The Path to Discovery of Windup and Central Sensitization

Pain was once thought to be a simple relay from injury to brain, but this understanding has been revolutionized by the discovery that the spinal cord actively processes and can amplify pain signals. This paper traces the historical path to discovering two fundamental pain mechanisms: windup and central sensitization. These discoveries emerged from early 1960s experiments showing that repetitive stimulation of small nerve fibers (C-fibers) could cause spinal neurons to respond with increasingly longer bursts of activity. This challenged the prevailing view that pain transmission was fixed and unchanging.

Understanding these mechanisms has been crucial for developing modern pain treatments and explaining why some people develop chronic pain after injury.

This is a historical review by Dr. Lorne Mendell, one of the original discoverers of windup. He traces the scientific journey from early nerve fiber research in the 1900s through the 1960s discovery of windup, to the 1980s identification of central sensitization. The review examines key experiments that showed how C-fibers (small, slow nerve fibers that carry pain signals) could cause spinal neurons to become increasingly active with repeated stimulation.

Later work revealed that injury could sensitize the entire spinal pain processing system, making it hyperresponsive to both painful and normally non-painful stimuli.

The research revealed that windup occurs when C-fibers are stimulated repetitively at rates of about 0.33Hz or faster, causing spinal neurons to discharge for progressively longer periods with each stimulus. This happens because C-fibers release both glutamate (which activates NMDA receptors) and neuropeptides like substance P (which activate neurokinin receptors), creating slow, long-lasting excitation that builds up with repetition. Central sensitization, discovered about 15 years later, showed that tissue injury could make the entire spinal pain system hypersensitive for hours or days. Both processes depend on the same molecular mechanisms - NMDA and neurokinin receptors - but windup requires synchronized nerve volleys while central sensitization can occur from diffuse injury signals.

These discoveries fundamentally changed pain medicine by showing that the spinal cord is not a passive relay but an active processor that can amplify pain signals. This explains many chronic pain conditions where people experience pain that seems disproportionate to their injury, or develop pain sensitivity in areas away from the original injury site. The identification of NMDA and neurokinin receptors as key players has led to new drug targets for treating chronic pain. For patients, this research validates that their pain experience can be real and severe even when tissue damage appears minimal - the nervous system itself has become hypersensitive.

For clinicians, it emphasizes the importance of early, aggressive pain control to prevent the development of central sensitization and chronic pain states.