Imaging of central itch modulation in the human brain using positron emission tomography

Hogg

Experimental Dermatology

et al. 2017

Section: Central Mechanisms Of Itch Inhibitionmentioning

confidence: 98%

Functional magnetic resonance imaging in dermatology: The skin, the brain and the invisible

Hogg

Experimental Dermatology

et al. 2017

Journal of Clinical Investigation

“…The supraspinal processing of itch and its corresponding scratch response in humans have recently been investigated by functional PET (fPET) and functional MRI (fMRI). Here induction of itch by histamine application coactivates the anterior cingulate and insular cortex, premotor and supplementary motor areas, cerebellum, primary somatosensory cortex, and thalamus (40)(41)(42). As done earlier for pain sensation, particular aspects of the itch sensation have been correlated with the activation of certain brain areas: spatial and temporal aspects may be processed in the primary somatosensory cortex, planning of the scratch response in the premotor and supplementary motor cortices, and affective and motivational aspects in the anterior cingulate (38,43) and insular cortex ( Figure 2).…”

Section: Figurementioning

confidence: 99%

“…When the modulation of itch by painful cold stimuli was examined by fPET, the periaqueductal gray matter was activated only when painful and itching stimuli were applied simultaneously (42). This activation was combined with reduced activity in the anterior cingulate, dorsolateral prefrontal cortex, and parietal cortex.…”

Section: Figurementioning

confidence: 99%

Frontiers in pruritus research: scratching the brain for more effective itch therapy

Paus

Schmelz

Bı́ró

et al. 2006

329

287

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...

“…Itch is an unpleasant sensation that elicits the desire to scratch and, as with chronic pain, can be deleterious (1-5). Itch can be triggered by exogenous (e.g., allergens, toxins, medication, illegal drugs, microbes) or endogenous (e.g., amines, proteases, neuropeptides, cytokines, prostanoids) stimuli (4) that transmit signals via C fibers to the central nervous system (3,(6)(7)(8)(9)(10)(11)(12)(13). While the existence of itchselective C fibers in the sensory nervous system appears to be generally acknowledged (6,7), the neuronal regulatory circuits and the signaling pathways of itch in both the peripheral and central nervous systems, including potential endogenous antipruritic mechanisms, are still mostly unknown (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

et al. 2014

In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.