An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Modern pain science defines pain as the brain's perception that body tissue is in danger and action is required—a threat response rather than a damage sensor.
Nociceptors (A-delta and C-fibers) detect noxious stimuli (mechanical, thermal, chemical) and transmit signals via dorsal root ganglia to spinal dorsal horn. Ascending pathways include spinothalamic (lateral: sensory-discriminative), spinoreticular (medial: affective-motivational), and spinohypothalamic. Pain is modulated by descending pathways from PAG, RVM, and cortex releasing endorphins, serotonin, norepinephrine. Peripheral sensitization involves inflammatory mediators (PGE2, bradykinin, NGF). Central sensitization involves NMDA receptor activation, glial activation, and loss of inhibition.
In cPNI, pain is understood as a multisystem output requiring assessment of nociceptive input, nervous system sensitization, immune/inflammatory status, metabolic factors (mitochondrial function, tissue pH), psychological factors (threat perception, context), and social factors. Chronic pain reflects CNS neuroplasticity and is maintained even without ongoing tissue damage. Treatment must address all contributing systems, not just suppress pain signals.
- Pain is 100% output from the brain, not input from tissues (Lorimer Moseley)
- Acute pain serves protective function; chronic pain (>3 months) represents maladaptive neuroplasticity
- Inflammation generates pronociceptive metabolites (PGE2, bradykinin, NGF) sensitizing nociceptors
- Central sensitization involves spinal and supraspinal amplification of pain signals
- Descending modulation from brain can increase (facilitation) or decrease (inhibition) pain
- Placebo analgesia demonstrates 30-40% pain reduction via endogenous opioid release
- Context, expectation, and meaning strongly modulate pain perception
- Chronic pain associated with brain changes: reduced PFC gray matter, altered insula/ACC activity
- Pain matrix includes S1, S2, insula, ACC, thalamus, PFC—but not pain-specific
- Resolution of inflammation via SPMs reduces pain by addressing peripheral sensitization
- inflammation — Inflammatory mediators (PGE2, bradykinin) sensitize nociceptors causing pain
- PGE2 — Prostaglandin sensitizing nociceptors; COX-2 product
- NGF — Nerve growth factor sensitizing and sprouting nociceptors in inflammation
- central sensitization — CNS amplification of pain signals underlying chronic pain
- peripheral sensitization — Increased nociceptor excitability from inflammatory soup
- thalamus — Relays nociceptive information to cortex; processes pain affect
- insular cortex — Processes pain affect and interoceptive awareness of body state
- anterior cingulate cortex — Processes pain unpleasantness and emotional suffering
- periaqueductal gray — Descending pain modulation via endogenous opioids
- endorphins — Endogenous opioids mediating placebo analgesia and pain inhibition
- SPMs — Specialized pro-resolving mediators resolve inflammation and reduce pain
- stress — Chronic stress impairs descending inhibition and worsens pain
- cortisol — Acute cortisol analgesic; chronic cortisol pro-nociceptive
- depression — Bidirectional: chronic pain causes depression; depression lowers pain threshold
- BDNF — In spinal cord, BDNF promotes central sensitization paradoxically
- placebo effect — Demonstrates brain's powerful top-down pain modulation
- context — Context dramatically alters pain perception (battlefield analgesia)
- nocebo effect — Negative expectations increase pain via descending facilitation
- fibromyalgia — Chronic widespread pain syndrome involving central sensitization
- microglia — Activated microglia release pro-inflammatory mediators maintaining pain