Scientists identify potential approach to chronic itch problem

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Chronic itch goes beyond being just a simple annoyance; it can greatly affect a person’s quality of life.

While scientists have some clues to its causes, effective therapies have been elusive.

Now, using a technique called quantitative high-throughput screening to sort through more than 86,000 compounds at the same time, researchers at NCATS and the National Institute of Dental and Craniofacial Research (NIDCR) report a new strategy that may eventually help alleviate chronic itch.

They’ve shown that blocking a receptor, or docking station, found on the surface of both mouse and human spinal cord neurons could be key.

Several years ago, Mark Hoon, Ph.D., and his colleagues at NIDCR found a receptor, Npr1, on mouse spinal cord neurons for a protein associated with itch.

The protein fit into Npr1 like a key into a lock, helping turn on the itch sensation.

Npr1 appeared to be a potential target for drugs to halt itch.

Nerves that stimulate skin are grouped in structures next to the spinal cord. Here, nerves in such a structure — called a dorsal root ganglion — that are involved in detecting an itch are labeled green. Nerves involved in sensing pain, temperature and other stimuli are shown in magenta. Credit: Hans Juergen Solinski, National Institute of Dental and Craniofacial Research

Hoon contacted NCATS scientist James Inglese, Ph.D., and his team for help in identifying compounds that could block Npr1 activity.

The researchers developed a series of assays, or tests, and used robots to screen compounds in human cells, finding approximately 1,400 molecules worth examining more closely.

They then developed additional assays to narrow the list to 15 compounds.

They showed a subset of these compounds could halt both human and mouse versions of the receptor from working.

A follow-up study in mice showed that blocking the receptor reduced scratching.

Next, the scientists will examine more candidate compounds and determine how they block Npr1.

They hope the findings will help them choose which compounds to study further and chemically modify as potential anti-itch drugs.

Hoon, Inglese and their colleagues reported the results online July 10 in Science Translational Medicine.

“This is a proof-of-concept study and an important application of what NCATS does,” Inglese said.

“We wanted to show that by pharmacologically blocking the target receptor, the approach could be successful in finding a drug to treat chronic itch.

Because it can take a long time to develop an ideal compound, the rationale behind the approach needs to be well vetted.”


Pruritus (syn.: itch) is an unpleasant sensory perception which causes an intense desire to scratch and which has a high impact on the quality of life.

Pruritus is the most frequent symptom in dermatology and can occur in acute or chronic forms (over 6 weeks in duration)1,2.

Further, the acute induction of pruritus, e.g. in an experimental model through a histamine stimulus, must be differentiated from the mechanisms that play a role in clinical forms of chronic pruritus2.

Pruritus can have its origin directly in the skin or can develop in the central nervous system via haematogenic or neurogenic mediators.

With this background the pathogenesis of pruritus is quite complex.

In recent years fundamental new insights have been gained into pruritus induction and transmission as well as involved nerves, receptors and mediators.

The understanding of the pathogenesis of pruritus has increased; the clinical assignment of the individual mechanism to the different pruritic diseases remains a task for future research.

FREQUENCY OF CHRONIC PRURITUS

According to a cross-sectional study in Oslo, acute pruritus affects 8.4% of the general population, while in a large French study 42% of patients with skin diseases stated that they experienced pruritus3,4.

In a German pilot study a life-time prevalence of 22.6% was surveyed5.

A recent cross-sectional observational study in >11,000 employees of 144 German companies demonstrated a point prevalence of 17% among German employees6.

quarter of the affected persons had suffered from pruritus for more than 5 years. 47% had never sought medical advice; 94% had undergone no treatment.

Although gender differences have been little explored, the higher level of pruritus among females has been reported5,7.

Focused on elderly people, only a small number of difficult-to-match studies have investigated prevalence and incidence of chronic pruritus.

The German study showed that prevalence increased with age from 12.3% (16~30 years) to 20.3% (61~70 years)6.

According to a Turkish study with 4,099 elderly dermatological patients, 11.5% reported pruritus, whereas the highest prevalence was in patients older than 85 years8. In a Thai-study with 149 elderly patients pruritic diseases were the most common ones (41%)9.

PRURITUS CLASSIFICATION

Several classifications have been published, considering these different aetiologies and clinical morphologies of chronic pruritus1,10,11.

The International Forum for the Study of Itch (IFSI; http://www.itchforum.net) has proposed a classification, which considers clinical as well as differential diagnostic reasons.

One part of the classification encounters the presence of skin changes: (I) “pruritus on primary diseased, inflamed skin” like in inflammatory, infectious, autoimmune disorders, lymphomas or drug reactions or (II) “pruritus on primary non-diseased, non-inflamed skin” like in neurologic or psychiatric origin.

Given that scratching damages the skin, consequently maintaining and reinforcing the inflammatory processes which induce further pruritus and predominating the clinical picture a third group was defined: (III) “secondary scratch lesions”, which includes patient’s with excoriations, crusts, papules, nodules and chronic secondary scratch lesions like prurigo nodularis (Table 1​,2,2Fig. 1).

A vicious circle may result between pruritus and mechanical stimulus responses.

However, the presence or absence of secondary scratch lesions does not allow the determination of origin. Thus, for differential diagnostic purposes, a categorization of underlying pruritogenic diseases has been proposed including dermatological, systemic, neurological and psychiatric/psychosomatic diseases.

Patients, with more than one underlying disease should be categorized as “mixed”.

If no underlying disease can be identified, pruritus should be classified as “pruritus of undetermined origin” (PUO) (Fig. 2)1.

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Fig. 1
Clinical groups of patients with chronic pruritus. Chronic pruritus occurs on primarily diseased skin (i.e., dermatosis, group 1) or on normal skin (group 2). Chronic scratch lesions may be predominant and alter the clinical picture (group 3).
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Fig. 2
Clinical classification in the management of chronic pruritus patients (1). As a first step, patients were grouped according to the clinical picture. Subsequent clinical, laboratory and radiological investigation enables categorization of patient concerning the underlying origin. If several diseases were found (e.g., dry skin and chronic renal insufficiency) the patient has a mixed (multifactorial) origin. If no causal disease is identified, the patient has a pruritus of unknown/undetermined origin (PUO).
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Table 2

Generalised pruritus on primarily inflammatory skin

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HISTAMINE 1 AND 4 RECEPTOR

Many mediators triggering itch have been investigated.

Among them, histamine has been a persistent candidate and is the most thoroughly studied pruritogen for decades.

Histamine binds to H1 receptor expressed on sensory nerve fibers and endothelial vessel walls.

Intradermal injections of histamine provoke vasodilation with redness, wheal and flare (the so-called triple response of neurogenic inflammation) accompanied with pruritus.

This model is still in use in pruritus research to induce acute itch.

Furthermore, intradermally injected substance P (SP) releases histamine and provokes itch.

However, antihistamines in normal dosages are of weak efficacy in several forms of chronic pruritus, as demonstrated in experimental studies as well as double-blind, cross-over trials15.

Recently, histamine 4 receptors were found on inflammatory cells mainly mast cells, eosinophilic granulocytes and T-lymphocytes16.

Gutzmer et al.17 showed that the Th2 lymphocytes of atopic dermatitis (AD) patients express a functionally active H4 receptor.

Stimulation of H4 receptor leads to up-regulation of the pruritogenic interleukin IL-31 (see below).

This newly found mechanism may explain the quick increase of pruritus intensity during flaring up of AD patients.

Interestingly, a mouse model suggests that a combination of H4 and H1 receptor antagonism might be a new strategy to treat pruritus related to allergic diseases.

In their experiments, the authors showed that H4 receptor antagonism fails to reduce the allergic inflammatory response but strongly inhibits allergen-induced itch18.

In sum, these results support the idea that histamine and the histamine 4 receptor but to a lesser degree also histamine 1 receptor may play a role in chronic pruritus pathophysiology.

INTERLEUKIN 31 (IL-31)

The newly discovered interleukin, IL-31 might have a major role in pathophysiology of pruritus, especially in atopic dermatitis19.

For example, IL-31 mRNA in the skin of NC/Nga mice (atopic dermatitis mouse model) with scratching behavior was found to be significantly higher than that in NC/Nga mice without scratching behaviour19.

IL-31 binds to a heterodimeric receptor consisting of the IL-31 receptor A and the oncostatin-M receptor.

In the skin it is found on sensory C-fibers and keratinocytes and in the dorsal spinal ganglia, where it probably contributes to the transmission of the signal pruritus.

IL-31 was shown to be significantly overexpressed in human AD skin compared with nonpruritic psoriatic skin inflammation20.

The concentration of IL-31 in the peripheral blood is also elevated in patients with AD and correlates with disease severity of AD21.

A link between bacterial colonization and induction of pruritus was also demonstated. Staphylococcal superantigen rapidly induced IL-31 expression in atopic individuals20.

In vitro, staphylococcal enterotoxin B but not viruses or T(H)1 and T(H)2 cytokines induced IL-31 in leukocytes.

In patients with AD, activated leukocytes expressed significantly higher IL-31 levels compared with control subjects.

IL-31 receptor A showed most abundant expression in dorsal root ganglia representing the site where the cell bodies of cutaneous sensory neurons reside.

These results suggest a direct link among staphylococcal colonization, subsequent T-cell recruitment/activation, and pruritus induction in patients with AD20.

In sum, IL-31 represents a new and promising target in pruritus therapy especially in AD.Go to:

NEUROPEPTIDES

Several observations support the idea of an important role of neuropeptides for the pathophysiology of pruritus in various skin diseases.

Neuropeptides such as SP, vasoactive intestinal peptide (VIP), somatostatin, and neurotensin provoke itch along with the characteristics of neurogenic inflammation such as erythema, wheal and flare. SP induces itch responses in human and mice which are mediated via activation of the neurokinin 1 receptor (NK1R) on mast cells and keratinocytes resulting in enhancement of inflammatory responses22supporting a indirect effect of SP in mediating pruritus.

Targeting the neuropeptides is a new concept in the treatment of itch. For example, a case series applying the NRK1 antagonstis aprepitant showed significant antipruritic effects in patients with prurigo nodularis and atopic predisposition23. Controlled trials are pending.


More information: Hans Jürgen Solinski et al. Inhibition of natriuretic peptide receptor 1 reduces itch in mice, Science Translational Medicine(2019). DOI: 10.1126/scitranslmed.aav5464

Journal information: Science Translational Medicine
Provided by National Institutes of Health

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