Abstract
Cutaneous neurophysiology encompasses specific itch mediators and nerve fibers that transmit itch peripherally and centrally. This chapter provides an overview of fundamental mechanisms of itch, from the skin to the spinal cord and brain. There are at least three subsets of pruriceptive C neurons which respond to histamine or to other pruritogens that mediate itch independently of histamine and then activate distinct spinothalamic and spinoparabrachial tract neurons. Peripheral itch mediators include histamine, proteases, interleukin (IL)-4, IL-13, IL-31, IL-33, and thymic stromal lymphopoietin (TSLP), while central itch mediators include opioids, gastrin-releasing peptide, and B-type natriuretic peptide. There are overlapping paradigms between chronic itch and chronic pain, including activation of multiple brain areas and shared neuromediators and receptors such as nerve growth factor and transient receptor potential (TRP) channels. However, itch-specific molecular and cellular pathways also exist. Topical and systemic medications that reduce itch sensitization by selectively counteracting itch-specific pathways represent promising treatment strategies.