In the past 30 years, we have accumulated evidence of a range of peripheral and central abnormalities associated with variants of chronic pain. The pain research literature is dominated by reports of peripheral abnormalities that may drive chronic pain transmission. All of these studies share the common assumption that perception of chronic pain reflects abnormal pain encoding at the level of the primary afferent. These peripheral changes include enhanced touch and pain sensitivity, increased innervation of painful tissue, abnormalities in immune responsiveness (including genetic polymorphisms that could predispose an individual to exhibit aberrant inflammatory cascades), and evidence co-existing muscle dysfunction. Furthermore, the involvement of brain factors, such as mood disturbances, personality factors, and pain-specific cognitive vulnerabilities, have consistently emerged as either putative predispositions and/or consequences of living with persistent pain. Brain imaging has expanded upon these findings by demonstrating that acute pain engages a network of brain regions that encode nociceptive information, with evidence of anatomical changes suggestive of enduring neuroplasticity. Long-term changes in brain regional gray matter volume and density that have been described across numerous pain populations also support the notion that chronic pain has “centralized” components. What is clear is that chronic pain profoundly affects—and potentially reorganizes—the peripheral and central nervous systems.
Persistent pain may reflect nociceptive distortions at multiple levels of the nervous system. Sensory distortion may result from abnormal signaling by the primary afferent sensory neuron (periphery), amplified relay of afferent sensory neuron signals by the dorsal horn interneurons (spinal cord), deficient descending pain modulation (spinal cord), and/or cortical alterations in how this information is encoded and integrated into conscious awareness. Notably, there is no cortical “quality control” for incoming sensory information that can earmark abnormal nociceptive input.
Most hypotheses of chronic pain pathogenesis assume that an inflammatory insult initiated a cascade of nociceptive signaling that failed to resolve. Inflammation promotes the sensitization of C-fiber nociceptors–the sensory nerves that transduce slow burning or aching pain—to enhance the efficiency with which they transmit noxious stimulus-related information to the spinal cord, in a state called peripheral sensitization. This potentiated signal could explain hallmark symptoms observed in chronic pain patients, such as hyperalgesia (enhanced pain perception) and allodynia (pain with a previously non-noxious stimulus). In some cases, histological evidence of increased tissue innervation is consistent with this hypothesis. However, continued provocation of the hyperalgesic tissue may, in some cases, promote a “wind-up” phenomenon. Wind-up describes the hyperexcitability of neurons in the dorsal horn of the spinal cord that can transmit a potentiated nociceptive signal to the brain. (Note that wind-up precedes but is not synonymous with spinal cord central sensitization.)
Central sensitization is the gateway to the onset of chronic pain, as it relies on persistent, low-level stimulation of nociceptors that enhance the synaptic efficiency of interneurons in the dorsal horn of the spinal cord (reviews by Clifford Woolf should be your primary source of information about C.S.). Central sensitization may explain some of the enigmatic symptoms of chronic pain that are more resistant to pain management, including pain aftersensations, dynamic mechanical allodynia, extra-dermatomal increases in pain sensitivity, and other phenomena. These symptoms cannot be explained by peripheral sensitization alone, indicating that a subset of pain patients exhibit symptoms that reflect aberrant spinal involvement. Note that allodynia or hyperalgesia alone do not support the presence of central sensitization, as these distortions in perception can be caused by peripheral and central processes.