Pain/Sensory Pathway Anatomy

Definitions

• 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)

Nociceptors

• 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

• 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