Pathophysiology
Clinical meaning
Pain signaling begins with transduction at peripheral nociceptors (A-delta fibres for sharp, localized pain; C fibres for dull, diffuse pain), followed by transmission via dorsal root ganglia to the dorsal horn of the spinal cord. In the dorsal horn, substance P and glutamate mediate synaptic transmission to second-order neurons that cross and ascend via the spinothalamic tract to the thalamus, then to somatosensory cortex for localization and limbic system for emotional processing. Descending inhibitory pathways from the periaqueductal grey and rostral ventromedial medulla modulate pain via endogenous opioids, serotonin, and norepinephrine. Neuropathic pain arises from damage to the somatosensory nervous system causing ectopic firing, central sensitization, and aberrant signaling (allodynia, hyperalgesia). Peripheral sensitization involves increased excitability of nociceptors from inflammatory mediators, while central sensitization involves wind-up and long-term potentiation in dorsal horn neurons.