Pathophysiology
Clinical meaning
Chronic pain (>3 months) involves neuroplastic changes that transform acute nociceptive signaling into a self-sustaining pathological state. Peripheral sensitization occurs when tissue injury releases inflammatory mediators (prostaglandins, bradykinin, substance P, NGF, CGRP) that lower nociceptor activation thresholds and increase firing frequency. With persistent nociceptive input, central sensitization develops in dorsal horn neurons: NMDA receptor activation by glutamate removes the magnesium block, allowing calcium influx that activates protein kinases (PKC, CaMKII), phosphorylating AMPA receptors and increasing synaptic efficacy (wind-up phenomenon). Microglial activation in the spinal cord releases pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) and brain-derived neurotrophic factor (BDNF) that further enhance neuronal excitability. Descending inhibitory pathways (serotonergic from raphe nuclei, noradrenergic from locus coeruleus) become dysfunctional, reducing endogenous pain modulation. Cortical reorganization occurs with chronic pain: somatosensory cortex remapping, prefrontal cortex volume reduction, increased limbic system activation linking pain to emotional suffering, and altered default mode network connectivity. These changes explain allodynia (pain from non-painful stimuli), hyperalgesia (amplified pain response), and the emotional-cognitive dimensions of chronic pain that distinguish it from acute nociception.