![]() The thalamus then assists in the interpretation of messages encoding itch. ![]() Messages are relayed from the peripheral afferents to their cell bodies in dorsal root or trigeminal ganglia followed by synapsing with second-order neurons in the spinal cord. These cells release mediators that activate cognate receptors on sensory neurons to release neuropeptides to contribute to the itch-scratch cycle. Neural activity drives the recruitment of immune cells, including mast cells and CD4+ T cells among others. The sensory neurons are considered histaminergic or non-histaminergic. Branching terminal fibers of afferent neurons which sense these substances reach the epidermis, the uppermost viable layer of skin immediately below the stratum corneum barrier. Allergens, pruritogens, and irritants are exogenous substances which interface with the skin in acute and chronic itch. The pleasure that accompanies scratching may serve to reinforce the motor activity to further ensure neuroimmune communication. This cascade includes multidirectional communication between the nervous and immune systems within the skin, perhaps primarily directed against components of the microbiota, which can evoke itch and pain ( FIGURE 1). ![]() More recent thinking is that in addition, scratching damages the epidermal barrier and facilitates an appropriate physiological cascade associated with sensing the insult ( FIGURE 1). Hence, itch is considered a protective sensation and response to the environment. Why do we have the sensation of itch? Conventional thinking has been that the major role of the sensation of itch and the subsequent motor response of scratching is to remove environmental insults from the skin, especially arthropods. The concepts of central inhibitory pathways and central sensitization were introduced. Itch associated with systemic processes including cholestasis and hematological conditions was noted to be distinct from histamine, consistent with current understanding that clinical itches are driven primarily by mediators and pathways that are independent from histamine. The triple response of Sir Thomas Lewis, manifest by vasodilatation, flare, edema and associated itch attributed to a ‟H-substanceˮ not necessarily exclusive to histamine, was consistent with mediators aside from histamine. The complete overlap between areas in which itch and pain were felt was indicative of shared neuronal pathways but could not explain the distinct motor responses of scratching an itch versus withdrawal from a painful stimulus. ![]() The sensation may be unpleasant, the scratching response rewarding, but patients who suffer from acute or chronic itch, which affects 15% of the population, are miserable. The poet Ogden Nash wrote that happiness is to have a scratch for every itch. Scratching an itch can also be pleasurable ( 269). Why such reinforcement occurs, unique to this topic, is indicative of the fascination that surrounds itch. The definition continues to appear regularly at the beginning of manuscripts. This definition was penned by Samuel Hafenreffer in 1660, with pruritus, an identical term, in place of itch. ‟Itching is an unpleasant sensation which provokes the desire to scratch.ˮ So began the previous review on the physiology of itching in this journal in 1941, written by the father of investigative dermatology, Stephen Rothman. Itch is a disease, not only a symptom of disease. We review the itch field and provide a current understanding of the pathophysiology of itch. There is now the potential to markedly alleviate chronic itch, a condition that does not end life, but often ruins it. The efforts associated with these approaches are positively impacting the care of itchy patients. Measures involve psychophysics and behavioral psychology. Mechanisms blur boundaries of the circuitry that blend neuroscience and immunology. Acute and chronic itch are being carefully scratched apart and reassembled by puzzle solvers across the biomedical spectrum. Itch is now appreciated as a complex and colorful Rubik’s cube. ![]() When the prior review on the physiology of itching was published in this journal in 1941, itch was a black box of interest to a small number of neuroscientists and dermatologists. These dynamics have led to increasingly deep dives into the mechanisms that underlie and contribute to the sensation of itch. The pathophysiological consequences of itch impact quality of life as much as pain. The physiological roles of itch are increasingly understood and appreciated. Itch is a topic to which everyone can relate. ![]()
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