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Pain wind-up
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Pain wind-up is a phenomenon of increased where repeated painful stimulation of peripheral nerves at sufficient intensity to stimulate group C nerve fibers leads to progressively increasing electrical response in the corresponding spinal posterior horn neurons. This slow, cumulative effect is partly due to the slow response of NMDA receptors, but may also be linked to sustained release of substance P, a neuropeptide, in the posterior horns.
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Pain wind-up is a phenomenon of increased where repeated painful stimulation of peripheral nerves at sufficient intensity to stimulate group C nerve fibers leads to progressively increasing electrical response in the corresponding spinal posterior horn neurons. This slow, cumulative effect is partly due to the slow response of NMDA receptors, but may also be linked to sustained release of substance P, a neuropeptide, in the posterior horns. The process leads to increased pain (hyperalgesia), increased pain response to otherwise non-painful stimuli (allodynia) and spontaneous pain.
After repeated stimulation, WDR (wide dynamic range) neurons experience a general increase in excitability. This hyper-excitability can be caused by an increased neuronal response to a noxious stimulus (hyperalgesia), a larger neuronal receptive field, or spread of the hyper-excitability to other segments. This condition is maintained by C fibers. C fibers cause central sensitization of the dorsal horn in the spinal cord in response to their hyperactivity. The mechanism underlying this phenomenon involves the release of glutamate by these pathologically sensitized C fibers. The glutamate interacts with the postsynaptic NMDA receptors, which aids the sensitization of the dorsal horn. Presynaptic neuronal voltage-gated N-calcium channels are largely responsible for the release of this glutamate as well as the neuropeptide, substance P. The expression of presynaptic neuronal voltage-gated N-calcium channels increases after a nerve lesion or repeated stimulation. Ziconotide is a specific antagonist of these N-type voltage gated Calcium channels. NMDA receptor activation (by glutamate) enhances postsynaptic Nitric Oxide Synthase. Nitric Oxide is thought to migrate back to the presynaptic membrane to enhance the expression of the voltage-gated N-calcium channels resulting in a pain wind-up phenomenon. Ketamine (NMDA receptor antagonist) and Nitric Oxide Synthase inhibitors can block pain wind-up. This abnormal central sensitization cycle results in increased pain (hyperalgesia) and pain responses from previously non-noxious stimuli evoke a pain response (allodynia).
Central sensitization of the dorsal horn neurons that is evoked from C fiber activity is responsible for temporal summation of “second pain” (TSSP). This event is called ‘windup’ and relies on a frequency greater or equal to 0.33Hz of the stimulus. Windup is associated with chronic pain and central sensitization. This minimum frequency was determined experimentally by comparing healthy patient fMRI’s when subjected to varying frequencies of heat pulses. The fMRI maps show common areas activated by the TSSP responses which include contralateral thalamus (THAL), S1, bilateral S2, anterior and posterior insula (INS), mid-anterior cingulate cortex (ACC), and supplemental motor areas (SMA). TSSP events are also associated with other regions of the brain that process functions such as somatosensory processing, pain perception and modulation, cognition, pre-motor activity in the cortex.
Pain wind up is particularly relevant during surgery. During surgery substantial pain wind-up can occur if not treated with the appropriate anesthetics causing the patient to wake up in hyperalgesic state. However, this can be prevented with opiates, ketamine, local anesthetics, or Ziconotide. Pain wind-up is not prevented by most inhalation anesthetics.
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