Prurito en dermatología. Generalidades y pruritógenos. Parte 1 / Pruritus in Dermatology: Part 1 — General Concepts and Pruritogens

El prurito es el síntoma más frecuente asociado a enfermedades dermatológicas y sistémicas. Su diagnóstico es clínico, aunque en ocasiones será necesario realizar pruebas complementarias para identificar o confirmar el origen. La medicina traslacional ha permitido descubrir nuevos mediadores pruritógenos y nuevos receptores. Saber reconocer adecuadamente la principal vía por la que media el prurito en cada paciente será clave para el éxito terapéutico. La vía histaminérgica predomina en enfermedades como la urticaria o las reacciones a fármacos, mientras que la vía no histaminérgica predomina prácticamente en la mayoría de las otras dermatosis incluidas en esta revisión. La clasificación del prurito, las pruebas complementarias, la fisiopatología y los pruritógenos implicados, incluyendo citoquinas y otras moléculas, así como la sensibilización central al prurito que sufren estos pacientes formarán parte de este primer manuscrito sobre el prurito (AU)

Pruritus is the most common symptom of dermatologic and systemic diseases. The diagnosis of pruritus is clinical, although additional tests may be necessary to identify or confirm the cause. Translational medicine has led to the discovery of new mediators of itch, or pruritogens, as well as new receptors. Knowing how to properly recognize the main pathway that mediates itch in each patient is the key to successful treatment. Although the histaminergic pathway predominates in conditions like urticaria or drug-induced pruritus, it is the nonhistaminergic pathway that predominates in nearly all other skin diseases covered in this review. Part 1 of this 2-part review discusses the classification of pruritus, additional testing, the pathophysiology of itch and the pruritogens implicated (including cytokines and other molecules), and central sensitization to itch (AU)

[Translated article] Pruritus in Dermatology: Part 1-General Concepts and Pruritogens / Prurito en dermatología. Generalidades y pruritógenos. Parte 1

Pruritus is the most common symptom of dermatologic and systemic diseases. The diagnosis of pruritus is clinical, although additional tests may be necessary to identify or confirm the cause. Translational medicine has led to the discovery of new mediators of itch, or pruritogens, as well as new receptors. Knowing how to properly recognize the main pathway that mediates itch in each patient is the key to successful treatment. Although the histaminergic pathway predominates in conditions like urticaria or drug-induced pruritus, it is the nonhistaminergic pathway that predominates in nearly all other skin diseases covered in this review. Part 1 of this 2-part review discusses the classification of pruritus, additional testing, the pathophysiology of itch and the pruritogens implicated (including cytokines and other molecules), and central sensitization to itch (AU)

El prurito es el síntoma más frecuente asociado a enfermedades dermatológicas y sistémicas. Su diagnóstico es clínico, aunque en ocasiones será necesario realizar pruebas complementarias para identificar o confirmar el origen. La medicina traslacional ha permitido descubrir nuevos mediadores pruritógenos y nuevos receptores. Saber reconocer adecuadamente la principal vía por la que media el prurito en cada paciente será clave para el éxito terapéutico. La vía histaminérgica predomina en enfermedades como la urticaria o las reacciones a fármacos, mientras que la vía no histaminérgica predomina prácticamente en la mayoría de las otras dermatosis incluidas en esta revisión. La clasificación del prurito, las pruebas complementarias, la fisiopatología y los pruritógenos implicados, incluyendo citoquinas y otras moléculas, así como la sensibilización central al prurito que sufren estos pacientes formarán parte de este primer manuscrito sobre el prurito (AU)

Distinct neural networks derived from galanin-containing nociceptors and neurotensin-expressing pruriceptors.

Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin (Gal) and one type of pruriceptors expressing neurotensin (Nts). The DRG microinjection and immunosuppression were performed in transgenic mice to achieve a successful tracing from specific types of DRG neurons to the primary sensory cortex. About one-third of nuclei in the brain were labeled. More than half of them were differentially labeled in two networks. For the ascending pathways, the spinothalamic tract was absent in the network derived from Nts-expressing pruriceptors, and the two networks shared the spinobulbar projections but occupied different subnuclei. As to the motor systems, more neurons in the primary motor cortex and red nucleus of the somatic motor system participated in the Gal-containing nociceptor-derived network, while more neurons in the nucleus of the solitary tract (NST) and the dorsal motor nucleus of vagus nerve (DMX) of the emotional motor system was found in the Nts-expressing pruriceptor-derived network. Functional validation of differentially labeled nuclei by c-Fos test and chemogenetic inhibition suggested the red nucleus in facilitating the response to noxious heat and the NST/DMX in regulating the histamine-induced scratching. Thus, we reveal the organization of neural networks in a DRG neuron type-dependent manner for processing pain and itch.

PIEZO1 transduces mechanical itch in mice.

Itch triggers scratching, a behavioural defence mechanism that aids in the removal of harmful irritants and parasites1. Chemical itch is triggered by many endogenous and exogenous cues, such as pro-inflammatory histamine, which is released during an allergic reaction1. Mechanical itch can be triggered by light sensations such as wool fibres or a crawling insect2. In contrast to chemical itch pathways, which have been extensively studied, the mechanisms that underlie the transduction of mechanical itch are largely unknown. Here we show that the mechanically activated ion channel PIEZO1 (ref. 3) is selectively expressed by itch-specific sensory neurons and is required for their mechanically activated currents. Loss of PIEZO1 function in peripheral neurons greatly reduces mechanically evoked scratching behaviours and both acute and chronic itch-evoked sensitization. Finally, mice expressing a gain-of-function Piezo1 allele4 exhibit enhanced mechanical itch behaviours. Our studies reveal the polymodal nature of itch sensory neurons and identify a role for PIEZO1 in the sensation of itch.

Medullary kappa-opioid receptor neurons inhibit pain and itch through a descending circuit.

In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla contains neurons that robustly inhibit nocioception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the rostral ventromedial medulla in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the rostral ventromedial medulla has never been achieved. We now expose a cellular circuit that inhibits nocioception and itch in mice. Through a combination of molecular, tracing and behavioural approaches, we found that rostral ventromedial medulla neurons containing the kappa-opioid receptor inhibit itch and nocioception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that rostral ventromedial medulla kappa-opioid receptor neurons inhibit nocioception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal grey that modulates nociception within the rostral ventromedial medulla. These discoveries highlight a distinct population of rostral ventromedial medulla neurons capable of broadly and robustly inhibiting itch and nocioception.

Circuit Mechanisms of Itch in the Brain.

Itch is an unpleasant somatic sensation with the desire to scratch, and it consists of sensory, affective, and motivational components. Acute itch serves as a critical protective mechanism because an itch-evoked scratching response will help to remove harmful substances invading the skin. Recently, exciting progress has been made in deciphering the mechanisms of itch at both the peripheral nervous system and the CNS levels. Key neuronal subtypes and circuits have been revealed for ascending transmission and the descending modulation of itch. In this review, we mainly summarize the current understanding of the central circuit mechanisms of itch in the brain.

Role of TRP ion channels in pruritus.

The transient receptor potential (TRP) channel superfamily responds to various physical, chemical, and environmental stimuli including the detection of sensations both harmful and non-harmful. Among these sensations is pruritus, or itch. There are at least 27 different TRP channels and about six of them are involved in pruriception. The function of these six receptors is primarily seen in the skin and the dorsal root ganglia. Identification and biological insights provided by these receptors in pruriception is important for human health as mutations and activations of many of these channels cause discomfort and disease. This review will focus on involvement of TRP channels in pruriception that may render these channels as the targets of many antagonistic topical medications, which may help patients' better cope with the pruritus that results from various cutaneous and systemic diseases.

A real-world study of the longitudinal course of itch severity and frequency in adults with atopic dermatitis.

Itch is a complex symptom that is both common and burdensome in atopic dermatitis (AD). Yet, little is known about the longitudinal course of itch in AD. A prospective, dermatology practice-based study was performed of adults with AD (n = 463). Patients were assessed at baseline and approximately 6, 12, 18 and 24 months. Itch was assessed using Numeric Rating Scale (NRS) average and worst-itch scores, and frequency of itch in the past week. Repeated-measures regression models were constructed to examine itch over time. Overall, 31.5% and 22.5% had moderate (4-6) or severe (7-10) NRS average-itch scores; 27.4% and 36.4% had moderate (4-6) or severe (7-10) NRS worst-itch scores; 12.7% and 62.0% had itch from eczema 3-4 and ≥ 5 days in the past week; 27.4% and 45.1% reported sometimes and often/almost always having itch, respectively. Among patients with baseline moderate (4-6) or severe (7-10) NRS average-itch scores, 21.2% and 16.3% continued to have moderate or severe scores at ≥ 1 follow-up visits. In repeated-measures regression models, persistent NRS average-itch scores were associated with baseline NRS average-itch [adjusted ß (95% CI): 0.75 (0.68, 0.82)] and food allergy [- 0.45 (- 0.84, - 0.07)]. Persistent NRS worst-itch was associated with baseline worst-itch NRS [0.73 (0.66, 0.80)] and Medicaid insurance [1.06 (0.17, 1.94)]. AD patients had a heterogeneous longitudinal course with fluctuating and complex overlapping patterns of average- and worst-itch intensity, and frequency.

BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk.

Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1. However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCß-Ca2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice.

An itch is a common sensation that makes us want to scratch. Most short-term itches are caused by histamine, a chemical that is released by immune cells following an infection or in response to an allergic reaction. Chronic itching, on the other hand, is not usually triggered by histamine, and is typically the result of neurological or skin disorders, such as atopic dermatitis. The sensation of itching is generated by signals that travel from the skin to nerve cells in the spinal cord. Studies in mice have shown that the neuropeptides responsible for delivering these signals differ depending on whether or not the itch involves histamine: GRPs (short for gastrin-releasing proteins) convey histamine-independent itches, while NMBs (short for neuromedin B) convey histamine-dependent itches. It has been proposed that another neuropeptide called BNP (short for B-type natriuretic peptide) is able to transmit both types of itch signals to the spinal cord. But it remains unclear how this signaling molecule is able to do this. To investigate, Meng, Liu, Liu, Liu et al. carried out a combination of behavioral, molecular and pharmacological experiments in mice and nerve cells cultured in a laboratory. The experiments showed that BNP alone cannot transmit the sensation of itching, but it can boost itching signals that are triggered by histamine. It is widely believed that BNP activates a receptor protein called NPRA. However, Meng et al. found that the BNP actually binds to another protein which alters the function of the receptor activated by NMBs. These findings suggest that BNP modulates rather than initiates histamine-dependent itching by enhancing the interaction between NMBs and their receptor. Understanding how itch signals travel from the skin to neurons in the spinal cord is crucial for designing new treatments for chronic itching. The work by Meng et al. suggests that treatments targeting NPRA, which was thought to be a key itch receptor, may not be effective against chronic itching, and that other drug targets need to be explored.

Spinal glial cells in itch modulation.

Glial cells are non-neuronal cells in the nervous system that are electrically non-excitable and outnumber neurons in humans. Glial cells have attracted attention in recent years for their active involvement in the regulation of neuronal activity, suggesting their contribution to the pathogenesis and progression of neurological diseases. Studies have shown that astrocytes, a type of glial cell, are activated in the spinal cord in response to skin inflammation and contribute to the exacerbation of chronic itch. This review summarizes the current knowledge about the role of astrocytes and other glial cells in the modulation of itch processing and the mechanism of their activation under itch conditions.

Multiplexed Representation of Itch and Mechanical and Thermal Sensation in the Primary Somatosensory Cortex.

The primary somatosensory cortex (S1) plays a critical role in processing multiple somatosensations, but the mechanism underlying the representation of different submodalities of somatosensation in S1 remains unclear. Using in vivo two-photon calcium imaging that simultaneously monitors hundreds of layer 2/3 pyramidal S1 neurons of awake male mice, we examined neuronal responses triggered by mechanical, thermal, or pruritic stimuli. We found that mechanical, thermal, and pruritic stimuli activated largely overlapping neuronal populations in the same somatotopic S1 subregion. Population decoding analysis revealed that the local neuronal population in S1 encoded sufficient information to distinguish different somatosensory submodalities. Although multimodal S1 neurons responding to multiple types of stimuli exhibited no spatial clustering, S1 neurons preferring mechanical and thermal stimuli tended to show local clustering. These findings demonstrated the coding scheme of different submodalities of somatosensation in S1, paving the way for a deeper understanding of the processing and integration of multimodal somatosensory information in the cortex.SIGNIFICANCE STATEMENT Cortical processing of somatosensory information is one of the most fundamental aspects in cognitive neuroscience. Previous studies mainly focused on mechanical sensory processing within the rodent whisking system, but mechanisms underlying the coding of multiple somatosensations remain largely unknown. In this study, we examined the representation of mechanical, thermal, and pruritic stimuli in S1 by in vivo two-photon calcium imaging of awake mice. We revealed a multiplexed representation for multiple somatosensory stimuli in S1 and demonstrated that the activity of a small population of S1 neurons is capable of decoding different somatosensory submodalities. Our results elucidate the coding mechanism for multiple somatosensations in S1 and provide new insights that improve the present understanding of how the brain processes multimodal sensory information.

What Do We Know about Pruritus in Very Young Infants? A Literature Review.

In infants, pruritus is frequently considered as absent because they do not scratch themselves. Because pruritus could induce severe adverse effects in this vulnerable population, we aimed to review existing evidence on the ability of young infants to experience itch and on how to assess itch-related discomfort in this population. A literature review was performed (Pubmed, Google Scholar). Neurological itch pathways are well described. Skin development starts early during gestation. At 34 weeks of gestation, skin is almost complete while skin adaptations occur after birth. Newborn skin is neurologically functional, including the ability for young infants to feel pain. Similarities and interactions between pain and pruritus support the hypothesis that infants could feel pruritus. However, the existence of pruritus in infants has never been evidenced. Many itchy conditions can affect them, suggesting non-negligible prevalence of infant pruritus among which atopic dermatitis (AD) is the most studied disease. Studies reported a negative impact of AD on children and their families. There is no existing validated method to assess pruritus in infants, although they may feel pruritus and chronic pruritus can lead to serious adverse effects. To appropriately diagnose pruritus appears of great interest among young infants. Development of a method is required to this aim.

Odevixibat: First Approval.

Odevixibat (Bylvay™) is a small molecule inhibitor of the ileal bile acid transporter being developed by Albireo Pharma, Inc. for the treatment of various cholestatic diseases, including progressive familial intrahepatic cholestasis (PFIC). In July 2021, odevixibat received its first approval in the EU for the treatment of PFIC in patients aged ≥ 6 months, followed shortly by its approval in the USA for the treatment of pruritus in patients aged ≥ 3 months with PFIC. Odevixibat is also in clinical development for the treatment of other cholestatic diseases, including Alagille syndrome and biliary atresia, in various countries. This article summarizes the milestones in the development of odevixibat leading to this first approval for PFIC.

Bullous Scabies: Clinical, Dermoscopic, and Pathologic Characteristics of Ten Patients.

Bullous scabies (BS) is a rare atypical clinical variant of scabies and is easily confused with bullous disorders. The diagnosis of BS is always a challenge, and physicians often misdiagnose BS patients. Patients with BS admitted from 2012 to 2020 were enrolled in this study. The clinical, dermoscopic, and pathological characteristics of the patients were analyzed retrospectively. Ten patients with BS were enrolled in this study. Seven of the 10 patients were male. The bullae were most commonly found on the thighs and arms (80% of patients). Only 30% of patients (3/10) tested positive for mites and/or eggs by the initial skin scraping, but 100% (5/5) of the patients who received dermoscopy tested positive. Among these 10 patients, only five received a skin biopsy. Subepidermal (4/5) and intraepidermal (1/5) bullae with eosinophil and neutrophil infiltration were observed in five patients. Direct immunofluorescence (DIF) indicated linear deposition of IgG in the basement membrane zone in three patients. Physicians should consider the possibility of BS in patients with blisters, pruritus, and poor response to corticosteroids. Dermoscopy should be prioritized for the differential diagnosis of BS to exclude other bullous disorders. Finally, a biopsy should be performed on each patient with bullae.

Dissecting the precise nature of itch-evoked scratching.

Itch is a discrete and irritating sensation tightly coupled to a drive to scratch. Acute scratching developed evolutionarily as an adaptive defense against skin irritants, pathogens, or parasites. In contrast, the itch-scratch cycle in chronic itch is harmful, inducing escalating itch and skin damage. Clinically and preclinically, scratching incidence is currently evaluated as a unidimensional motor parameter and believed to reflect itch severity. We propose that scratching, when appreciated as a complex, multidimensional motor behavior, will yield greater insight into the nature of itch and the organization of neural circuits driving repetitive motor patterns. We outline the limitations of standard measurements of scratching in rodent models and present new approaches to observe and quantify itch-evoked scratching. We argue that accurate quantitative measurements of scratching are critical for dissecting the molecular, cellular, and circuit mechanisms underlying itch and for preclinical development of therapeutic interventions for acute and chronic itch disorders.

Common and discrete mechanisms underlying chronic pain and itch: peripheral and central sensitization.

Normally, an obvious antagonism exists between pain and itch. In normal conditions, painful stimuli suppress itch sensation, whereas pain killers often generate itch. Although pain and itch are mediated by separate pathways under normal conditions, most chemicals are not highly specific to one sensation in chronic pathologic conditions. Notably, in patients with neuropathic pain, histamine primarily induces pain rather than itch, while in patients with atopic dermatitis, bradykinin triggers itch rather than pain. Accordingly, repetitive scratching even enhances itch sensation in chronic itch conditions. Physicians often prescribe pain relievers to patients with chronic itch, suggesting common mechanisms underlying chronic pain and itch, especially peripheral and central sensitization. Rather than separating itch and pain, studies should investigate chronic itch and pain including neuropathic and inflammatory conditions. Here, we reviewed chronic sensitization leading to chronic pain and itch at both peripheral and central levels. Studies investigating the connection between pain and itch facilitate the development of new therapeutics against both chronic dysesthesias based on the underlying pathophysiology.

The Implications of Pruritogens in the Pathogenesis of Atopic Dermatitis.

Atopic dermatitis (AD) is a prototypic inflammatory disease that presents with intense itching. The pathophysiology of AD is multifactorial, involving environmental factors, genetic susceptibility, skin barrier function, and immune responses. A recent understanding of pruritus transmission provides more information about the role of pruritogens in the pathogenesis of AD. There is evidence that pruritogens are not only responsible for eliciting pruritus, but also interact with immune cells and act as inflammatory mediators, which exacerbate the severity of AD. In this review, we discuss the interaction between pruritogens and inflammatory molecules and summarize the targeted therapies for AD.