Itching, Ionic Channels, Immune System, Magnesium and Antioxidants

Abstract

An itch, or pruritus, is a sensation that induces the need to scratch. Chronic pruritus, which is prevalent in 8–25% of the population, arises from diverse etiologies among which are several skin diseases. Itch originates from a complex interaction between the skin’s surface, chemical mediators, and the nervous system, driven by an overactive immune system. A comprehensive review of itching is hereby provided, covering its initial steps, mediators, relationship with the spine, ion channels, topical and systemic treatments, and the effects of magnesium and antioxidants. Ion channels present in keratinocytes, immune cells and sensory neurons play a critical role to preserve skin homeostasis. The dysregulation of ionic channels such as calcium, potassium, sodium, or chloride contributes to the production of inflammation, as well as skin barrier problems, and keratinocyte dysfunction that are key elements in the pathophysiology of itch. There is cross-talk between the three elements that intensify itching. Furthermore, the signals reaching the brain induce scratching, creating a vicious cycle between itching and scratching that further exacerbates itching. In this review, we have examined the important role of ion channels in itch. New medications and clinical trials based on ion channels as therapeutic targets are required to provide tools for the treatment of chronic itch. Magnesium efficiently inhibits itch by modulating voltage- and ligand-gated ion channels. Antioxidants prevent itch by blocking the unwarranted amount of reactive oxygen species (ROS) and dysregulating the innate immune signaling pathways. The strategy combining both magnesium and antioxidants constitutes an important advancement towards new approaches for the treatment of itching with very limited side effects. A number of clinical trials are needed to confirm the usefulness of ion channel-targeted antioxidant and anti-itch strategies to enhance the comprehensiveness and foresight of the conclusions.

Introduction

An itch, or pruritus, is an impression that induces the necessity to scratch. Itch has been classified, depending on its duration, as acute (lasting <6 weeks) or chronic (>6 weeks). In several studies in Europe, the incidence of chronic pruritus ranges from 8% to 25%.^1–4 In the United States, itch annually accounts for more than 7 million ambulatory consultations.⁵ Patients with chronic pruritus have diminished quality of life due to sleep problems,⁶ temperament disorders,¹ and a negative psychosocial impact.^7,8 Chronic itch is strongly associated with aging, especially in people older than 85 years.⁹ Itch in older patients may be associated with multiple factors. An important factor is the progressive loss of skin barrier function associated with aging.¹⁰ In addition, itch in the elderly may be produced by a general immuno-senescence described as a modification to a T helper cell type 2-mediated cytokine reply.¹¹ In relation to the cause of itch, sex variances exist. While itch in men is associated with comorbid systemic diseases,¹² in women it is more frequently associated with psychosomatic characteristics, neuropathic signals, and secondary scratch injuries.¹³ In addition, 18−20% of pregnant women suffer from pruritic disorders during pregnancy.¹⁴ Itch is not only associated with dermatological diseases; it is also a common symptom arising in the background of different systemic diseases, and neuropathic and psychogenic diseases. Furthermore, there is a genetic predisposition to itch.¹⁵ The International Forum for Study of Itch differentiates four clinical groups without considering their underlying pathophysiologic mechanisms.¹⁶ Group 1 (dermatologic itch), associated with skin diseases such as inflammatory, allergic, or infectious diseases and insect bites; Group 2 (systemic itch), associated with extracutaneous diseases such as from blood, kidney, liver, or other organs or drugs; Group 3 (neuropathic itch), secondary to neurologic diseases;¹⁷ and Group 4 (psychogenic itch), which is ascribed to psychiatric disorders.¹⁸ Also is common the pruritus of miscellaneous origin.¹⁹ The present review is focused on dermatitis-related itch (ie, Group 1), but does not exclude that many of the mechanisms described herein may also be present in the other types of itch. The molecular and cellular ways causing the itch feeling in the skin have been assessed, with special emphasis on the role of ion channels.

Emerging evidence highlights the direct role of Staphylococcus aureus in triggering itch in atopic dermatitis (AD). Beyond its well-known ability to exacerbate inflammation through superantigens and barrier disruption, S. aureus can directly activate pruriceptive sensory neurons, driving itch and scratch-induced skin injury. Recent findings demonstrate that the S. aureus serine protease V8 breaks proteinase-activated receptor 1 (PAR-1) on sensory neurons, leading to heightened pruritus. Notably, inhibition of PAR-1 significantly decreases itch and skin injury caused by S. aureus contact. Additionally, skin pH performs a critical role in controlling S. aureus colonization and epidermal barrier function.²⁰ The higher pH observed in AD promotes bacterial over-growth and alters epidermal protease activity, which in turn affects the processing of pruritogenic mediators.

The itching process is started by signals from the environment under a certain genetic background that affect specific areas of the skin, in a process involving the immune system. All these circumstances produce a series of signals that activate, through ion channels, the afferent nerve fibers in the spinal circuit and brain, thus relaying the feeling of itch and inducing scratching.

First Steps of Itch

Itching includes an interaction between genetic predilection, immune system dysfunction, and environmental triggers.¹⁹ The immune mechanisms in itching are comparable to those in normal skin but with highly augmented activation.²¹ In the beginning of itching, several mechanisms interact in the form of cross-talk, promoting each other. For example, keratinocytes release antimicrobial peptides, which activate plasmacytoid dendritic cells to secrete interferon-α, which in turn initiates both innate and adaptive immune responses²² (Figure 1).

Figure 1.

The itching begins with the arrival of pruritogens that interfere with the skin. When these substances reach the epidermis, they interact with the afferent nerve endings. Nerve activity drives immune system cells (CD4 T lymphocytes, mast cells, etc.) to release mediators such as cytokines, neuropeptides, etc, which activate sensory neurons. This produces a series of nerve impulses that travel first through the dorsal root and then up the spinal cord to the brain. There, the thalamus assists in the interpretation of the itching sensation.

The main job of the sensation of itch is the removal of environmental insults from the skin (eg, allergens, pruritogens or irritants), which is followed by the motor response of scratching.²³ This response damages the epidermal barrier, inducing several communications between the skin, the nervous system and the immune system that eventually result in the induction of itch and pain. Transmission of itch from the skin to the spinal cord requires multidirectional connections between the nervous and the immune systems.²³

Cutaneous nerve fibers called pruriceptors, which are either exogenous or endogenous, activate whichever the histaminergic or the non-histaminergic itch pathways.²⁴ The activators are produced by keratinocytes and immune cells such as granulocytes, mast cells, and T lymphocytes reaching the skin through blood. After activation of the skin nerves, the pruritus sign is at that time transmitted along neural pathways to the spinal cord and then to the brain, which answers by inducing scratching.²²

The nerve endings that initiate the sensation of pain are called nociceptors and are classified into three groups: Aβ, Aδ, and C. A synaptic contact with nociceptors has been found in keratinocytes.²⁵ Aβ are myelinated fibers, situated in the dermis, that act as mechanoreceptors focused in the stretch, hair movement or perception of pressure. In the epidermis, Aδ and C fibers are characterized into two biophysically different major afferent groups, unmyelinated C-fibers and lightly myelinated Aδ. C fibers are around 0.2–1.5 µm in diameter and have a transmission velocity of fewer than 2 m/s, while Aδ fibers are 2–5 µm in diameter and have a conduction speed of up to 8 m/s. These two types of fibers are thermoreceptors and nociceptors,²⁶ as well as efficient pruriceptors recognizing exogenous and endogenous pruritogens.

In the skin, cross-talk between nociceptors and keratinocytes results in increased inflammation and itching. The neurons secrete calcitonin gene-related peptide (CGRP) and neuropeptides such as substance P (SP)²⁷ that induce the proliferation of keratinocytes. In turn, these cells release neurotrophic components such as glial cell line–derived neurotrophic factor (GDNF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF),²⁸ and cytokines.²⁹ There are two groups of biochemical receptors participating in pruritus: the main and most frequent group is related to a G protein–coupled receptor (GPCR), and the other group is made by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway (ie, cytokine/chemokine receptors). Both receptors communicate the pruritogenic signal by activation of channels (see below). In sensory neurons, the activation of these channels induces an action potential, and then sends the pruritogenic signal primary to the spinal cord and afterward to the brain, producing the sensation of itching. In the dorsal root ganglia (DRG), reside the cell bodies of these nerves with axons that innervate the skin and dendrites that synapse in the dorsal horn of the spinal cord. There is a complex connection between these nerve fibers and the skin microenvironment, because nerve communication is controlled by skin pH, temperature, and pain. The binding of exogenous and endogenous pruritogens to their receptors induces the onset of itching in these sensory nerves.³⁰

Itch Mediators

Pruritus has intricate interactions amongst the immune and nervous systems. For pruritus there are two ways: histamine-dependent and histamine-independent. Caused by mast cell degranulation, histamine-dependent itching is typically related to allergic and urticaria responses. Interleukin (IL)-31 and proteases are involved in histamine-independent itching, associated with diseases like atopic dermatitis and chronic kidney disease.³¹ Itch begins when cutaneous receptors are activated. There are two types of receptors: those associated with the G protein (GPCRs) and those related to the transient receptor potential channels (TRP).

The connections between skin and nerve endings are produced by mediators. Histamine is mostly produced by mast cells and basophils,³² but sporadically by keratinocytes.³³ Itch-sensory nerve fibers near mast cells attach to a diversity of itch-inducing molecules or pruritogens through receptors that are also expressed in immune cells such as basophils, eosinophils, and mast cells³⁴ and keratinocytes.³⁵ Activation of histamine receptors induces the liberation of neuropeptides (mainly CGRP and SP) and the stimulation of neurogenic inflammation.³⁶ This is another example of cross-talk between nerve endings and keratinocytes.

Neuropeptides are based on short chains of amino acids, with several working as neurotransmitters. Neuropeptide signaling plays an important role in pruritus. The release of SP occurs mostly by dermal sensory nerve endings and other cells, including keratinocytes.³⁷ SP has a higher specificity for the neurokinin receptor NK1, which is present in multiple cells, including sensory nerve endings, keratinocytes, immune cells, endothelial cells, and fibroblasts. The binding of SP to the MrgprX2 receptor in mast cells induces degranulation and the liberation of histamine and tryptase.³⁸ In addition, some degranulation products induce the release of SP by sensory nerve endings, thus intensifying itch.³² In patients with AD, CGRP has been found to increase IL-13 production.³⁹ A neuropeptide called brain-derived natriuretic peptide (BNP), involved in pruritus, has recently been identified. BNP is expressed by pruriceptors, and higher BNP levels have been found in the skin of AD patients. The production and relief of BNP are induced by IL-31.⁴⁰ The neuropeptide Endothelin-1 (ET-1) is produced by the spinal cord and several cells, such as keratinocytes, sensory neurons, and endothelial cells. Expression of ET-1 is increased and is related to that of IL-25 in the skin of patients with AD. In keratinocytes there is another cross-talk, where IL-25 increases ET-1 expression and, in turn, ET-1 induces IL-25 expression⁴¹ (Figure 2).

Figure 2.

Three-way cross-talk between the skin, the nervous system and the immune system. Neuronal ion channels and protein-coupled receptors are activated by damaging stimuli and inflammatory mediators. This induces neuronal depolarization, increase excitability, and detach of neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and nerve growth factor (NGF). These neuropeptides control tissue cell functions and immune system, induce the synthesis of cytokines, degranulation of mast cells, and additionally catches immune cells, such as macrophages, dendritic cells, basophils, eosinophils, and T cells and keratinocytes. Neuronal cytokine receptors activate anti-inflammatory cytokines (IL-4, IL-13, IL-31), increasing neuronal excitability and discharge neuropeptides, making a feed‑forward loop for neuroinflammation. In addition, signals such as Ca²⁺ and pSTAT3 induce nerve activation that, by inducing itching, leads the patient to scratch, inducing another cross-talk. CGRP, calcitonin gene-related peptide; SP, substance P; and nerve growth factor (NGF).

Endogenous opioids constitute an exclusive family of neuropeptides, with the most important members being β-endorphin and dynorphin A. These compounds have opposite effects on pruritus: while the former promotes itch, the latter inhibits it.⁴²

Neurotrophins constitute a family of specialized proteins that act as growth factors to promote the development, survival, function, and plasticity of neurons. The main neurotrophins include Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF). NGF levels are increased in diseases associated with itch, such as psoriasis or AD.⁴³ In AD, BDNF levels are increased in serum and eosinophils.⁴⁴

Interleukins are a group of related proteins produced by hematopoietic cells, including eosinophils, basophils, T helper 2 (TH2) cells and mast cells, whose function is to regulate immune responses. In vitro studies using primary keratinocytes showed that IL-4 and IL-13 induces the reduction of the expression of proteins involved in the epidermal barrier.⁴⁵ The IL-4/IL-13 axis induces the fabrication of thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 in keratinocytes, thus contributing to the malicious encircle of neurogenic inflammation.⁴⁶ In AD, a strong correlation has been found between skin inflammation and IL-13 gene expression that is mediated by the IL-4Ra/IL-13Ra1 axis. Simultaneously, this axis induces negative feedback that downregulates extracellular IL-13.⁴⁷ IL-31 and IL-33 form an IL-31/IL-33 axis that interacts synergistically. Upon keratinocyte activation by allergens or pathogens, IL-33 is produced that initiates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and induces IL-31 gene expression, regulating the production of cytokines such as IL-31 and IL-17A, and inducing mast cell degranulation. IL-33 also enhances IL-4 expression and promotes IL-31 transcription.⁴⁸ Symptom severity has been associated with high serum and tissue levels of both cytokines, thus sustaining the biological importance of this axis.⁴⁹ IL-31 is a pruritogenic cytokine with a heterodimeric receptor, IL-31 receptor A (IL31RA)/oncostatin M receptor, that is expressed by keratinocytes, innate immune cells, eosinophils, T cells, and cutaneous nerve endings.⁵⁰ IL-31 contributes to the malicious circle of neurogenic inflammation through its effects on keratinocytes.⁵¹ IL-33 triggers skin barrier dysfunction by downregulating the expression of filaggrin, claudin-1, keratin 1, and keratin 10, thus contributing to neurogenic inflammation.⁵²

Thymic stromal lymphopoietin (TSLP) is a cytokine whose function is to drive TH2 immune responses, promoting dendritic cell, T cell, and mast cell activation. TSLP acts as an “alarmin” signaling.⁵³ TSLP is only present in pathological conditions such as the wounded skin of sick patients, in several cell types such as keratinocytes, epithelial cells, dendritic cells, mast cells, and fibroblasts.⁵⁴ Activation of TSLP induces the expression of pro-inflammatory cytokines such as IL-4, IL-5, and IL-13. In patients with AD, the severity of the disease (measured by SCORAD index) is correlated with the overexpression of TSLP.⁵⁵

Itch and Vertebral Spine

Once the afferent nerve fibers have been activated, communications are transmitted from the peripheral afferents to their cell bodies in the dorsal root or the trigeminal ganglia, and then to second-order neurons in the spinal cord. Then, in the interpretation of the messages that encode itch, the thalamus is assisted.⁵⁶ Itch can be caused by neural alterations, either through an increase in activation systems or a decrease in regulation systems.²³ Classically, the association between cutaneous regions and itch has been linked to the nerves that regulate regions known as dermatomal localizations, but larger regions may also be involved. Scalp dysesthesia has been associated with an itchy sensation of the scalp and can be caused by degenerative alterations at C2–C7.^57,58 Brachioradial pruritus is usually located in the proximal upper extremities and shoulders laterally to the C3–C7 dermatomes, and is frequently linked with deteriorating fluctuations in the cervical spine.^59,60 Notalgia paresthetica is localized in the area medial to the scapula on the mid-to-upper back, and it is related to the spinal nerves that ascend from T2-T6.^61,62 Finally, anogenital pruritus is related to degenerative modifications of the lower spine at L4-S2.⁶³ Recently, a good association has been found between the complete spinal biomechanical modifications and the state of the skin, measured using the Eczema Area and Severity (EASI) test, and the CGRP levels. The EASI values were associated with the different sections of the spine, ie, the cervical, the sagittal balance, the thoracic, and the lumbar spine.⁶⁴ The importance of the spinal biomechanical alterations in itching was demonstrated since the EASI levels of patients in the control group were reduced after using the compound cream for 2 weeks, but after 3 months they returned to original values and the dermatitis symptoms flared up again. In contrast, in patients given the chiropractic treatment both the EASI and the CGRP levels remained low after 3 months.⁶⁴ In conclusion, itch is strongly related to spinal biomechanical alterations.

Role of Ion Channels in Itch

Ion channels can be split into two distinctive groups: histamine-dependent and histamine-independent. Histamine-associated itch is primarily included in several patients with urticaria and drug reactions, and plays a minor role in patients with AD and other conditions. This restraint is due to the relative lack of effect of antihistamines on itch. This suggests that histamine-independent channels are the primary handler of itch in the periphery.²³

Ion channels were initially recognized for their function in thermos-sensation and nociception (information about noxious stimuli). However, these sensors have appeared as critical causes of itch. Ion channels are made of glycoproteins and are essential in the activity of all cells. They change chemical signals, temperature variations, and mechanical powers into calcium-mediated indicator transduction pathways. These channels conduct ions and can be selectively permeable to one or more of them.

Neuropeptides activate or modulate ion channels, primarily indirectly through metabotropic receptors, G-protein-coupled receptors (GPCRs). Unlike fast-acting classical neurotransmitters, neuropeptides modify the activity of calcium or potassium channels through slower signaling cascades, regulating neuronal excitability in the long term. The activation of histamine receptors leads to neuropeptide release (mostly CGRP and SP) from TRPV1 activation, membrane depolarization, and following stimulation of an action potential by voltage-gated ion channels producing neurogenic inflammation.³⁶

The activation of nerve fibers and skin cells such as keratinocytes and immune cells is mediated by ion channels. These channels control a number of processes, including apoptosis, differentiation, proliferation, and immune responses.²² Dysregulated channel activity has been found to lead to an uncontrolled calcium influx that triggers a cascade of signals that, in turn, reprograms the functional activity of crucial immune cells and controls pain and itch through neuroimmune cross-talk.⁶⁵ Ion channels are important elements in the pathophysiology of itch.⁶⁶ These channels have been related to processes such as immune-related inflammation, skin barrier alterations and keratinocyte malfunctions.⁶⁶ Ion channels also work as transducers and signal amplifiers on cutaneous sensory neurons, converting chemical, mechanical, or thermal stimuli into electrical signals (ie, action potentials) that travel to the brain to create the sensation of itch.

The ion channels primarily involved in itch are described herein. Precise ion channels have been identified to be related to psoriasis. Cation channels are critical for intracellular signaling, skin barrier function and immune cell activation. Calcium channels touch the activation of immune cells and keratinocyte differentiation.²² Potassium and chloride channels regulate processes that are altered in itching, such as ion homeostasis and cellular activation.^22,66 These ion channels, especially those in the Transient Receptor Potential (TRP) family, are triggered by various pruritogens (itch-inducing substances) and act as the final common pathway for transmitting itch signals, regardless of whether the pathway is histaminergic (histamine-dependent) or non-histaminergic.

The sensitization to pruritus is an interesting phenomenon. Unrelated to the initial cause, there is an augmented receptiveness of peripheral and central pruriceptive neurons to their afferent input in the framework of chronic itch.¹⁹

Histaminergic Channels

Calcium channels are critical for numerous cellular functions, including apoptosis, cellular proliferation and differentiation, as well as immune responses. They influence the activation of immune cells and keratinocyte differentiation.²²

TRP channels (Transient Receptor Potential channels) are a family of ion channels that control inflammatory reactions and cell growth.⁶⁶ The TRP family has been related to different features of itch pathogenesis, including keratinocyte spread to immune function. The most important channels in relation to itch are TRPA1, TRPV1 (Transient Receptor Potential Cation Channel Subfamily V Member 1), TRPV3, TRPV4, TRPM4 (Transient Receptor Potential Cation Channel Subfamily M Member 4) and TRPM8.⁶⁷ The involvement of TRP channels playing a central role in psoriatic pruritus has been demonstrated in recent studies. In murine models, blocking TRP channels such as TRPV1 and TRPA1 can improve pruritus and other self-protective actions without necessarily dropping inflammation.⁶⁸ In conclusion, TRP channels are important players in psoriasis pathogenesis, preserving skin homeostasis by managing Na⁺, Ca²⁺, and Mg²⁺, mainly through keratinocytes.⁶⁹ When the TRPV channel action is not regulated, the calcium flux becomes altered, inducing a cascade of signals that alter the functional activity of critical immune cells, modulating pain and itch signals through a neuroimmune crosstalk. Through these cascades, inflammatory responses become amplified, autoimmune conditions are increased, inflammatory cytokine release is enhanced, and pain/itch control signaling is meadiated via neuroimmune crosstalk.⁶⁵

TRPA1 is often co-expressed with TRPV1 and has been associated with both histaminergic and non-histaminergic itch. This channel is triggered by oxidative stress and environmental irritants.⁷⁰ TRPA1 is mainly expressed in sensory neurons, keratinocytes, neutrophils, vascular endothelial cells, and other inflammatory cells.⁷¹ It is upregulated in human psoriatic skin lesions, therefore indicating a potential role in the inflammatory process, and has emerged as a significant regulator of neurogenic inflammation.⁷¹ In summary, in keratinocytes TRPA1 stimulation plays an important task in regulating procedures connected to skin barrier function, differentiation, proliferation, and inflammation.

TRPV1 is preferentially expressed in keratinocytes and sensory neurons. The activation of TRPV1 results in an influx of calcium ions into cells, playing an essential role in moderating cellular differentiation, proliferation, and inflammation. In addition, calcium influx is necessary for various signaling pathways implicated in skin homeostasis, disease etiology and pathogenesis. TRPV1 releases pro-inflammatory cytokines, intensifying the inflammatory cascade.⁷² Nerve growth factor (NGF) induces stimulation of TRPV1 in psoriasis, releasing substance P, a neuropeptide implicated in neurogenic inflammation that induces neurogenic pruritus through a difficult neuro-immune feedback loop.⁷³ In preclinical models, inhibition of TRPV1 reduces inflammation and improves skin lesions.⁷⁴ In addition, in animal models of psoriatic conditions, TRPV1 plays an important role in preserving the regulation of epidermal proliferation and skin barrier function.⁷⁴ In conclusion, TRPV1 is involved in multiple aspects of itch pathogenesis such as skin barrier dysfunction, inflammation, and immune cell regulation.²²

TRPV3 is generally expressed in keratinocytes of the basal layer and on hair follicles, suggesting a role in epidermal and follicular functions that regulate cell differentiation, proliferation, and barrier formation.⁷⁵ TRPV3 can possibly contribute to several skin pathologies. Both mice and humans with gain-of-function mutations have severe itching, hyperkeratosis, augmented inflammatory cytokines in serum (IL-1α, IL-6, IL-17), elevated total IgE levels and high levels of TSLP. This lymphopoietin induces the activation of the IL-23/IL-17 axis, which is critical in the induction of psoriasis.⁷⁶ In addition, the stimulation of TRPV3 induces the secretion of ATP and prostaglandin E2 (PGE2), which directly activate C-fibers, inducing pain and itch sensations; this may explain the finding of persistent pruritus in patients with psoriasis.⁷⁶ In conclusion, TRPV3 is involved in inflammatory signaling, keratinocyte function, and itch sensation.

TRPV4 is highly expressed in keratinocytes. Skin samples from people with psoriasis show high TRPV4 expression.⁷⁷ This channel plays a critical role in reacting to mechanical and osmotic stress. In psoriasis, TRPV4 stimulates disease expansion by intensifying ATP release and neuropeptide excretion, and by activating the IL-23/Th17 pathway. In response to histaminergic pruritogens, keratinocytes depend on TRPV4 for calcium influx, inducing the phosphorylation of Extracellular Signal-Regulated Kinase (ERK).⁷⁸ In a psoriasis-like mouse model, TRPV4 knockout or pharmacological antagonism decreases immune cell infiltration, epidermal thickening, and skin inflammation.²¹

TRPM4 is a nonselective calcium-activated cation channel that regulates membrane potential and cellular signaling by linking intracellular calcium with transmembrane electrical signaling.⁷⁹ TRPM4 is expressed in macrophages, T cells, and keratinocytes. In psoriatic skin, when the TRPM4 channel is not regulated, it becomes associated with abnormal calcium signaling. This results in higher production of cytokines such as IL -17 and IL-22, which are needed for disease development. Additionally, TRPM4 controls the activation of T cells and their transfer to irritated skin, thereby increasing local inflammation.⁸⁰ In conclusion, TRPM4 affects various aspects of keratinocyte proliferation, immune cell function, and inflammatory signaling.

TRPM8 is triggered by cold and cooling composites such as menthol. In relation to psoriasis, TRPM8 has anti-inflammatory and anti-pruritic effects.⁸¹ In a mouse psoriasis model, thymol improved psoriasis-like skin lesions, reduced the heightened itch, and decreased the infiltration of dermal neutrophils, dendritic cells, and Th17 cells that are at the origin of psoriasis. Moreover, thymol overturned the increased expression of pro-inflammatory cytokines both in serum (TNF-α, IL-6, IL-1β, IL-17A, and IFN-γ) and in the skin (TNF-α, IL-22, IL-23, IL-17A, IL-17F, IL-17C, IL-6, IL-1β, and IFN-γ).⁸² These interesting results indicate that TRPM8 stimulation plays a main role in itching. In 30 patients with prurigo nodularis, treatment with a TRPM8 agonist (topical Cryosim-1) reduced itch significantly, ameliorated sleep disorder, and achieved higher patient satisfaction compared to placebo. Treated patients showed no adverse effects from Cryosim-1. In addition, TRPM8 agonists decreased skin and serum levels of cytokines, including IL-22, IL-1β, IL-6, IL-17, and IFN-γ.⁸³ The mechanism by which TRPM8 agonists inhibit itching seems to be multifaceted. The TRPM8 agonists block both histaminergic and non-histaminergic itch pathways. Furthermore, TRPM8 has been found to be specific, since the effect of agonists requires functional TRPM8 channels or integral TRPM8-expressing afferent neurons.⁸¹ This channel is another example of the existence of balances, some enhancing itching and others inhibiting it.

Piezo 1 and 2

Itch is a feeling in the skin that induces the need to scratch. Recently, our knowledge of the immune and nervous systems that produce the feeling of itching has increased enormously. It has recently been found that depending on the type of stimulus used to provoke the sensation of itching, the itch pathway used is different. In most cases, chemical intermediaries of itching, for example histamine, are inoculated in the skin, activating receptors of sensory neurons. In patients with chronic itching, light mechanical stimulation is used to induce itching. Using mouse models, research demonstrated that the neuronal trails used by chemical itch inductors and the ones that respond to mechanical stimulation are different. Different groups of sensitive neurons, spinal interneurons, and transmitting neurons were discovered in the two pathways, demonstrating that the itch transmission depends on the activators.⁸⁴ The procedure by which mechanical stimuli are transformed into electrochemical signs is called mechanotransduction, and it is critical for biological activities such as neuronal cell development, pain sensation, and red blood cell volume regulation. In 2010, Piezo1 and Piezo2 channels, a novel family of mechanically triggered cation channels in eukaryotes, were described.⁸⁵ Piezo1 is preferentially expressed in the dorsal root ganglion neurons co-expressing the Transient Receptor Potential Vanilloid 1 (TRPV1) nociceptor marker. In animal models of inflammatory pain, genetic elimination of Piezo1 diminished intermediately-adapting mechanically activated currents, and reduced tactile pain sensitivity. Knockdown Piezo1 also altered, below inflammatory stress, the excitability of the neurons expressing TRPV1. Therefore, Piezo1 emerges as a key mediator in the transmission of mechanical and inflammatory pain.⁸⁶ Recently, Piezo1 and Piezo2 were found to be present totally in the axon of a subpopulation of human digital Meissner corpuscles; these are specialized nerve endings in the skin that are accountable for detecting delicate touch and low-frequency vibrations.⁸⁷ Interestingly, Piezo1 plays key roles in bone mass control and mechanotransduction. Studies have emphasized Piezo2 as a supplementary companion of Piezo1 in the control and conservation of skeletal growth and homeostasis.⁸⁸ Remarkably, it has recently been described that the intensity of intrinsic dermatitis is connected to that of spinal biomechanical modifications.⁶⁴ In reply to powers generated by the tissue or externally to the cell, Piezo1, which is present in the plasma membrane, opens its cation-permeable porous to permit Ca2+ to arrive the cytosol. This Piezo1-mediated calcium influx directs various Ca²⁺-dependent downstream signaling pathways and administers housekeeping cellular procedures. Therefore, the cellular job of Piezo1 depends on two important items: its expression and setting on various cell types. Also Ca²⁺ depends on penetrability and the kinetics of inactivation that determine the largeness and period of the change of cytosolic Ca.²⁺⁸⁹ Mechanical energy is transmitted from the Piezo channels to the spinal interneurons and spinal projection cells, relaying this data to the brain.⁶⁴

Potassium Channels

Potassium (K⁺) is necessary for various biological processes, such as cell proliferation, apoptosis, and activation of the immune system. Its dysregulation has been linked to the pathogenesis of itching and psoriasis.⁹⁰ Potassium channels, particularly Kv1.3, show important functions in the regulation of itch and psoriasis by moderating ‑ cell function, keratinocyte behavior, and inflammatory processes.

Kv1.3, voltage-gated potassium channel, is expressed preferentially in stimulated T cells and is necessary for the immigration and stimulus of T cells, predominantly Th17 cells, which are important elements to psoriatic inflammation. In psoriatic lesions, expression of Kv1.3 is increased in effector memory T cells, helping to increase their activation and persistence in the skin.⁹¹ In vitro experiments in psoriatic lesions showed that the Kv1.3 inhibitor PAP-1 dose-dependently blocked IL-2 and IFN-γ production and suppressed T cell proliferation.⁹²

Chloride Channels

Chloride (Cl⁻) ion channels are implicated in preserving cell volume regulation, ion homeostasis, and signal transduction. These channels are present in several cell types, including immune cells and keratinocytes, and they participate in several physiological and pathological processes. The dysregulation of these channels can contribute to the characteristic features of itch and psoriasis, such as keratinocyte hyperproliferation, impaired barrier function, chronic inflammation and immune cell signaling.⁶⁶

Anoctamin 1 (ANO1/TMEM16A) is an important channel mediating nociception and itch. ANO1 is activated by intracellular Ca²⁺ and depolarization. It is highly expressed in smooth muscle, epithelial cells, interstitial cells of Cajal and sensory neurons (nociceptors). Nerve injury induces upregulation of ANO1 expression in Dorsal Root Ganglion (DRG) neurons.⁹³ In neuropathic pain models such as spinal nerve ligation, spinal nerve injury, and chronic contraction injury, ANO1 expression is increased with the development of pain.⁹⁴ ANO1 increase is associated with an increment of injury-related issues such as inducing transcription factor 3 (ATF-3), caspase-3, protease-activated receptor (PAR2), and neurokinin-1 receptors.⁹⁵ In animal models, ANO1 regulates cell proliferation and differentiation of keratinocytes.⁹⁶ Finally, ANO1 has been associated with the control of inflammatory responses in epithelial cells, implying that the lack of regulation could aggravate the inflammatory environment in psoriatic lesions.

Sodium Channels

Sodium (Na⁺) channels are critical controllers of action potential and excitability. They are essential for preserving cellular homeostasis and help signal transduction. In the skin, these channels influence in keratinocyte proliferation and differentiation, as well as the immune cell function. The alteration of sodium channels has been involved in the pathophysiology of psoriasis.⁹⁷

Nav Channels

Voltage-gated ion channels (VGIC) are a superfamily accountable for generating and transmitting action potentials. The foundational members of the VGIC superfamily are the voltage-gated sodium (Na_v) channels that in humans are divided into nine subtypes (Na_v1.1-Na_v1.9); each is specifically expressed in different tissues and cell types.⁹⁸ The structure of these channels comprises an α subunit with four homologous repeats I–IV, each with six transmembrane parts (S1-S6). Sections S1 to S4 fold to a voltage-sensing domain, whereas S5 and S6 enclose the pore domain through which sodium ions pass.⁹⁹ Interestingly, Na_v1.7, Na_v1.8, and Na_v1.9 are often called peripheral Nav channels because their expression occurs mainly in peripheral sensory neurons, such as the dorsal root ganglion neurons.¹⁰⁰ These channels relay sensory information from the periphery to the spine. Na_v1.8 is different from many other sodium channels for its unique activation and inactivation characteristics. In relation to other Na_v subtypes, activation happens at higher depolarized membrane potentials and has longer deactivation kinetics.¹⁰¹ These characteristics permit continued energetic activity even when other subtypes have become inactivated. The speed with which it recovers from inactivation allows for high-frequency repetitive firing. This gives it a mechanism that links hyperexcitability and pain.¹⁰² Salvatierra et al described a mutation in Na_V1.9 (heterozygous de novo p.L811P gain-of-function) associated with incapacitating itch and different pain perception.¹⁰³ Using mouse models, these authors found that Na_V1.9^–/– mice showed, in response to pruritogens, a significantly reduced scratching conduct, while Na_V1.9^L799P/WT mutation mainly increased itch. In KO mice of Na_V1.7, Na_V1.8 and Na_V1.9, Kremer et al demonstrated that beside the proposed general role of Na_V17 and Na_V1.9 in itch signaling, Na_V1.8 sustained prolonged itching.¹⁰³ Nav1.8 alter the redox balance by reducing superoxide dismutase 2 (SOD2) activity, thus preventing its deacetylation and mitochondrial localization, and thereafter inducing ROS deposition in keratinocytes.¹⁰⁴ In turn, elevated ROS levels activate pro-inflammatory signaling pathways, provoking the increase of inflammatory mediators such as IL-1β and IL-6.¹⁰⁴

Non-Histaminergic Channels

This group includes the channels involved in itching that are resistant to antihistamines. They also differ from histaminergic channels because there are mechanosensitive C-fibers responsive to cowhage (Mucuna pruriens), a plant known as a non-histaminergic pruritogen.¹⁰⁵ The active component of cowhage stimulates mas-related G protein-coupled receptors (Mrgprs). When injected into the skin, cowhage causes intense itching without triggering the histamine response typically associated with allergic reactions.

Mas-Related G-Protein-Coupled Receptor (GPCR) Member X2 (MRGPRX2)

The current attention on Mrgprx2 is due to its function in drug-induced hypersensitivity and its participation as a non-IgE receptor on mast cells.¹⁰⁶ This class A GPCR consists of 330 amino acids with a classic seven‑transmembrane α-helices structure.¹⁰¹ The extracellular N-terminal of MRGPRX2 is critical for ligand binding, while the intracellular C‑terminal interrelates with heterotrimeric G proteins.¹⁰⁷ The expression of MRGPRX2 is mostly on mast cells and dorsal root ganglia, but is also present on other cells such as basophils, eosinophils and keratinocytes.¹⁰⁷ Interestingly, MRGPRX2 has shown affinity for many ligands, either endogenous and exogenous, such as cortistatin‑14, substance P, pro-adrenomedullin N-terminal peptide 12, vasoactive peptide, human cathelicidins LL‑37, human β-defensins 2, cathepsin S and eosinophil cationic protein.¹⁰⁶ Therefore, this receptor can play an important role in different situations. These diverse ligands signal through Gαi and Gαq and β-arrestins pathways. These ligands induce mast cell degranulation through various pathways, rapidly releasing several stored bioactive mediators, such as histamine and tryptase. Later, de novo produced mediators such as prostaglandins and leukotrienes are liberated into the close milieu.¹⁰⁷ At the same time, a group of cytokines and interleukins are produced and released, contributing to the late phase and often continuing the chronic inflammatory response. Mast cell mediators have pro-inflammatory and immunomodulatory activity and are associated with several symptoms in chronic skin inflammatory conditions. Interestingly, MRGPRX2 mRNA induction is associated with itchy skin in patients with chronic spontaneous urticarial¹⁰⁸ and its activation produces an augmented skin reaction in such patients.¹⁰⁹ The suppression of MRGPRX2 by Celastrol (which reduces calcium ion influx) inhibits mast cell degranulation in atopic dermatitis.¹¹⁰ These data strongly support an association between MRGPRX2 and itching in humans.

Proteinase-Activated Receptors (PARs)

PARs are a subfamily of GPCRs with four members, PAR1-PAR4. They play important functions in thrombosis, wound healing, hemostasis, embryonic development, cancer progression, and inflammation.¹¹¹ PARs activation requires the cleavage of the extracellular domain by a protease. This mechanism allows the exposure of a new amino terminus and act as a ligand to activate PARs.¹¹² Activating and deactivating proteases control the PARs activity. The source of proteases can be from external sources such as fungi, mites, bacteria, cockroaches, and plants, or endogenous sources such as keratinocytes, mast cells, macrophages, dendritic cells, B cells, T cells, and neutrophils¹¹³ in the skin, the functions of PARs include skin barrier homeostasis, inflammation, as well as itch and pain.¹¹⁴

Between the four members of the PAR family, PAR2 has an important role in the skin inflammatory response, inducing Th2 inflammation, obstructing skin barrier reparation, and disturbing the keratinocytes differentiation. In dermatological diseases, inflammation is the greatest predominant pathological development and the role of PAR2 in inflammation is well recognized. PAR2 is crucial for controlling skin homeostasis, immune and inflammatory responses, and tumor surveillance. It also contributes to the spread of itch and pain feelings in the skin. PAR2 plays a critical function in the mechanisms that induce inflammatory skin diseases such as acne vulgaris, rosacea, psoriasis, and AD.¹¹⁵

PAR2 molecule is a transmembrane protein with 397 amino acids that is divided into an extracellular region (N-terminus and extracellular loops), a transmembrane region (seven transmembrane helices), and an intracellular (intracellular loops and C-terminus) region. PAR2 is expressed on several types of cells, including epithelial, smooth muscle, and endothelial cells.¹¹⁶ After PAR2 activation, the transduction signaling occurs across classical G proteins dependent pathway, activating phospholipase C (PLC) and producing diacylglycerol (DAG) and inositol triphosphate (IP3). It also activates the enrollment of Ca²⁺ and the stimulation of protein kinase C (PKC). Consequently, a frequent method to identify PAR2 stimulation is to quantify intracellular Ca²⁺ flux.¹¹⁷ The next step in this pathway is the phosphorylation of IKKα and IKKβ. This leads to the stimulation and movement of NF-ĸB to the nucleus. Activation of NF-κB and the inflammatory mediator intercellular adhesion molecule-1 (ICAM-1) could be a pro-inflammatory axis triggered by PAR2 signaling.¹¹⁶ On keratinocytes, activation of PAR2 induces the release of leukotriene B4 (LTB4), causing itch by the high-affinity receptor BLT1-expressing neurons.¹¹⁸ In addition, thymic stromal lymphopoietin is released; this pruritogenic cytokine activates TRPA1-expressing sensitive neurons.¹¹⁹ PAR2 is expressed on several cells, including eosinophils, monocytes, macrophages, dendritic cells, neutrophils, T cells and mast cells, in the dermis and in the granular layer of the epidermis.¹²⁰

Glutamate Receptors

In the CNS, glutamate is the main excitative neurotransmitter that binds to some receptors, such as the AMPA, NMDA, and kainate receptors, respectively called after the molecules that selectively bind to them. These receptors frequently work in complex networks in concert with each other. The N-methyl-D-aspartate (NMDA) receptor is mainly located in the CNS and is crucial in synaptic malleability and central felling of pain and itch. This receptor is additionally expressed in peripheral sensory neurons in the dermal–epidermal junction. Under inflammatory conditions, other cells of non-neuronal origin such as macrophages may also add to the local glutamate pool. The NMDA receptor plays a role as a ligand-gated channel permitting the passage of cations such as Na⁺, K⁺ and Ca.²⁺¹²¹

Itch Treatment

Given its prevalence, the treatment of itch is an important healthcare problem, and several therapeutic products are currently available.¹²²

Topical Treatments

Emollient creams hydrate, soften and soothe dry skin by forming a protective lipid film over the stratum corneum, which acts as a barrier to seal in moisture and reduce transepidermal water loss. These creams fill the gaps between skin cells with oils, improving skin barrier function and preventing the entry of irritants.¹²³

Corticosteroids act primarily by binding to intracellular glucocorticoid receptors, which then translocate to the nucleus to control gene expression (genomic mechanism) or directly alter cell signaling (non-genomic mechanism). Corticosteroids reduce inflammation by inhibiting pro-inflammatory cytokines and increasing anti-inflammatory proteins, while also inhibiting immune cell migration and function.¹²⁴

Calcineurin inhibitors such as tacrolimus and pimecrolimus block T cell activation by decreasing the production of IL-2.¹²⁵ These molecules have a very similar structure, although pimecrolimus penetrates the skin less than tacrolimus.

Janus Kinase (JAK) Inhibitors

The JAK-STAT pathway includes a family of four JAK kinases and seven Signal Transducer and Activator of Transcription (STATs). A signaling cascade starts after binding of a ligand to its receptor that triggers JAK activation. Receptor phosphorylation causes the formation of dimeric STATs that control the transcription of target genes. This pathway is present in many different cell types, including immune cells, keratinocytes, and peripheral sensory neurons, and it promotes both JAK and STAT activity in inflammation and itching. The JAK-STAT pathway is involved in the induction of IL-4, IL-5, IL-13, IL-22, IL-31, and TSLP, all of which contribute to the induction of itch. JAK inhibitors are among the most active systemic treatments for itch. However, these inhibitors are associated with a high frequency of adverse effects such as severe infections, important cardiovascular events, lymphoma, and thrombosis. Oral JAK inhibitors target different JAKs; the JAK1/2 is Ruxolitinib and there is a pan-JAK inhibitor (ie, one that inhibits all four JAK isoforms) with the name Delgocitinib. Topical JAK inhibitors have very positive effects on the skin, reducing the severity of skin rashes and decreasing itching.¹²⁶

Phosphodiesterase Inhibitors

In patients suffering from itch, elevated phosphodiesterase-4 (PDE4) activity has been detected in mononuclear cells. While preserving skin integrity, PDE4 inhibitors are anti-inflammatory drugs that control inflammatory responses. PDE4 inhibitors are an effective alternative for AD treatment because, contrary to corticosteroids, they help avoid skin atrophy and the subsequent decline of the epithelial barrier. Crisaborole is a boron-based benzoxaborole that binds to a single metal site, whereas Roflumilast acts with roughly 300–1000 times higher potency by deeply engaging PDE4’s catalytic metal, glutamine, and a water residue. By blocking phosphodiesterase, Roflumilast stops the failure of cAMP and diminishes overall inflammation.¹²⁷

Aryl hydrocarbon receptor (AhR) selective agonists decrease the expression of pro-inflammatory cytokines, including Tapinarof.¹²⁸

GABAergic drugs such as Gabapentin and Pregabalin are used in neuropathic pain and chronic itch conditions. These drugs reduce itch through the modulation of neurotransmitters by binding in the CNS to voltage-gated calcium channels. The blockage of these ion channels reduces calcium influx to nerve terminals and by this way excitatory neurotransmitters of itch such as glutamate and substance P were inhibited.¹²⁹ The use of gabapentin is associated with several infrequent side effects, fluctuating from neurological appearances such as myoclonus and ataxia to modifications of behavior including child violence and suicidal ideas. Furthermore, respiratory problems, questions connected to pregnancy, sleep troubles, and infrequent difficulties such as encephalopathy and myopathy have been reported.¹³⁰

Systemic Treatments

Phototherapy is an operative treatment for several kinds of pruritus. While the precise devices by which phototherapy decreases itch differ across pruritic circumstances, its effects may result from immune suppression and/or neural modulation.¹³¹ Also, nerve fiber density and nerve growth factor may decrease, as well as the activation of peripheral nerves. However, the availability of ultraviolet (UV) phototherapy is limited, as it requires two to three treatments per week during 10 to 14 weeks.¹³²

Monoclonal antibodies (mAb) have evolved rapidly over the last years, with the mAb market being conquered by entirely human molecules, introducing bispecific molecules, and entering into competition from biosimilars.¹³³ At present, mAb are intended to focus on specific immune pathways involved in disease pathogenesis. The Th2 response and its associated cytokines (IL-4, IL-13, and IL-31) contribute to the persistence of pruritus in AD. They disrupt skin barrier function, epidermal differentiation, and immune system regulation, while promoting an increased density of sensory nerve fibers and neurosensitization. Specifically, IL-31 is key in both acute and chronic pruritus. Treating inflammation and restoring the skin barrier is crucial for alleviating pruritus. Dupilumab inhibits binding to the IL-4Rα subunit, and therefore inhibits IL-4 and IL-13 signaling. This makes the subsequent reduction of the release of pro-inflammatory cytokines and chemokines, and the obstruction of the inflammatory response associated with TH2 cells.¹³⁴ Tralokinumab is an antibody with strong affinity to IL-13 that reduces inflammation because it avoids binding to specific receptors.¹³⁵ Lebrikizumab is a mAb with strong affinity and selectivity for soluble IL-13; by this way the development of the IL-4Rα–IL-13Rα1 heterodimer compound is prevented. Lebrikizumab does not inhibit IL-13 binding to IL-13Rα2 (a decoy receptor); therefore, IL-13 can be internalized. IL-13 is a crucial cytokine because serum levels are directly associated with itching severity.¹³⁶ Tralokinumab and lebrikizumab showed no important secondary effects, and both showed similar efficiency in moderate to severe AD. Nemolizumab is an anti-IL-31 receptor α-chain (IL-31RA) mAb with high effectiveness in reducing pruritus. Adverse effects include aggravation of AD, nasopharyngitis, upper respiratory tract infections, raised creatine kinase, peripheral edema and severe asthma aggravation.¹³⁷

JAK inhibitors block the cascade of signals between the binding of a cytokine to its receptor and the transcription of target genes implicated in inflammatory pathways.¹³⁸ These inhibitors are very active for itching associated with AD, but they carry a high risk of adverse effects. Upadacitinib and Abrocitinib are reversible and selective inhibitors of JAK1 and Baricitinib shows a high affinity for JAK1 and JAK2. Upadacitinib shows the maximum efficiency among the JAK inhibitors, but is the one with the maximum toxicity. The effectiveness of Abrocitinib is nearly similar to that of Upadacitinib, and it rapidly inhibits itching but also with very high toxicity. Despite inducing dual JAK1/JAK2 inhibition, Baricitinib has lower overall effectiveness compared to the other two inhibitors.

Kappa Opioids

There are two types of opioid receptors with opposing effects on itch production. On one hand, we have κ-opioid receptors (KORs) that inhibit itching, and on the other hand, μ-opioid receptors (MORs) that increase itch. These receptors react with different ligands. The inhibitory interneurons in the spinal cord Bhlhb5-positive release dynorphin that binds to KORs on the Gastrin-Releasing Peptide Receptor (GRPR)-positive neurons. This results in the suppression of chemical itch. Under chronic itch situations, differences in the equilibrium between MORs, which are activators of itch, and KORs, which are contrary inhibitors of itch, in the opioid system are linked to neural sensitization. One therapeutic approach to itching is the use of agonists of KOR through Nalfurafine and Difelikefalin. Another approach is to use a KOR agonist with a MOR antagonist such as the combination of Nalbuphine and Butorphano. The objective is to reduce itch feeling to the CNS by correcting the inequality.¹³⁹ However, side effects of KOR agonists consist of psychotomimesis, dysphoria, and sedation, and as a result of these effects, clinical trials have been interrupted.¹⁴⁰ These side effects delay the progress of KOR agonists for medical use, except Nalfurafine in Japan and Korea and, more recently, Difelikefalin in the United States.

Antimetabolites Methotrexate (MTX) is an antifolate metabolite that blocks nucleic acids as well as the synthesis of purine and exerts its effects by multiple mechanisms that suppress inflammatory and immune responses.¹⁴¹ MTX inhibits inflammation in immune cells through the control of cell-specific signaling pathways. This makes MTX a drug of choice for treating an extensive number of autoimmune and inflammatory diseases.¹⁴² Originated from 6-mercaptopurine, Azathioprine is a synthetic purine analog. Through the disruption of purine metabolism, it blocks nucleic acid synthesis, thus affecting cell reproduction, as well as the immune response by blocking the functional activity of T and B cells. This results in the reduction of inflammatory activities.¹⁴³ Cyclosporine, through its union with cyclophilin, inhibits calcineurin. This union forms a complex that blocks calcineurin activity, an enzyme that dephosphorylates NFAT, which regulates cytokine transcription and inhibits IL-2 expression. Cyclosporine has shown effectiveness in the treatment of itching. However, a large number of adverse effects have been reported, including increased susceptibility to infection, hypertension, headache, tremors, paresthesia, nephrotoxicity, gingival hyperplasia, hirsutism, hypertriglyceridemia, and gastrointestinal symptoms.¹⁴⁴ Mycophenolate mofetil (MMF) disrupts purine biosynthesis by obstructing inosine monophosphate dehydrogenase (IMPDH), an enzyme that converts inosine monophosphate to xanthosine monophosphate, a crucial stage in purine synthesis. This selectively inhibits B- and T‑cell proliferation because the de novo synthesis pathway to create guanosine nucleotides is blocked.¹⁴⁵ The greatest side effects are nausea, vomiting, and abdominal cramping. Long‑term treatment has been associated with an increased risk of herpes infections.

GABAergic Drugs

Gabapentin and Pregabalin are medications used for the treatment of neuropathic pain and several chronic itch disorders. In the cerebral cortex, γ-aminobutyric acid (GABA) is the major repressive neurotransmitter, preserving the repressive tone that counterbalances neuronal irritation. The disruption of this balance leads to the appearance of seizures. GABA is made in the terminals of GABAergic axons and released in the synapse. Here it acts on two receptors: GABAA, controlling chloride access into the cell, and GABAB, which have several roles, increasing potassium conductance, reducing calcium access, and blocking the presynaptic release of other transmitters. Gabapentin and Pregabalin reduce itch through the modulation of neurotransmitters, decreasing central neural sensitization. In the CNS, at nerve terminals, the drugs reduce calcium influx through inactivation of voltage-gated calcium channels. Similarly, these drugs intensify GABA inhibitory neurotransmission in the CNS. In addition, by increasing spinal cord GABA from primary afferent neurons, they reduce the release of SP and CGRP, which are important itch mediators.¹⁴⁶ The safety and efficacy of Gabapentinoids have been evaluated by pooling data from 50 studies with 12,398 participants. Most adverse events concerned the nervous system (7 effects) or psychiatric (3 effects) illnesses. With Pregabalin there were more unfavorable results than with Gabapentin.¹⁴⁷

NMDA Receptor Targets

Topical administration of the NMDA-receptor antagonist Ketamine has proven to be effective in chronic itch through reducing peripheral nerve sensitivity. In retrospective studies, after using topical ketamine in individuals with different pathological itches, 55–63% of patients had relief of itch.¹²¹ Only 0–16.7% of patients reported side effects, which frequently involved local reactions such as a burning feeling and redness. Intravenous or inhaled ketamine has central effects that differ from the topical formulation. Due to the multiple effects of NMDA acting in the CNS, it has been suggested that these ketamine preparations may decrease central itch neural sensitization by reducing neural plasticity; however, before making this conclusion, extra investigation is required in this area.¹⁴⁸

Topical Treatment with Magnesium for Itching

Magnesium is a mineral nutrient essential for human health and welfare. Magnesium is involved in several structural and metabolic functions, and it is also essential in electrophysiological functions. Magnesium ion (Mg²⁺) is an electrolyte that exists in all body fluids, particularly with intracellular distribution. In nerve cells, Mg²⁺ is distributed in many cellular structures such as the cell nucleus, cytoplasm, mitochondria, and endoplasmic reticulum (ER). Mitochondria store the highest concentration of Mg²⁺ in the cell because they function as the location of cellular respiration and also the place of major synthesis of adenosine triphosphate (ATP). In eukaryotic cells, because of the mitochondrial Mg²⁺ dynamics, there are specific Mg²⁺-sensitive channels that facilitate Mg²⁺ permeation through the inner mitochondrial membrane.¹⁴⁹ Other transporters and exchangers are relevant for maintaining cellular Mg²⁺ homeostasis¹⁵⁰ on the cell membrane and organelle membranes. Intracellular Mg²⁺ (Mg²⁺i) is key for cell energy metabolism by adjusting oxidative phosphorylation by Mg²⁺ in the mitochondrial matrix, resulting in the enhancement of mitochondrial ATP synthesis.¹⁵¹ Mg²⁺ ions are also necessary for neuronal health and activity. These ions are disseminated through the cell and cross various compartments. Magnesium is necessary for several nerve cell functions, such as cell cycle control, enzyme stimulation, protein synthesis, genome stabilization, control of biochemical and signaling pathways, energy metabolism, and variation of membrane ion transport mechanisms.¹⁵² The extra‑ or intracellular stimuli produce variations in cytosolic Mg²⁺ levels. From the cellular stocks or entering from the extracellular liquid, Mg²⁺i can be quickly rallied, acting as a signal transducer and cellular supervisor that controls the action of various target cell molecules.¹⁵³

Ion channels are membrane proteins that, depending on the channel, discern the movement of ions across the cell membrane. The action of these channels depends on ligand binding, voltage changes, or intracellular signaling molecules. In the presence of aqueous solutions as well as body fluids, Mg²⁺ ions exert a pull-on dipole of water molecules. Under this condition, as Mg²⁺(aq), they show a large ionic radius that binds to the ion-specific sites (such as Ca²⁺, K⁺, or Na⁺) of ion channels, inhibiting its passage through the ion channel. Because the pores of the ion channels are very narrow and the hydration double layer of Mg2+ (aq) is difficult to remove, it prevents the passage of Mg2+ ions through the ion channels. In this way, Mg2+ ions become a good inhibitor of activity in different ion channels. After the Mg2+ ions bind inside the channel pore, it turn out to be impossible for competing cations to remove them, completely blocking the channel and preventing the passage of other cations¹⁵⁴ (Figure 3).

Figure 3.

Inhibition of ion channels by magnesium. Ion channels are like “gates” in the cell membrane that permit the passage of ions (such as sodium, potassium, or calcium). Under physiological conditions, Ca²⁺ passes through the ion channel (Figure on the left). If there is a large amount of Mg²⁺ in the medium, it competes with Ca²⁺, inhibiting its passage through the ion channel (central figure). Furthermore, Mg²⁺ can bind two H²O molecules, forming a large particle that blocks the passage of Ca²⁺ through the ion channel (Figure on the right).

Another way of channel inhibition by Mg²⁺ is the competition with Ca²⁺i. This competition is more obvious in the presence of millimolar [Ca²⁺]i. Therefore, Mg²⁺ not only blocks channels by taking their high-affinity Ca²⁺-binding sites, but also by binding to low-affinity metal-binding ones¹⁵⁵ (Figure 3). Through other mechanisms, Mg2+ influences the function of ion channels. Mg2+ produces electrostatic exchanges with the pores or gated areas of the channel, allosteric variation of the channel’s configuration, or variations in surface charge that modify the recognition of the membrane potential.¹⁵² Magnesium has a critical function operating in physiological and pathophysiological circumstances; this interesting molecule becomes very attractive as a therapeutic instrument in basic science as well as in practical medicine.

The pathophysiology of pruritus begins with the excitation of cutaneous sensory neurons by pruritogens, mainly via activation of GPCRs expressed on peripheral nerve terminals. This induces an inflammatory reaction. During this process, large quantities of ROS are produced initially by neutrophils and subsequently by macrophages. ROS removes infectious agents, but it can also cause tissue damage and is part of the inflammatory spectrum.¹⁵⁶ In addition, some channels such as TRPV4 promote Ca²⁺ overload, amplify ROS production, impair antioxidant defenses, and trigger inflammatory signaling¹⁵⁷ when they become activated under ischemic stress. Finally, the immune system releases cytokines such as IL-4, IL-13, and IL-31, which can act as pruritogens. Skin inflammation damages the skin barrier, thus continuing a loop of pruritus and inflammation. By controlling inflammatory pathways, calming immune responses, and reinstating skin homeostasis, natural anti-pruritic agents break this loop.¹⁵⁸ For a long time, it has been recognized that plant extracts have beneficial effects as anti-oxidants on itch (Figure 4).

Figure 4.

Inhibition of ion channels by anti-oxidants. Activation of keratinocytes and immune cells produce ROS and cytokines that help Ca²+ to cross the ionic channel (Figure on the left). In the presence of anti-oxidants, inflammation and ROS are inhibited, and then the passage of Ca²⁺ through the ion channel is inhibited (Figure at the right).

In studies conducted on humans, magnesium has demonstrated its effect through its anti-inflammatory properties. The transdermal administration of magnesium oil ameliorates the quality of life of subjects with fibromyalgia by reducing pain, fatigue, depression, and sleep disorders.¹⁵⁹ The induction of magnesium wound healing was due to its antioxidant effects.¹⁶⁰ On the skin, magnesium acts as a ROS scavenger, increasing the number of fibroblasts, blood vessels and the amount of collagen.¹⁶¹ In the immune response, magnesium induces the polarization of macrophages, causing them to switch from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype.¹⁶² Also, it has been found that magnesium accelerates skin barrier recovery, a major objective in AD treatment.¹⁶³ Bathing in a magnesium-rich Dead Sea salt solution improves skin barrier function and hydration, and reduces inflammation in atopic dry skin.¹⁶⁴

Topical Treatment with Antioxidants for Itching

Flavonoids, such as Diosmin, Quercetin, and 6-methoxyflavanone, are compounds with antioxidant and anti-inflammatory properties. These compounds block free radicals and ROS, reduce oxidative stress, and in the periphery, they reduce pro-inflammatory cytokines and chemokines.¹⁶⁵ Additionally, in mouse model studies, flavonoids were described to block X2MRGPRX2 through activation of mast cells. MRGPRX2 shows a critical role in many chronic itch situations as well as in AD, urticaria, and chronic prurigo.¹⁶⁶ Altogether, by reducing oxidative stress and subsequent inflammation, they decrease peripheral and possibly central itch sensitization.

Resveratrol and curcumin are both current ordinary constituents normally used as dietary supplements.¹⁶⁷ Due to its anti-inflammatory, antioxidant, and neuroprotective effects, Resveratrol has been shown to improve neuropathic pain. Several reports describe that resveratrol controls pain pathways by impeding pro-inflammatory cytokines and controlling neuroinflammation. In animal models, resveratrol decreased pain sensitivity and ameliorated motor function, probably by cooperating with pathways such as NF-κB and nuclear factor erythroid 2-related factor 2 (Nrf2), which are intricate in inflammation and oxidative stress.^168,169 The effects of resveratrol on neuroinflammation and oxidative stress are probably critical in stopping neuronal injury and decreasing pain.

Curcumin is a polyphenol compound derived from traditional Chinese medicine. The active compound Curcuma longa (turmeric) is a well-documented anti-inflammatory, antioxidant, anti‑apoptotic agent with neuroprotective properties in in vitro and in vivo studies.^170,171 By blocking NLRP3 inflammasome activation, curcumin controls both central and peripheral inflammation, both elements are critical in itching.¹⁶⁹ Finally, by activating signaling pathways such as AMPK and sirtuins, curcumin similarly promotes neuronal survival.¹⁷² In both pharmacological assays and in vivo experiments, curcumin has been shown to be innocuous without secondary effects.^173,174

Papaya or Pawpaw (Carica papaya L.) is a plant from the Caricaceae family. The immature fruit is used for diuresis, as an aborticide agent, as a galactogogue, and as a mild laxative. Various parts of the plant are used in the treatment of several diseases. Uses of C. papaya that are technically authenticated comprise the wound‑healing effects of the leaves.¹⁷⁵ Using rats as an experimental model, the anti-inflammatory result of an ethanolic extract of Carica papaya leaves has been described. The extract decreased carrageenan-induced paw edema, and also persistent edema induced using the formaldehyde arthritis model.¹⁷⁶ In lipopolysaccharide (LPS)-stimulated human macrophages, the methanol extract of Papaya leaves decreased the secretion of pro-inflammatory cytokines such as IL -1α, IL-1β, IL-6, IL-8 and tumor necrosis factor (TNF)-α.¹⁷⁷ By using organic solvents, the ethyl acetate fraction of Papaya leaf juice presented the best anti-inflammatory activity. In a macrophage cell line activated with LPS, this preparation inhibited the expression of nitric oxide (NO) and pro-inflammatory enzymes, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), and cytokines (IL-1β and IL-6). The results also showed that its anti-inflammatory mechanisms were mediated by the MAPK signaling pathway.¹⁷⁸ In adults, papaya leaf ingestion for short-term use is commonly safe. However, it should be used with caution during pregnancy and in people with liver impairment.¹⁷⁹

Rosemary

Carnosic acid (CA), a Rosmarinus officinalis L. phenolic diterpene, has been shown to have antioxidative and anti-inflammatory properties.^180,181 In mice, the bioactive compound inhibited phorbol 12-myristate 13-acetate (PMA)-induced ear inflammation. In mouse skin, this compound decreased the expression of IL-1β and TNF-α and COX-2. In PMA-treated ears, histopathological examination revealed a decrease in leukocyte penetration and epidermal ulceration.¹⁸⁰ From keratinocytes activated with sodium lauryl sulfate and retinoic acid, CA obtained from new Rosemary leaves powerfully repressed the production of IL-6, IL-8, and MCP-1. In addition, from an activated macrophage cell line, CA inhibited the production of NO, TNF-α, and prostaglandin E 2 (PGE 2). CA also inhibited the nuclear translocation of nuclear factor (NF)-κB.^178,181 The only adverse reaction described was an increase in blood pressure in patients with primary hypotension.¹⁸² Therefore, in this population of patients, rosemary should be consumed with caution.

Ferulic acid is a natural compound with antipruritic effects. In Wistar rats, oral administration of Ferulic acid inhibited carrageenan‑induced edema, augmented dye escape made by acetic acid, and formation of granuloma made by cotton pellet.¹⁸³ In another study using mouse ear edema induced by tetradecanoylphorbol acetate (TPA), topical administration of Ferulic acid reduced inflammation by 71.02% compared to controls, thereby confirming its anti-inflammatory activity.¹⁸⁴ The antipruritic activity of Ferulic acid was measured in another study that assessed the incidence of scratching. Oral administration of Ferulic acid to mice 24 hours before challenge with a histamine-releasing agent injected subcutaneously to provoke scratching behavior resulted in a significant inhibition (to 25%) of scratching behavior compared to control levels.¹⁸⁵ At present, Ferulic acid is widely used in dermatology. Eighteen human studies have evaluated Ferulic acid in various cutaneous conditions, demonstrating effectiveness in improving skin erythema, pigmentation, hydration, elasticity, and texture. Ferulic acid was also effective both alone and in combination with other active ingredients in subjects with and without dermatologic diagnoses. In addition, consumption in adults is safe with no adverse effects.¹⁸⁶

Green tea beverages prepared from tea leaves are not just part of the rich cultural heritage but also provide health benefits. The main component is (−)-epigallocatechin gallate (EGCG), with an exclusive chemical structure and strong biological activities. Its specific stereo-chemical configuration allows it to interrelate with biological targets such as enzyme dynamic sites or cell membrane receptors to control cellular physiological works.¹⁸⁷ These features result in several biological actions (including antimicrobial effects, antioxidant and anti-inflammatory properties), and also improve gut microbiota. In mouse models of acute and chronic itch, behavior tests defined the effects of EGCG. Acute itch was induced by compound 48/80 and chloroquine; green tea polyphenon 60 or EGCG administered either local or systemic ameliorated the itch significantly. In vitro assays using a dorsal root ganglion-derived cell line showed that compound 48/80 induced intracellular ROS that was significantly reduced by adding EGCG. Using mice as an animal model, EGCG reduced imiquimod-provoked chronic psoriatic itch conduct and skin epidermal hyperplasia. These results demonstrated that EGCG is a promising approach for anti-itch therapy.¹⁸⁸ Using mice as an animal model, EGCG reduced L-arginine-induced acute pancreatitis and the consequent pulmonary injury. EGCG inhibited oxidative stress and eliminated NOD-like receptor protein 3 (NLRP3) inflammasome stimulation in the lung.¹⁸⁹ A systematic review and meta-analysis were performed to evaluate the efficiency and safety of Polyphenon E, a standardized, highly concentrated green tea leaf extract (Camellia sinensis) primarily containing catechins like EGCG, 15% and 10% in the treatment of warts. Concerning the primary result, both Polyphenon E 15% and 10% significantly increased the probability of complete elimination of the initial lesions and new verrucae related to controls. No substantial heterogeneity was detected. The most frequent local skin signs/symptoms were erythema and itching. Regarding safety and tolerability, local skin signs and symptoms were usually uncommon. Recurrence rates were very low.¹⁹⁰

Melatonin is a natural hormone made by the brain’s pineal gland in response to darkness that regulates the body’s sleep-wake cycle (circadian rhythm). Melatonin is also produced in the nerves and peripheral organs, as well as in human skin. It also has quite a lot of other properties, including control of immune and endocrine roles and antioxidant capacities such as scavenging free radicals and activation of antioxidant enzymes. Melatonin blocks tyrosinase activity and cell growth over inhibition of DNA synthesis.¹⁹¹ Melatonin may enhance wound healing using several mechanisms: (1) strong antioxidant activity, (2) anti-inflammatory activities, (3) infection regulator, (4) control of vascular reactivity and angiogenesis, (5) painkiller (pain-relieving) properties, and (6) anti-pruritic (anti-itch) results.¹⁹² In children with AD, melatonin reduced sleep‑onset latency and ameliorated disease severity with an important difference in SCORAD scores. No adverse events were reported, confirming its tolerability.¹⁹³ Compared with placebo, melatonin supplementation given to 40 adult patients with mild to moderate AD improved disease gravity based on body surface area (BSA) and SCORAD scores (p<0.001), as well as sleep quality, and quality of life, without any reported adverse effects.¹⁹⁴

Niacinamide (nicotinamide) is the water-soluble amide isotype of vitamin B3. Often given as a food supplement, it is now being used in the treatment of skin diseases. Since the body does not store niacinamide naturally, it has to be obtained from external sources. Niacinamide has anti-inflammatory, antioxidant, and antipruritic properties, and it is used in numerous dermatological products. Its effects are based on the inhibition of poly-ADP-ribose-polymerase (PARP)-1 and many molecules involved in the cell signaling cascade, including intercellular adhesion molecule-1, major histocompatibility complex II, IL-1, IL-12, TNF-α and macrophage migration inhibitory factor-1. In blistering disorders, the capacity of nicotinamide to block pro‑inflammatory cytokine pathways has been considered the primary mechanism for its beneficial effects.¹⁹⁵ The activity of Niacinamide in eliminating pruritus is thought to be complex and is due to numerous mechanisms. It can stabilize mast cells and thus reduce histamine release, improve the manufacture of cutaneous ceramides, deficits of which enhance dry skin and pruritus, and it inhibits the increased activity of T helper-1. Topical Nicotinamide has also been shown to be helpful in treating AD since it reduces transepidermal water loss (TEWL), probably through ceramide production.¹⁹⁶ A recent study, in patients with mild AD showed significant improvement using the Niacinamide body creams in relation to the clinical symptoms, the skin barrier function and the quality of life. No adverse reactions were detected at the end of the study.¹⁹⁷

Conclusion and Outlook

Itching involves at least a three-way relationship between the skin, the nervous system and the immune system. Throughout this review, the cross-talk between these different elements has been highlighted several times. For example, stimuli that activate ion channels in nerve endings induce the secretion of neuropeptides that activate eosinophils, mast cells, macrophages, etc, which in turn release inflammatory mediators, thus increasing the excitability potential in sensory neurons.¹⁹⁸ Neuropeptides contribute to neurogenic inflammation and further intensify the itch reaction. These neurotransmitters, in turn, act on inflammatory cells, generating a neuro-inflammatory cross-talk that promotes a positive feedback loop (itch–scratch cycle). Patients experience increased responses to minor pruritic stimuli, and the sensation persists even after the stimulus has disappeared. This sensation is known as neuro-sensitization and can happen at either the central or the peripheral levels. Furthermore, a brain reward system is activated through scratching, involving the dopaminergic system, which explains why scratching provides pleasure and reinforces the addictive itch–scratch cycle.¹⁹⁹ Chronic itch includes cross-talk among multiple cellular nets, such as the stromal, immune and sensory nervous systems. The cells of these groups can individually induce itch feeling, and their activation by recurrent scraping can produce a malicious itch–scratch cycle that is a trademark of chronic skin diseases and prurigo nodularis.¹⁶⁹ Of note, all the systems involved in itching induce mechanisms or release molecules that increase the severity of symptoms. There are no “brakes”, as occurs, for example, in the immune system, where under normal conditions there is a balance between activation and deactivation.²⁰⁰ Therefore, the objective of the treatment should be to eliminate the cross-talks, thereby breaking the self-stimulation dynamics.

In this review, emphasis has been placed on itching to analyze both the roles of ion channels and the immune system. Topical and systemic treatments of itch have been described. Perhaps the major difference between both types of treatments is the severity of side effects. For example, it is difficult to think that monoclonal antibodies that inhibit important molecules of the immune system would not weaken the patient against infections or other problems. However, natural products administered topically do not have harmful effects. This review has described how magnesium can block the ion channels causing itching and how antioxidants can block inflammation by inhibiting the production of ROS and the immune system. Recently, itching in patients with AD using topical mineral salts, including magnesium and antioxidants, has been described with spectacular results and no side effects.²⁰¹ These observations can potentially be the turning point in the treatment of itching. However, a greater number of clinical trials are needed to confirm the usefulness of ion channel-targeted antioxidant and anti-itch strategies to enhance the comprehensiveness and foresight of the conclusions. These trials should validate the use of these therapeutic tools in the various pathological conditions associated with itching, as well as in different geographical or genetic areas.

Funding Statement

There is no funding to report.

Abbreviations

AD, atopic dermatitis; AhR, Aryl hydrocarbon receptor; ANO1/TMEM16A, Anoctamin 1; ATF-3, activating transcription factor 3; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; BNP, brain-derived natriuretic peptide; CA, Carnosic acid; CGRP, calcitonin gene-related peptide; DAG, diacylglycerol; DRG, Dorsal Root Ganglion; ER, endoplasmic reticulum; ERK, Extracellular Signal-Regulated Kinase; ET-1, Endothelin-1; GABA, Gamma-aminobutyric acid; GDNF, glial cell line–derived neurotrophic factor; GPCR, G protein–coupled receptor; GRPR, Gastrin-Releasing Peptide Receptor; ICAM-1, intercellular adhesion molecule-1; IFN-γ, interferon γ; IL-, interleukin-; IMPDH, inosine monophosphate dehydrogenase; IP3, inositol triphosphate; JAK, Janus kinase; KORs, κ-opioid receptors; LTB4, leukotriene B4; mAb, Monoclonal antibodies; MMF, Mycophenolate mofetil; MORs, μ-opioid receptors; MRGPCR, Mas-related G-protein-coupled receptor; MRGPRX2, Mas-related G‑protein-coupled receptor member X2; MTX, Methotrexate; Na_v, voltage-gated sodium; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; Nrf2, Nuclear factor erythroid 2-related factor 2; PAR-1, proteinase-activated receptor 1; PAR-2, proteinase-activated receptor 2, caspase-3; PARP, poly-ADP-ribose-polymerase; PDE4, phosphodiesterase-4; PGE2, prostaglandin E2; PLC, phospholipase C; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; SP, substance P; STAT, signal transducer and activator of transcription; TH2, T helper 2; TNF-α, Tumor Necrosis Factor-α; TPA, tetradecanoylphorbol acetate; TRP, transient receptor potential channels; TRPV1, Transient Receptor Potential Cation Channel Subfamily V Member 1; TRPM4, Transient Receptor Potential Cation Channel Subfamily M Member 4; TRPV1, Transient Receptor Potential Vanilloid 1; TSLP, thymic stromal lymphopoietin; UV, ultraviolet.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work.

Disclosure

Dr. Ignacio Umbert is the owner of the patent number EP4335431B1. The authors report no other conflicts of interest in this work.