In hyper-reactive skin, free nerve endings have abnormally high sensitivity. Their stimulation leads to the release of neuropeptides such as substance P or calcitonin gene-related peptide (CGRP). On the other hand, external aggressions induce both the release of pro-inflammatory mediators by immune cells from keratinocytes and neutrophils (PMNs), and histamine degranulation by mast cells and basophils.