The neurobiology of itch, which is formally known as pruritus, and its interaction with pain have been illustrated by the complexity of specific mediators, itch-related neuronal pathways and the central processing of itch. Scratch-induced pain can abolish itch, and analgesic opioids can generate itch, which indicates an antagonistic interaction. However, recent data suggest that there is a broad overlap between pain- and itch-related peripheral mediators and/or receptors, and there are astonishingly similar mechanisms of neuronal sensitization in the PNS and the CNS. The antagonistic interaction between pain and itch is already exploited in pruritus therapy, and current research concentrates on the identification of common targets for future analgesic and antipruritic therapy.

In microneurography experiments 56 unmyelinated nerve fibers were studied in the cutaneous branch of the peroneal nerve of healthy volunteers. Units were identified with the "marking" technique as mechanically and heat-responsive (CMH; n ϭ 30), heat-responsive (CH; n ϭ 13), or unresponsive to mechanical and heat stimulation (CM i H i ; n ϭ 13). None of the units showed spontaneous activity.These units were tested for responsiveness to iontophoresis of histamine (1 mA, 20 sec) from a small probe (diameter, 6 mm), which induced itch sensations lasting several minutes. Twenty-three units were unresponsive to histamine, and 25 units responded weakly with a few spike discharges after iontophoresis.Eight units, however, responded with sustained discharges to histamine, and their discharge patterns were matching the time course of the itch sensations. All C-units in this group were mechanically insensitive, and five of them were heat-responsive. They had very low conduction velocities of only 0.5 m/sec, on average, which is significantly lower than conduction velocities of the "polymodal" CMH units. This slow conduction velocities attributable to small axon diameters may be one reason why these units have not been encountered in previous studies. Histaminesensitive C-units had very large innervation territories extending up to a diameter of 85 mm on the lower leg.We conclude that these C-fibers represent a new class of afferent nerve fibers with particularly thin axons but excessive terminal branching. This type of C-fiber probably represents the afferent units long searched for mediating itch sensations.

Chronic itch is a common and distressing symptom that arises from a variety of skin conditions and systemic diseases. Despite this, there is no clinically based classification of pruritic diseases to assist in the diagnosis and cost-effective medical care of patients with pruritus. The proposed classification focuses on clinical signs and distinguishes between diseases with and without primary or secondary skin lesions. Three groups of conditions are proposed: pruritus on diseased (inflamed) skin (group I), pruritus on non-diseased (non-inflamed) skin (group II), and pruritus presenting with severe chronic secondary scratch lesions, such as prurigo nodularis (group III). The next part classifies the underlying diseases according to different categories: dermatological diseases, systemic diseases including diseases of pregnancy and drug-induced pruritus, neurological and psychiatric diseases. In some patients more than one cause may account for pruritus (category "mixed") while in others no underlying disease can be identified (category "others"). This is the first version of a clinical classification worked out by the members of the International Forum for the Study of Itch. It is intended to serve as a diagnostic route for better evaluation of patients with chronic pruritus and aims to improve patients' care.

We examined whether neuronal proteinase-activated receptor-2 (PAR-2) may be involved in pruritus of human skin. The endogenous PAR-2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR-2 was markedly enhanced on primary afferent nerve fibers in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR-2 agonists provoked enhanced and prolonged itch when applied intralesionally. Moreover, itch upon mast cell degranulation was abolished by local antihistamines in controls but prevailed in AD patients. Thus, we identified enhanced PAR-2 signaling as a new link between inflammatory and sensory phenomena in AD patients. PAR-2 therefore represents a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.

Itch is a common skin sensation, with substantial effects on behaviour. Neurophysiological research has permitted accurate definition of neural pathways of itch, and has confirmed the distinctiveness of itch pathways in comparison with pain. A clinical classification of itch, based on such improved understanding, describes the difference between peripheral (pruritoceptive) and central (neurogenic or neuropathic) itch. New specific and sensitive investigational methods in people and animals enable us to better understand this bothersome symptom, and have important clinical implications. We describe the clinical classification of itch, new findings on neuropathophysiology of itch, methods for assessment, and improved treatments.

The perioperative administration of systemic small-dose lidocaine reduces pain during surgery associated with the development of pronounced central hyperalgesia, presumably by affecting mechanoinsensitive nociceptors, because these have been linked to the induction of central sensitization and were shown to be particularly sensitive to small-dose lidocaine.

This Review highlights selected frontiers in pruritus research and focuses on recently attained insights into the neurophysiological, neuroimmunological, and neuroendocrine mechanisms underlying skin-derived itch (pruritogenic pruritus), which may affect future antipruritic strategies. Special attention is paid to newly identified itch-specific neuronal pathways in the spinothalamic tract that are distinct from pain pathways and to CNS regions that process peripheral pruritogenic stimuli. In addition, the relation between itch and pain is discussed, with emphasis on how the intimate contacts between these closely related yet distinct sensory phenomena may be exploited therapeutically. Furthermore, newly identified or unduly neglected intracutaneous itch mediators (e.g., endovanilloids, proteases, cannabinoids, opioids, neurotrophins, and cytokines) and relevant receptors (e.g., vanilloid receptor channels and proteinase-activated, cannabinoid, opioid, cytokine, and new histamine receptors) are discussed. In summarizing promising new avenues for managing itch more effectively, we advocate therapeutic approaches that strive for the combination of peripherally active antiinflammatory agents with drugs that counteract chronic central itch sensitization. The study of pruritus in a nutshellItching (pruritus) is perhaps the most common symptom associated with numerous skin diseases and can be a lead symptom of extracutaneous disease (e.g., malignancy, infection, and metabolic disorders) (1, S1). However, despite approximately a century of pruritus research (2, S2, S3), there is no generally accepted therapy for the treatment of itch, and many mysteries, misconceptions, and controversies still haunt this rather neglected, yet clinically important and scientifically fascinating, niche in the life sciences (3, 4, 5). It is the brain that itches, not the skinPruritus causes the desire to scratch the skin and is experienced as a sensation arising in the skin. However, like all other skin sensations, itch, strictly speaking, is an extracutaneous event - a product of CNS activities. The intense itch we feel after an insect bite, in a patch of atopic eczema, during an episode of food-induced urticaria, or in association with diabetes, uremia, or scabies mite infection (S1) represents a neuronal projection of a centrally formed sensation into defined regions of the integument (localized pruritus) or into large territories of our body surface (generalized pruritus).Interestingly, our individual reception of and emotional response to itch strongly depends on its exact quality: while a tickling sensation usually is experienced as pleasurable, persistent itch is an annoying or even torturous sensation (S4). While one is tempted to interpret this as indicating a distinct molecular and/or structural basis of these different itch qualities, it has proven excruciatingly difficult to identify their molecular, structural, and neurophysiological differences (ref. 1; see below).As pruritus can arise from localized or systemic, peripheral o...

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