What is the role of peripheral and central sensitization in the pathophysiology of complex regional pain syndrome (CRPS)?

Updated: Jun 20, 2018
  • Author: Gaurav Gupta, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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Mechanical, thermal, and chemical stimuli activate peripheral nociceptors that transmit pain messages through lightly myelinated A-delta fibers and unmyelinated C fibers projecting to Rexed layers I, II, and V in the spinal cord. This process leads to the release of excitatory amino acids, such as glutamine and asparagine, which then act upon N -methyl-D -aspartic acid (NMDA) receptors, causing the release of substance P (SP). SP then lowers the threshold for synaptic excitability in normally silent second-order interspinal synapses. [9, 1, 10, 11, 12]

Peripheral sensitization occurs when persistent or repetitive noxious stimulation of high-threshold, polymodal C fibers results in enhanced sensitivity, lower stimulus thresholds, and the prolonged, enhanced activation of dorsal horn cells, especially those with glutamate receptors. In addition to SP, algogenic substances that are typically involved in tissue damage and capable of inducing transduction centripetally include potassium, serotonin, bradykinin, histamine, prostaglandins, and leukotrienes. Neuropeptides, such as SP and calcitonin gene-related peptide (CGRP), are also transported to the endings of nociceptive afferents where they can instigate ortho- and retrograde actions including, but not limited to, neurogenic inflammation, which can incite a host of additional hostile algogenic mechanisms.

Chronic CNS sensitization is engendered through afferent processing by second-order nociceptor-specific neurons and wide-dynamic-range (WDR) neurons in the spinal cord. WDR neurons contribute more to sensitivity than nociceptor-specific neurons, because both nociceptive and non-nociceptive afferents converge to synapse on a single WDR neuron, and WDR neurons respond with equal intensity regardless of whether the neural signal is noxious (hyperalgesia) or not.

Hyperalgesia and allodynia initially develop at the injury site. However, after CNS sensitization occurs through WDR neural activity, the area of pain expands beyond the initial region of tissue pathology. The peripheral changes described eventually cause an injury environment, where primary afferents, including nociceptors, demonstrate an increased sensitivity to circulating or experimentally injected subcutaneous norepinephrine. [14, 1, 10, 11, 12, 15, 16, 17, 18, 19, 20]

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