Cytokines, Inflammation, and Pain

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Inflammatory responses in the peripheral (PNS) and central nervous systems (CNS) play key roles in the development and persistence of many pathologic pain states.1 Certain inflammatory cytokines in spinal cord, dorsal root ganglion (DRG), injured nerve or skin are known to be associated with pain behaviors and with the generation of abnormal spontaneous activity from injured nerve fibers or compressed/inflamed DRG neurons.
Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells (Table 1). Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (IL) (cytokines made by one leukocyte and acting on other leukocytes). Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action).
It is common for different cell types to secrete the same cytokine or for a single cytokine to act on several different cell types (pleiotropy). Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines. They are often produced in a cascade, as one cytokine stimulates its target cells to make additional cytokines. Cytokines can also act synergistically or antagonistically (Fig. 1).
Cytokines are made by many cell populations, but the predominant producers are helper T cells (TH) and macrophages. Cytokines may be produced in and by peripheral nerve tissue during physiologic and pathologic processes by resident and recruited macrophages, mast cells, endothelial cells, and Schwann cells. After a peripheral nerve injury, macrophages and Schwann cells that gather around the injured site of the nerve secrete cytokines and specific growth factors required for nerve regeneration. Localized inflammatory irritation of the DRG not only increases proinflammatory cytokines but also decreases anti-inflammatory cytokines.2 Cytokines can also be synthesized and released from the herniated nucleus pulposus, synthesized inside the spinal cord,3 the DRG soma,4 or the inflamed skin.5 Furthermore, cytokines may be transported in a retrograde fashion from the periphery, via axonal or nonaxonal mechanisms, to the DRG and dorsal horn, where they can have profound effects on neuronal activity6 and, therefore, contribute to the etiology of various pathologic pain states.
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