REVIEWS The neurobiology of itch Akihiko Ikoma*, Martin Steinhoff‡, Sonja Ständer§, Gil Yosipovitch|| and Martin Schmelz¶ Abstract | 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. Central sensitization Historically, the sensations of itch and pain have been In this review, we first introduce the definition and Plastic changes in the CNS regarded as closely related; weak activation of noci- clinical classification of itch. We then focus on the inter- (adaptive or pathological) that ceptors has been proposed to mediate itch, and stronger action between itch and pain on a peripheral and central lead to enhanced responses activation results in weak pain — the ‘intensity theory’1. level. These interactions will be specified in terms of and/or lower thresholds. Current data in rodents are still compatible with this the mediators involved and their activity in pain and idea2. However, the identification of primary afferent itch processing. Evolving similarities in the patterns of neurons in humans3 and spinal projection neurons in peripheral and central sensitization, and their therapeu- cats4 that respond to histamine application with a simi- tic implications, are also highlighted. This functional lar time course as the itch sensation clearly favours the approach is followed by a detailed analysis of the role ‘specificity theory’, which stipulates that separate sets of of selected mediator systems, including PARs, TRP neurons mediate pruritus and pain. However, these his- channels, opioids and cannabinoids in the modulation tamine-sensitive neurons also respond to capsaicin, an of itch, but also pain. Finally, the neuronal basis for the *Department of Dermatology, algogen (a pain-producing substance), and could there- itch sensation is discussed, with a description of hista- 5 Kyoto University, Shogin- fore be termed ‘itch selective’ rather than ‘itch-specific’ . mine-dependent and histamine-independent primary Kawahara-cho 54, Sakyo-ku, Research into itch has tried to identify specific pruritic afferent fibres, spinal projection neurons and the cen- Kyoto 606-8507, Japan. mediators and mechanisms as opposed to algesic ones. In tral processing of itch. We also discuss results of central ‡ Department of Dermatology, contrast to the separated neuronal pathways, the results imaging experiments that visualize the similarities and IZKF Münster, and Boltzmann Institute for Immunobiology have revealed that a broad overlap exists between pain and differences between itch and pain processing. of the Skin, §Department of itch processing in terms of mediators, mechanisms For each aspect we not only focus on the particular Dermatology, University and even therapeutic approaches: protease-activated relevance of mediators and mechanisms for itch, but Hospital, Von-Esmarch-Str. 58, receptor 2 (PAR ) and members of the transient receptor also emphasize the complex interaction between pruri- 48149 Münster, Germany. 2 ||Departments of Dermatology, potential (TRP) family have been implicated as targets tus and pain processing, including typical antagonistic Neurobiology and Anatomy, for both algesic and pruritic mediators, and sensitiza- modulation and unexpected similarities. Wake Forest University School tion of peripheral nerve endings by nerve growth fac- of Medicine, Winston-Salem, tor (NGF) is a known pathophysiological mechanism Itch: definition and classification North Carolina 27157, USA. in both chronic itch and pain. There are strikingly Itch was defined more than 340 years ago by the ¶Department of Anaesthesiology, Mannheim, similar patterns of central sensitization between allodynia German physician Samuel Hafenreffer as an “unpleas- University of Heidelberg, and punctate hyperalgesia for pain, as well as between ant sensation that elicits the desire or reflex to scratch”. Theodor Kutzer Ufer 1–3, alloknesis and punctate hyperknesis for pruritus. These This definition is still valid, but for many reasons we 68135 Manheim, Germany. similarities are already being translated into similar differentiate between acute and chronic pruritus, and Correspondence to M.S. e-mail: martin.schmelz@ therapeutic approaches, such as gabapentin treatment it is understood that chronic itch is a complex, unpleas- anaes.ma.uni-heidelberg.de or the use of antidepressants against neuropathic pain ant sensory experience with many similarities to pain. doi:10.1038/nrn1950 and chronic itch. Both sensations are multidimensional with sensory NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JULY 2006 | 535 REVIEWS Allodynia discriminative, cognitive, evaluative and motivational Pain inhibits itch. It is common experience that the itch The perception of a stimulus as components. A mechanism-based definition of itch has sensation can be reduced by the painful sensations caused painful when previously the been proposed6 that separates itch that is induced in by scratching. The inhibition of itch by painful stimuli same stimulus was reported to a healthy nervous system by peripheral (pruriceptive) has been shown experimentally using different types of be non-painful. and central (neurogenic) mechanisms from itch that is stimulus (for example, heat, physical and chemical) to 8 Punctate hyperalgesia caused by diseased neurons (neuropathic). However, induce pain . Painful electrical stimulation reduced hista- Type of central sensitization for the pathophysiology of most clinical itch conditions is mine-induced itch for several hours at a distance of up to pain in which the pain elicited unclear, and therefore operational classifications are 10 cm from the stimulated site, which suggests a central by punctate mechanical stimuli more appropriate for clinical use. Clinical relevance mode of action9. Recent results suggest that noxious heat is more prolonged and stronger than normally experienced. is obviously highest in chronic itch conditions that stimuli and scratching produce a stronger itch inhibi- last longer than 3 months. In many cases such as dry tion than noxious cold stimuli10. Consistent with these Alloknesis skin, atopic eczema, psoriasis, urticaria, scabies and results, itch is suppressed inside the secondary zone of Type of central sensitization for other inflammatory skin diseases, chronic itch com- capsaicin-induced mechanical hyperalgesia11. Evidence itch in which touch triggers the prises more complex skin-associated symptoms than for an antagonistic interaction between pain and itch also sensation of itch. are seen in, for example, acute insect bite reactions comes from a genetic approach: sensitivity in pain tests Punctate hyperknesis (TABLE 1). Other types of chronic itch include those was inversely correlated to sensitivity in experimental Type of central sensitization for that accompany diseases of organs other than the skin, pruritus in mice strains12. This finding also has implica- itch in which the itch evoked by such as chronic renal failure, chronic liver disease and tions for the current search for genes that control pain punctate mechanical stimuli is 13 more prolonged and stronger lymphoma, and metabolic conditions such as hyper- sensitivity , which might involve mechanisms that are than normally experienced. thyroidism. Neuropathic itch arises from diseases or relevant for itch modulation. disorders of the CNS or PNS, such as brain tumours, Itch can be reduced by painful stimuli; analgesia multiple sclerosis, peripheral neuropathy (for example, can reduce this inhibition and so enhance itch14. This postherpetic itch) and nerve compression or irritation phenomenon is particularly relevant to spinally admin- (for example, notalgia paresthetica and brachoradial istered µ-opioid receptor agonists, which induce seg- pruritus). Such itches are often neuropathic in char- mental analgesia that is often combined with segmental acter, and the itch sensation could be combined with pruritus15. Given that µ-opioids can induce itch, it is burning and stinging7. Other forms of itch are related to not surprising that µ-opioid receptor antagonists have psychological or psychiatric disorders, such as itch that antipruritic effects in experimental itch studies16, 17, and is associated with delusions of parasitosis or related to also in patients with cholestatic itch18. It is remarkable obsessive-compulsive disorders (for example, neurotic that, in some patients with cholestatic itch, the reduction excoriations). Ideally, therapeutic approaches should be of itch by naloxone is accompanied by the induction of chosen according to a mechanism-based classification. pain19 and withdrawal-like reactions20 not seen in healthy However, as opposed to acute histamine-induced itch, controls, which suggests an upregulation of endogenous specific pruritic mediators and therapeutic targets for opioids in patients with cholestatic itch. Whereas the anti-