Describe the physiology of pain, including the pathways and mediators

Key definitions:

  • Pain
    Pain is an "unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in such terms." Pain can be broadly classified by:
    • Aetiology
      • Nociceptive pain
        Stimulation of nociceptors by noxious stimuli.
      • Visceral pain
      • Neuropathic pain
        Nervous system dysfunction.
    • Duration
      • Acute pain
        Pain due to symptoms of current pathology.
      • Chronic pain
        Pain occurring after the pathological process has resolved.
  • Hyperalgesia
    Increased response to a normally painful stimulus.
    • Primary hyperalgesia
      Local reduction in pain threshold.
    • Secondary hyperalgesia
      Hyperalgesia away from the site of injury due to alteration in spinal cord signaling.
  • Allodynia
    Painful response to a normally painless stimuli. Occurs due to pathological synapse between second-order neurones in the spinal cord.

  • Anaesthesia dolorosa
    Pain in an area which is anaesthetised.

Peripheral Nociception

Nociceptors are receptors which respond to a noxious stimulus. Nociceptors:

  • Can be stimulated or sensitised by:
    • Chemical signals
      See table.
    • Mechanical signals
      • Shear stress
    • Thermal signals
      • Hot nociceptors activate above 43°C
      • Cold nociceptors activate below 26°C
  • Stimulation initiates a nervous impulse
  • Sensitisation increases a receptors sensitivity to a stimulating mediator

Key chemical stimulating and sensitising mediators include:

Stimulating Mediators Sensitising Mediators
H+ Prostaglandins
K+ Leukotrienes
ACh Substance P
Histamine Neurokinin A
5-HT Calcitonin GRP


Impulses are conducted by two types of primary afferent fibres:

  • Aδ fibres:
    • Small (~2-5μm diameter)
    • Myelinated
    • Conduct sharp pain at up to 40m.s-1
    • Mediate initial reflex responses to acute pain
    • Synapse in laminae I in the dorsal horn
      Substance P is the neurotransmitter at the NK1 receptor.
  • C fibres:
    • <2μm diameter
    • Unmyelinated
    • Conduct dull pain at 2m.s-1
    • Synapse in laminae II in the dorsal horn
      Substance P is the neurotransmitter at the NK1 receptor.

Pain Pathway and Site of Action of Analgesics

The response to a painful stimulus requires a cascade of processes:

  • Activation of nociceptors
    Membrane depolarisation in response to stimulus. If the stimulus is great enough to reach the threshold potential, an action potential is generated.
    • NSAIDS reduce nociceptor mediated inflammation
    • Opiates act on peripheral MOP receptors
    • Local anaesthetics prevent signal propagation
  • Synapse in the dorsal horn
    Input from both Aδ and C fibres, and descending interneurons.
    • Descending inhibitory input reduces nociceptive transmission
      Basis of "gate control" theory. Descending input increased with:
      • Touch
        Aβ 'touch' fibres stimulate inhibitory interneurons in the dorsal horn, 'closing the gate' by increasing descending inhibition and prevent signals from peripheral C fibres from rising to the thalamus.
      • Arousal
      • Opioid receptors
        Particularly MOP (pre- and post-synaptically).
        • Opioids act pre-synaptically to reduce Substance P and glutamine release.
      • α2 receptors
        Clonidine, tricyclic antidepressants, noradrenaline-reuptake inhibitors, and endogenous catecholamines.
      • Gabapentin and pregabalin inhibit presynaptic neurotransmitter release
    • Wide dynamic range neurones
      Receive afferent input from chemical, thermal, and mechanoreceptors.
      • Typically more difficult to stimulate
      • Important in wind-up
        Mediated by NMDA agonism.
        • Ketamine reduces windup and central sensitisation
      • Lead to secondary hyperalgesia
      • Lead to allodynia
        Via additional synapses to sensory neurones in lamina III and IV.
      • Interneuron synapses with a second-order neurones fibre
        These secondary afferents:
    • Cross within 1-2 vertebral segments and ascends in the spinothalamic tract
    • Receives input from descending fibres
    • Opioids act post-synaptically to hyperpolarise second-order neurones
  • Reflex arc

  • Higher centres
    Pain perception occurs in the somatosensory cortex.

Neuropathic Pain

Pain due to a lesion of the somatosensory system, rather than a stimulus itself. Neuropathic pain is divided into:

  • Central neuropathic pain
    From CNS injury, e.g. spinal cord injury, CVA, multiple sclerosis.
  • Peripheral neuropathic pain
    Damage from:
    • Diabetes
      Ischaemia of Schwann cells causes demyelination, causing the exposed axon to generate action potentials inappropriately.
    • Trauma
      Transected axons may regrow with endings that spontaneously fire or that have altered threshold potentials.

Mechanisms of Neuropathic Pain

  • Neuroma
    Healing of damaged nerves leads to neuroma formation. Neuromas:
    • Are more sensitive to painful stimuli
    • Cause spontaneous pain
    • May sprout and innervate local tissues
      Movement of these tissues may lead to pain.
  • Windup
  • Phantom limb pain
    Neurons damaged in removal of a limb develop additional synapses, leading to phantom sensations.

Features of Neuropathic Pain

Neuropathic pain is associated with:

  • Injury or disease that causes nerve injury
  • Burning or electrical quality
  • Reduced or absent sensation
  • Poor response to typical analgesia

Chronic Regional Pain Syndrome

Damage to the SNS can lead to abnormalities in autonomic function:

  • Change in temperature due to vasomotor dysfunction
  • Altered sweating
  • Reduced hair growth
  • Osteoporosis
  • Hyperalgesia and allodynia

Pain in the Elderly

Nervous System Changes:

  • Peripheral Nervous System
    • Nerve deterioration
    • Decreased myelination
    • Decreased conduction velocity
    • Reduced range and speed of ANS responses
    • Increased resting sympathetic tone
  • Central Nervous System
    • Decreased pain perception
    • Increased sensitivity to anaesthetic and analgesics
      Reach ceiling effects more rapidly.
    • Degeneration of myelin
      Subsequent cognitive dysfunction due to neuronal circuit dysfunction.
    • Generalised atrophy
    • Decreased neurotransmitter production


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Last updated 2019-07-18

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