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Scratch that itch
- Nothing but skin and bone

To broaden our thinking about the intimate connection betweenthe skin and the nervous system, the final skin-related Reviewin this series, by Ralf Paus and colleagues (25), raises someintriguing new possibilities in managing a symptom unique todermatology: pruritus, or itching. Despite many years of research,the exact cause of itching is unknown and represents a complexphysiological phenomenon. An itch can be defined as an unpleasantsensation that provokes an often uncontrollable desire to scratch,which ironically can be inexplicably pleasurable. Scratchingis believed to relieve the itch by inducing mild pain that causesa temporary distraction from the itch. Frequently, one worsensthe other, since damage to the outer layers of the skin by scratchingcan release additional proinflammatory agents that further exacerbateitching. This phenomenon is known as the itch-scratch cycle,which lies at the center of current neurophysiological researchin the skin (26).

Pruritus can be a symptom of innumerable skin diseases; however,it can also occur when there is no visible evidence of a skinlesion and instead results from a disruption in processing ofthe itch sensation in the brain or the circuitry connectingit with the skin. There are many systemic diseases that cancause itch, including kidney failure, hepatitis C infection,multiple myeloma, and liver disease, among others, suggestingthat stimuli from outside the skin-brain circuit can enter thepathway and cause itching.

Pruritus has been a challenge from the research perspectivedue to the subjective nature of itching itself, the absenceof a precise physiological definition or quantitative measures,and the lack of suitable in vitro or in vivo models to mimicthe symptoms. Despite these challenges, recent advances in understandingthe neurophysiological basis of itch have revealed some surprisingnew insights. The skin is home to a complex network of nervesthat transmit different sensations, including itch, pain, touch,cold, and heat. In the simplest of terms, itching is a responseto a chemical stimulus that transmits these signals back tothe brain (27). Teasing out which nerve fibers are responsiblefor itch has been a formidable task, and for many years it wasbelieved that itch simply hijacked nerve circuits from the painpathways and was merely a modified form of pain. However, thediscovery of itch-specific neurons revealed that there are,in fact, distinct sensory systems for itch and pain (nociception).In their Review (25), Paus and colleagues discuss some potentiallynovel therapeutic opportunities that have arisen from a betterunderstanding of itch from the point of view of the skin aswell as the brain.

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