Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus

Pruritus (itch) can be defined as an unpleasant cutaneous sensation associated with the immediate desire to scratch. Recent findings have identified potential classes of endogenous "itch mediators" and establish a modern concept for the pathophysiology of pruritus. First, there in no universal peripheral itch mediator, but disease-specific sets of involved mediators. Second, numerous mediators of skin cells can activate and sensitize pruritic nerve endings, and even modulate their growth. Our knowledge of itch processing in the spinal cord and the involved centers in the central nervous system is rapidly growing. This review summarizes the current information about the significance of neuron-skin interactions, ion channels, neuropeptides, proteases, cannabinoids, opioids, kinins, cytokines, biogenic amines, neurotransmitters, and their receptors in the pathobiology of pruritus. A deeper understanding of these circuits is required for the development of novel antipruritic strategies.     

Pathophysiology of pruritus in atopic dermatitis: an overview

Pruritus is an essential feature of atopic dermatitis (AD) and the diagnosis of active AD cannot be made without the history of itching. Because of the high impact on life quality, most of the patients measure the severity of eczema by the intensity of pruritus rather than appearance of skin lesions. However, although pruritus is a cardinal symptom of AD, its mechanism and association with the cutaneous nervous system is not completely understood. Recently, a considerable progress has been achieved in clarifying the complex pathophysiology of pruritus in AD. As a cutaneous sensory perception, itch requires excitation of neuropeptide-containing free nerve endings of unmyelinated nociceptor fibers. It is well known that histamine and acetylcholine provoke itch by direct binding to 'itch receptors' and several mediators such as neuropeptides, proteases or cytokines indirectly via histamine release. Interestingly, some variations of these complex mechanisms could be demonstrated in patients with AD. This review highlights the recent knowledge of different mechanisms which may be involved in regulating pruritus in patients with AD potentially leading to new therapeutic applications for the treatment of itch in AD.     

Itch associated with skin disease: advances in pathophysiology and emerging therapies

Itch, also known as pruritus, is the major symptom in skin diseases with a variety of etiologies and pathophysiologies. Significant progress has been achieved in understanding the pathophysiology of itch in the last 5 years. Neurophysiological experiments in humans and animals have revealed that itch is carried by specific C nerve fibers. Recent studies have demonstrated that peripheral mediators other than histamine are involved in induction of itch. Mast cell tryptase seems to be an important mediator in itch by its activation of proteinase activated receptor 2 in the sensory nerves. Opioids have central and peripheral itch producing activity. Neuropeptides, such as substance P, induce itch by their effect on mast cells. Based upon our improved understanding of the neurophysiology of itch a clinical classification of itch has been proposed. The classification highlights differences between peripheral pruritoceptive itch, neuropathic itch (itch related to damage to afferent nerve fibers) and neurogenic itch (itch originating in the central nervous system without any evidence of nerve damage). Emerging therapies based on these findings include topical vanilloid receptor antagonists, topical antihistamines, and topical arachidonic acid inhibitors, as well as inhibitors of non-histamine inflammatory mediators, immunomodulators and strontium salts. Systemic therapies include thalidomide, opioid antagonists, phototherapy with narrow band UVB and experimental treatments with cutaneous field stimulation and vagal nerve stimulation. With the new information it seems we will be able to better help our dermatologic patients who have itch, however we are not closer to identifying a single agent specifically targetable to this symptom.     

皮肤源性瘙痒发生机制的研究进展

瘙痒是皮肤疾病中最常见的症状,但其发生机制尚未完全明确.目前认为存在独立的痒觉神经传导通路,主要由外周无髓C纤维传人信号至脊髓背侧角的最浅层,Lamina Ⅰ脊髓丘脑束上行至丘脑,进一步投射至皮质区.皮肤源性瘙痒与多种瘙痒介质密切相关,除组胺以外,乙酰胆碱、蛋白酶、P物质、前列腺素、细胞因子等多种介质及其受体参与瘙痒的发生.就瘙痒的临床分型、痒觉神经传导通路、瘙痒介质等进行综述.     

Causes,pathophysiology, and treatment of pruritus in the mature patient

Chronic itch is a common and debilitating health condition in the elderly. There are several common causes of itch in the mature population, such as skin xerosis, immunosenescence, and neuropathic changes. In addition, skin diseases, such as seborrheic dermatitis and stasis dermatitis, systemic conditions (end-stage renal disease and diabetes), or psychogenic derailments, such as depression, anxiety, and dementia, can all serve as triggers of pruritus. Polypharmacy, a common occurrence among the elderly population, may also serve as a cause of itch that may or may not be accompanied by dermatitis. Such medications as μ opioids and calcium channel blockers have been found to have a connection with pruritus in the advanced aging population.Determining the exact trigger for pruritus in the elderly may be especially challenging, because itch can be idiopathic in many cases. The role of treatments should not only take into account elimination of various underlying cutaneous, systemic, or psychogenic conditions associated with itch but also focus on the skin changes that are characteristic of the aging process. Development of such treatment options can be guided by elucidation of the mechanisms underlying the pathophysiology of itch in the geriatric population.     

New insights into the mechanisms behind mechanical itch

Gentle tactile stimuli, such as insects crawling on the skin, can cause itching sensation called mechanical itch. Recent studies have begun to shed light on the neural mechanisms of mechanical itch. Interestingly, the neural pathway for mechanical itch is apparently different from that for chemical itch triggered by the activation of pruriceptors with various mediators. Mechanical itch dysesthesia is frequently seen in patients with chronic itch. Mechanisms of this dysesthesia are plausibly involved in central sensitization. In this review, we summarize the current knowledge of mechanical itch under normal and pathological conditions.     

Itch in atopic dermatitis - pathophysiology and treatment

Pruritus is an essential feature of atopic dermatitis with a high impact on the quality of life. Although the pathophysiology of atopic dermatitis itch is not fully understood, recent studies have demonstrated that a variety of mechanisms contribute to the induction and maintenance of the symptom. For example, an increased number of cutaneous nerve fibers and neuropeptides were identified in atopic dermatitis skin. Histamine and histamine 4 receptor as well as interleukin 31 are novel key players identified in itch induction, in addition to inflammatory cells such as mast cells, eosinophils and lymphocytes. The new findings suggest that target-specific therapies are most likely to control atopic dermatitis itch. To date, only few therapies are available and controlled studies are pending.     

Chronic Pruritus in the Absence of Specific Skin Disease

Chronic pruritus is a major and distressing symptom of many cutaneous and systemic diseases and can significantly impair the patient’s quality of life. Pruritus perception is the final result of a complex network involving dedicated nerve pathways and brain areas, and an increasing number of peripheral and central mediators are thought to be involved. Itch is associated with most cutaneous disorders and, in these circumstances, its management overlaps with that of the skin disease. Itch can also occur without associated skin diseases or primary skin lesions, but only with nonspecific lesions secondary to rubbing or scratching. Chronic itch with no or minimal skin changes can be secondary to important diseases, such as neurologic disorders, chronic renal failure, cholestasis, systemic infections, malignancies, and endocrine disorders, and may also result from exposure to some drugs. The search for the cause of pruritus usually requires a meticulous step-by-step assessment involving careful history taking as well as clinical examination and laboratory investigations. Few evidence-based treatments for pruritus are available. Topical therapy, oral histamine H1 receptor antagonists, and phototherapy with UV radiation can target pruritus elicitation in the skin, whereas antiepileptic drugs, opioid receptor antagonists, and antidepressants can block signal processing in the CNS.     

瘙痒介质及其受体的研究进展

瘙痒的产生是一个复杂的多因素作用的结果,其具体机制尚不完全清楚.研究已证实,瘙痒具有特异的神经传导通路,多种内源性物质与瘙痒的发病密切相关.近年来的研究表明,组胺4型受体、蛋白酶活化受体-2、白介素-31受体、神经激肽受体-1在皮肤无髓C神经纤维的表达可能介导瘙痒的发生,而神经营养素和神经生长因子及其受体则可能作为一种瘙痒敏感剂,促进瘙痒的形成与发展.这些化学介质及其受体在瘙痒发生的病理生理机制中并不是孤立地起作用,而是与神经细胞、免疫细胞及皮肤细胞紧密联系.     

Inflammatory mediators causing cutaneous chronic itch in some diseases via transient receptor potential channel subfamily V member 1 and subfamily A member 1

Chronic itch with an itch–scratch vicious circle is a significant problem in a large amount of diseases. Some of these diseases, such as psoriasis, atopic dermatitis, prurigo nodularis, Sézary syndrome, uremic pruritus, diabetes and jaundice, are common. For a very long time, chronic itch has been a thorny problem with few effective treatments. Because of this, itch researchers and dermatologists seek to find the mechanisms among chronic itch, inflammatory cytokines and neurons. As an immediate area of research focus, we are going to find the peripheral cross‐talk between neurons and skin cells. Two receptors, named transient receptor potential channel vanilloid 1 and transient receptor potential channel ankyrin transmembrane protein 1, have been shown to play important roles in chronic itch. Many advances have been made so far this decade. This review talks about the updated mechanism of itch‐related inflammatory cytokines via transient receptor potential channels in cutaneous chronic itch and corresponding diseases. The search for itch‐related inflammatory mediators and the structure of transient receptor potential channels this decade could deepen our understanding of the mechanism of itch and help us find more treatments of chronic itch in the future.     

Histaminergic nerves demonstrated in the skin. A new direct mode of neurogenic inflammation?

Abstract An intradermal administration of histamine into human skin results in a local erythema, edema and often also the sensations of itch and/or pain. These effects have classically been attributed to the presence of histamine-containing mast cells. However, in the present investigation, we report the observation of histamine-immunoreactive nerves in the skin of Sprague-Dawley rats using a new and highly sensitive immunohistochemical approach. These data suggest a more direct route of cutaneous histamine effects, mediated exclusively by the peripheral nervous system. The findings could also give a new basis for explaining histamine-related issues, such as itch.     

Modern aspects of cutaneous neurogenic inflammation

Recent findings have shed new light on the role of peripheral nerves in the skin and established a modern concept of cutaneous neurobiology. Closely related monodirectional and/or bidirectional pathways exist in which the central and peripheral nervous system, the endocrine and immune system, and almost all skin cells are involved. Information is emerging about the factors involved in these immunomodulatory mechanisms, which are defined as neuropeptides, neurotransmitters, neurotrophins, and neurohormones. The interaction between peripheral nerves and the immune system is mediated by different types of cutaneous nerve fibers that release neuromediators and activate specific receptors on target cells in the skin such as keratinocytes, mast cells, Langerhans cells, microvascular endothelial cells, fibroblasts, and infiltrating immune cells. These interactions influence a variety of physiologic and pathophysiologic functions including cellular development, growth, differentiation, immunity, vasoregulation, leukocyte recruitment, pruritus, and wound healing. A variety of mechanisms lead to the termination of cellular responses to released neuropeptides under physiologic circumstances. Herein, we highlight some of the recent advances of neurocutaneous biology and discuss the role of nerves in mediating cutaneous inflammation. Understanding the mechanisms and the factors controlling neuromediators and their receptors and degrading enzymes will lead to the identification of novel therapeutic targets for the treatment of cutaneous diseases.     

Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems

Abstract: The interaction between components of the nervous system and multiple target cells in the cutaneous immune system has been receiving increasing attention. It has been observed that certain skin diseases such as psoriasis and atopic dermatitis have a neurogenic component. Neuropeptides released by sensory nerves that innervate the skin and often contact epidermal and dermal cells can directly modulate functions of keratinocytes, Langerhans cells (LC), mast cells, dermal microvascular endothelial cells and infiltrating immune cells. Among these neuropeptides the tachykinins substance P (SP) and neurokinin A (NKA), calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP) and somato statin (SOM) have been reported to effectively modulate skin and immune cell functions such as cell proliferation, cytokine production or antigen presentation under physiological or pathophysiological conditions. Expression and regulation of their corresponding receptors that are expressed on a variety of skin cells as well as the presence of neuropeptidespecific peptidases such as neutral endopeptidase (NEP) or angiotensinconverting enzyme (ACE) determine the final biological response mediated by these peptides on the target cell or tissue. Likewise, skin cells like keratinocytes or fibroblasts are a source for neurotrophins such as nerve growth factor that are required not only for survival and regeneration of sensory neurons but also to control responsiveness of these neurons to external stimuli. Therefore, neuropeptides, neuropeptide receptors, neuropeptidedegrading enzymes and neurotrophins participate in a complex, interdependent network of mediators that modulate skin inflammation, wound healing and the skin immune system. This review will focus on recent studies demonstrating the role of tachykinins, CGRP, SOM and VIP and their receptors and neuropeptide-degrading enzymes in mediating neurogenic inflammation in the skin.     

Thromboxane A2 induces itch-associated responses through TP receptors in the skin in mice

Thromboxane A2 (TXA2), a metabolite of arachidonic acid produced by cyclooxygenase and thromboxane synthase, is thought to participate in chronic dermatitis. This study investigated the involvement of TXA2 in cutaneous itch. An intradermal injection of U-46619, a stable analogue of TXA2, elicited scratching, an itch-associated response, in mice. Dose-response curve was bell shaped with a maximum effect at 10 nmol per site. The action of U-46619 was inhibited by a coinjection of the TP antagonist ONO-3708 and was abolished by TP receptor deficiency. TP receptor was mainly expressed in nerve fiber in the skin and keratinocytes. Thromboxane synthase was also expressed in keratinocytes. U-46619 increased intracellular Ca2+ ion concentration in primary cultures of dorsal root ganglion neurons and keratinocytes. The results suggest that TXA2 synthesized by keratinocytes acts as an itch mediator. It may elicit itch through the activation of TP receptors on primary afferents and keratinocytes; keratinocytes may produce itch mediators including TXA2. Thus, thromboxane synthase inhibitor and TP receptor antagonists will be candidates for antipruritic medicines.     

Neuropeptides: role in inflammatory skin diseases

The cutaneous nervous system recently has been demonstrated to interact with multiple target cells in the skin and to mediate actions important in inflammatory conditions. Neuropeptides released by cutaneous neurons such as substance P (SP), vasointenstinal peptide (VIP), calcitonine gene regulated peptide (CGRP), proopiomelancortin (POMC) peptides and others modulate the function of immunocompetent and inflammatory cells as well as epithelial and endothelial cells. They have been found to function as mediators of cell proliferation, cytokine and growth factor production as well as adhesion molecule and cell surface receptor expression. In addition many cells including keratinocytes, fibroblasts, endothelial cells and inflammatory cells have been shown to release several neuropeptides and they express their corresponding receptors. These findings indicate that neuropeptides participate in the complex network of mediators that regulate cutaneous inflammation, hyperproliferation and wound healing.     

Renal itch

Renal itch is localized or generalized itch, affecting patients with chronic renal failure, where there is no primary skin disease and no systemic or psychological dysfunction that might cause pruritus. It does not result from raised serum urea levels. The prevalence of renal itch has increased with the growing population in chronic renal failure and is a considerable cause of morbidity. The prevalence of itch increases with deteriorating renal function but does not improve significantly with dialysis. The pruritus is independent of duration of dialysis or cause of renal failure. The aetiology of renal itch is unclear. There is little evidence of a major role for histamine and antihistamines are rarely beneficial. Hyperparathyroidism, abnormal cutaneous innervation and endogenous opioids have been postulated as contributory factors. Treatment of renal itch is difficult. Naltrexone, oral activated charcoal, UVB phototherapy and ondansetron have been shown to be effective. Topical capsaicin may be of benefit in patients with localized pruritus. The definitive treatment for renal itch remains renal transplantation.     

Efficacy of naltrexone on acetylcholine-induced alloknesis in atopic eczema

Atopic eczema (AE) is a chronically pruritic inflammatory skin disease. Although the mediators and exact mechanisms eliciting and sustaining pruritus are not completely known, AE patients in clinical trials have been shown to benefit under treatment with morphine antagonists. Naltrexone (NAL) is a relatively pure morphine antagonist that blocks the effects of opioids twice as much as naloxone. NAL exhibits minimal pharmacological activity and displaces endorphines at mu- and kappa-receptors without its own intrinsic activity. NAL's excellent oral bioavailability and linear increases in the area under plasma concentration-time curve make it ideal for use in experimental studies. We designed our present experiments similar to former experiments evaluating both peripheral cutaneous sensations and central itch procession in order to gain more information about the possible distribution of opioid receptors and their involvement in the pathophysiology of pruritus. Eleven AE patients participated in our double-blind study. Either 25 mg of NAL (Nemexin) or a placebo (PLA) was given to the participants 60 min prior to the acetylcholine (ACH) injection [intracutaneous (i.c.) injection of 0.02 ml of 0.55 M]. A PLA stimulus with buffered saline served as control on the opposite forearm. We used laser Doppler flowmetry to measure the vasomotoric changes after ACH injection and recorded the duration and intensity of itch with a visual analogue scale (VAS). Following the evaluation of wheal and flare sensation, we obtained the area of itchy skin around the injection site (alloknesis) by gently stroking the surrounding skin with a brush in the centripetal direction towards the injection site. The results were planimetrically evaluated. Oral NAL reduced the perifocal itch significantly (P < 0.009). In four of our observations the area of alloknesis completely disappeared. Itch duration was reduced by 20 s and the intensity of itch was diminished, yet not significantly. NAL had no significant effects on cholinergic vasoreactions measured by the laser Doppler (P > 0.50) and especially failed to decrease the initial flux response, which is a typical sign of an altered vascular reaction (P > 0.25). The decrease of wheal (P = 0.008) and flare (P = 0.01) extension indicates an appropriate dosage of our treatment for this experiment. The most significant effects of NAL were observed in parameters of itch processing such as alloknesis (P = 0.009) and flare extension (P = 0.01). Therefore we favour the concept that NAL might have a stronger impact on central nervous mechanisms than on peripheral nociceptive structures.