducing prostaglandin E2 (PGE2) synthesis by locally induced COX-2
  • Inflammation also changes protein synthesis in the cell body in the DRG, resulting in changed expression and transport of receptors like TRPV1 and opioid receptors to the periphery
  • Sodium channels
  • Important in modulating neuronal excitability, signalling and conduction of neuronal action potentials to the CNS
  • A rapidly inactivating fast sodium channel blocked by tetrodotoxin is present in all sensory neurons
  • Primary site of action for local anaesthetics, but also in sympathetic and motor neurons so specific blocking is impossible
  • Subtypes of slowly activating and inactivating tetrodotoxin-resistant sodium channels are present in some nociceptive fibres
  • After injury, changes in sodium channel kinetics contribute to hyperexcitability
  • The SCN9A gene for Na 1.7 channel shows the importance of sodium channels in pain:
  • Loss of function results in insensitivity to pain
  • Gain of function produces erythromelalgia and severe pain
  • Most nociceptor afferents are in the dorsal root ganglia
  • Those innervating the head, oral cavity and neck are in the trigeminal ganglia, and project to the brainstem trigeminal nucleus
  • C and A-delta fibres convey information to nociceptive-specific neurons within laminae I and II of the superficial dorsal horn, and also to more generalised neurons in lamina V
  • Large myelinated A-beta fibres transmit light touch or innocuous mechanical stimuli to deep laminae III and IV

Spinal Cord Transmission[edit]

  • Primary afferent terminals contain a range of substances which act as neurotransmitters
  • Amino acids (glutamate, aspartate)
  • Peptides (substance P, calcitonin gene-related peptide CGRP)
  • Neurotrophic factors (brain-derived neurotrophic factor)
  • Primary afferent terminal stimulation causes glutamate release, activating AMPA receptors causing rapid signalling regarding location and intensity of noxious stimuli
  • This is the 'normal mode' - high intensity stimulus elicits brief, localised pain, and the stimulus-response relationship is predictable and reproducible
  • Summation of repeated C-fibre inputs causes a progressively more depolarised post-synaptic membrane and removal of magnesium block from NMDA receptors
  • Three patterns of central sensitisation:
  • Wind-up
  • Progressive increase in postsynaptic action potential output occurs during a train of stimulus
  • Evoked by low frequency C-fibre stimuli
  • Long-term potentiation
  • Induced by high frequency stimuli, a response that outlasts the conditioning stimulus
  • Implicated in learning and memory in the hippocampus/pain sensitisation
  • Secondary hyperalgesia
  • Caused by centrally mediated changes in dorsal horn sensitivity/functional connectivity of A-beta mechanosensitive fibres
  • Sensitivity increased beyond the area of tissue injury
  • Intense and ongoing stimuli further increase excitability of dorsal horn neurons