**7.3.** *IL-1β, IL-6,* **and** *TNF-α* **and "neurogenic inflammation"**

The orthodontic tooth movement is accompanied by releasing neuropeptides from peripheral endings of sensor nerves, which permeate the dental pulp and periodontium, as well as from the inflammatory cells localized in the periodontal tissue. Released neuropeptides regulate the microcirculation of the pulp and mediate in inflammatory processes during remodeling of bones, characteristic for orthodontic tooth movement [19]. Such neural effect, which is generally called "neurogenic inflammation," is connected to the pain, which partially occurs during stretching and pressing of the tissue under the influence of mechanical forces and partially because of the interaction of numerous inflammatory mediators with local pain receptors [38, 40].

The main mediators of neutrogenic inflammation are neuropeptides, SP and CGRP, which are proven to have vasodilatation effect, increase vascular permeability and participate in the inflammatory processes related to the damage, and recovery of the tissue [41]. The increase of the level of these neuropeptides is recorded in gingival fluid immediately after the effect of orthodontic forces, which occurs simultaneously with the increase of the level of pro-inflammatory cytokines *IL-1β*, *IL-6*, *TNF-α* in this liquid [42]. Although the ratio of neuropeptides and cytokines included in the process of inflammation, which occurs during the orthodontic tooth movement, is still not entirely clear, the data show that SP and CGRP stimulate the excretion of *IL-1β*, *IL-6*, and *TNF-α* from fibroblast of human dental pulp, but they do not work synergistically [16, 42]. The neuropeptide SP is included in the resorption phase of the reshaping of the bone during the orthodontic tooth movement by stimulating the creation of RANKL in the cells of human dental pulp similar to fibroblasts [43]. The SP expression may be prevented by *TGF*-*β* [44], whose excretion overlaps with the initial stage of reparation of periodontal tissue.

The effects of neuropeptides to cytokines are not unidirectional [19, 38]. *IL-1β* and *TNF-α* secreted from inflammatory cells after the stimulation with SP lead to the creation of nerve growth factor (NFG), which then leads to the increased production of SP and CGRP, which establishes the mechanisms of positive feedback during the inflammatory response [41].
