Central Sensitization

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It is apparent that not all sensitization in response to injury can be accounted for by changes in the threshold of peripheral nociceptors. Furthermore, under some conditions, preventing afferent impulses from reaching

Figure 4 A sensory terminal illustrating the receptors and channels as well as some elements of signaling pathways (PKA and PKC) that may be involved in sensitization. Sensitizing molecules PGE2, NGF, bradykinin, and serotonin act on their receptors to affect the VR1 receptor and the TTX-insensitive Na channel via intracellular signaling. Sensitization of VR1 should result in an increased response to noxious heat and protons as well as capsaicin. Sensitization of TTX-resistant Na channel results in a reduced threshold for steady impulse discharge.

Figure 4 A sensory terminal illustrating the receptors and channels as well as some elements of signaling pathways (PKA and PKC) that may be involved in sensitization. Sensitizing molecules PGE2, NGF, bradykinin, and serotonin act on their receptors to affect the VR1 receptor and the TTX-insensitive Na channel via intracellular signaling. Sensitization of VR1 should result in an increased response to noxious heat and protons as well as capsaicin. Sensitization of TTX-resistant Na channel results in a reduced threshold for steady impulse discharge.

the spinal cord can abolish sensitization. This suggests that some of the changes underlying sensitization must take place central to the peripheral nerve. One mechanism may involve the dorsal root reflex conducted antidromically in sensory nerve fibers from their terminals in the spinal cord, but there is evidence that exclusively central mechanisms also contribute.

It has been recognized for many years that small-diameter afferent fibers differ qualitatively from large ones in the central effects that they exert. Specifically, successive volleys in large-diameter fibers elicit constant central effects, whereas the response to volleys in small-diameter afferent fibers, particularly unmyeli-nated fibers, can increase in frequency and duration if the peripheral stimuli occur at a high enough rate (at least once per 4 sec in the cat). This progressive increase in the central discharge of cells in the spinal cord has been referred to as windup and represents one component of the more comprehensive phenomenon known as central sensitization. Other components are much longer lasting and are thought to require metabolic changes in postsynaptic cells that are induced by the activation of NMDA and metabotropic glutamate receptors. They also lead to changes in gene expression in postsynaptic cells, e.g., c-fos, and additionally to a wider zone of postsynaptic cells being activated due to structural changes. The possibility exists that these changes also lead retrogradely to changes in transmitter release from presynaptic terminals via signaling molecules such as nitric oxide.

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