Sensitization of Itch Signaling: Itch Sensitization—Nerve Growth Factor, Semaphorins

Itch (or pruritus) has been defined as an unpleasant sensation that provokes the desire to scratch. Itch is also believed to signal danger from various environmental factors or physiological abnormalities. Therefore, it frequently accompanies a variety of inflammatory skin conditions and systemic diseases. Histamine is the best-known pruritogen in humans and also acts as an experimental itch-causing substance. Clinically, antihistamines, i.e., histamine H-receptor blockers, are commonly used to treat all types of itching resulting from renal and liver diseases, as well as from serious skin diseases such as atopic dermatitis. However, antihistamines often lack efficacy in patients with chronic itch that may involve other agonists, including proteases, neuropeptides, cytokines, and opioids, and their cognate receptors, such as thermoreceptors, PARs, Mrgprs, and opioid receptors. Such pruritogenic mediators and modulators released in the periphery may directly activate itch-sensitive fibers, especially C-fibers, by binding to specific receptors on the nerve terminals (Ikoma et al. 2006; Paus et al. 2006; Xiao and Patapoutian 2011). Nerve fibers are also activated by exogenous mechanical, chemical, and biological stimuli, resulting in itch responses (Akiyama et al. 2010; Tominaga and Takamori 2010). Histological analyses have shown that epidermal nerve densities are increased in patients with atopic dermatitis and xerosis, suggesting that the higher density is partly responsible for itch sensitization in the periphery. Such hyperinnervation is probably caused by an imbalance of nerve elongation factors, such as nerve growth factor (NGF), and nerve repulsion factors, such as semaphorin 3A (Sema3A), produced by keratinocytes (Tominaga and Takamori 2010). These axonal guidance molecules may also act on keratinocytes, immune cells and vascular endothelial cells, and be indirectly involved in the modulation of itching. This chapter presents recent knowledge regarding itch sensitization associated with epidermal nerve density controlled by NGF and Sema3A, especially in atopic dermatitis.