Neurophysiological and neurochemical basis of modern pruritus treatment

Authors


Sonja Ständer, MD, Clinical Neurodermatology, Department of Dermatology, University of Münster, Von-Esmarch-Strasse 58, D-48149 Münster, Germany, Tel.: +49 251 836504, Fax: +49 251 836522, e-mail: sonja.staender@uni-muenster.de

Abstract

Abstract:  Chronic pruritus of any origin is a frequent discomfort in daily medical practice, and its therapy is challenging. Frequently, the underlying origin may not be identified and symptomatic therapy is necessary. Conventional treatment modalities such as antihistamines often lack efficacy, and hence new therapeutic strategies are necessary. The neuronal mechanisms underlying chronic pruritus have been partly identified during the past years and offer new therapeutic strategies. For example, mast cell degranulation, activation of neuroreceptors on sensory nerve fibres and neurogenic inflammation have been identified to be involved in induction and chronification of the symptom. Accordingly, controlling neuroreceptors such as cannabinoid receptors by agonists or antagonists showed high antipruritic efficacy. Pruritus is transmitted to the central nervous system by specialized nerve fibres and sensory receptors. It has been demonstrated that pruritus and pain have their own neuronal pathways with broad interactions. Accordingly, classical analgesics for neuropathic pain (gabapentin, antidepressants) also exhibit antipruritic efficacy upon clinical use. In summary, these recent developments show that highlighting the basis of pruritus offers modern neurophysiological and neurochemical therapeutic models and the possibility to treat patients with refractory itching of different origin.

Abbreviations:
AD

atopic dermatitis

CB

cannabinoid receptor

CNS

central nervous system

CyA

cyclosporin A

NGF

nerve growth factor

PAR-2

proteinase-activated receptor-2

PEA

palmitoylethanolamine

SP

substance P

TRP

transient receptor potential

Introduction

Pruritus (synonym: itch) is an unpleasant sensation inducing the desire to scratch. As a physiological self-protective sensation, pruritus guards the skin against harmful substances including parasites or plants (1). Moreover, pruritus is a major and distressing symptom of many skin and systemic diseases. Acute itch may occur along with, for example, urticaria where it is solely histamine-induced and responds completely to antihistamines. More often the physician faces chronic, severe, generalized pruritus in chronic diseases such as atopic dermatitis (AD), cholestatic liver disease and renal failure. Chronic rubbing and scratching lead to secondary skin lesions such as excoriations, lichenification, prurigo and scars. Along with scratching, inflammatory mediators are released that potentially induce or aggravate pruritic sensations resulting in an itch–scratch cycle (2). This diversity of underlying diseases and clinical presentation of pruritus was the reason of defining a classification for improving the medical care of patients.

Current classifications of pruritus

Pruritus is not a disease per se but a symptom of many diseases respectively disease states. Accordingly, intensity and quality of pruritus, clinical characteristics, and clinical presentation of patients may vary. Several diseases share same characteristics. For example, in urticaria, mastocytosis, cholestatic pruritus and hydroxyethyl starch-induced pruritus, itching can be worsened mechanically by severe scratching. Others such as pruritus in renal disease or AD share same clinical appearance, e.g. prurigo nodules. Thus, the clinical characteristics allow concluding the underlying causes only to a certain degree. Accordingly, two recently defined classifications are orientated either to the neurophysiological origin of pruritus or to the clinical picture and symptoms of the patient (3,4). Twycross et al. (4) classified itch originating in the skin (pruritoceptive – pruritic nerves are activated by pruritogens at their sensory endings), in primarily diseased nervous system (neuropathic – lesioned pruritic neurons themselves generate itch), in the healthy central nervous system (CNS) (neurogenic – central mediators generate itch without neuronal damage) and central processing (psychogenic). The International Forum for the Study of Itch (IFSI) distinguishes three clinical groups of patients: (3) pruritus on primarily non-inflamed skin – patients who complain about generalised or localised pruritus without the initial occurrence of skin changes, pruritus on primarily inflamed skin – a skin disease (dermatosis, cutaneous lymphoma) underlies pruritus chronic secondary scratch lesions – ranging from simple linear or round erosions, excoriations, crusts to macular amyloidosis, lichen simplex, lichen amyloidosus, or prurigo nodularis have to be considered separately. The latter have always been described as own and independent entities, but are today regarded as secondary scratch-induced disease states and phenomenon, preceded by pruritus based on primarily inflamed or non-inflamed skin.

The clinical classification may act as a diagnostic tool but it does not indicate the appropriate antipruritic therapy. Generally, pruritus can be directly evoked in the skin mainly by chemical mediators. In addition, it may also be generated or modified in the CNS independently of peripheral stimulation (1). Conventional therapies often fail to alleviate these types of chronic pruritus. However, recent progress in understanding the neurophysiology of pruritus better has contributed to develop new neurochemical antipruritic therapeutic strategies (5). Moreover, chronic and acute pruritus are based on same cutaneous neurobiology; however, in chronic forms of pruritus, central mechanisms are subjected to neuroplasticity resulting in sensitization towards itch (6). Accordingly, new antipruritic therapies aim to interfere with both cutaneous and central mechanisms.

General principles of antipruritic treatment

Considering the diversity of underlying causes in pruritus, for each neurophysiological form of pruritus own studies and therapeutic recommendations are necessary. In addition, for each patient an individual therapeutical approach considering age, pre-existing diseases and medications, severity of pruritus, impact on quality of life and underlying origin of pruritus is necessary. Before starting any therapy, a careful diagnostic evaluation is of high priority, also for identifying any underlying diseases (2). However, some general principles addressing each kind of pruritus can be recommended: the patient should be informed about general, pruritus-relieving measures applicable in most forms of pruritus. Creams/lotions, e.g. with menthol, camphor, urea, polidocanol or tannin can temporarily reduce pruritus and can be applied by the patient individually or in case of night-time pruritus (7). Menthol and camphor activate receptor channels of the transient receptor potential (TRP) family and induce cold sensation, which masks pruritus for a short time (8,9). Depending on the underlying cause, the scope of causal, antipruritic therapies ranges from the specific treatment of an underlying dermatosis, avoidance of a contact allergen, discontinuation of a medication, specific internal (e.g. iron application in iron deficiency), neurological and psychiatric therapies up to the surgical therapy of an underlying neoplasm (2). Pruritus often stops quickly when the underlying disease improves, e.g. during/after chemotherapy in Hodgkin’s disease or adjustment of impaired thyroid function. Next, a combined or consecutive, step-by-step, symptomatic treatment is necessary. Symptomatic therapies do not interfere with the origin of the pruritus (e.g. treatment of iron deficiency) but may relieve the symptoms of pruritus by interfering with the transmission of pruritus in the peripheral or CNS. The use of antihistamines and short-term treatment with topical glucocorticosteroids are supplemented by modern topical and systemic therapies (5).

Targeting pruritus elicitation in the skin

Itch, burning pain, noxious heat and cold as well as mechanical stimuli are generated in the papillary dermis and epidermis on nociceptors of slow-conducting unmyelinated C-fibres (conduction velocity 0.5–2 m/s). Many receptor systems are functionally expressed on these afferences such as histamine receptors (H1, H3, H4), proteinase-activated receptor 2 (PAR-2), transient receptor potential vanilloid 1 (TRPV1), cannabinoid receptor 1 and 2 (CB1, CB2) and mu-opioid receptor (MOR). All receptors contribute to cutaneous induction (H1, TRPV1, PAR-2) or inhibition of pruritus (CB, MOR) (1,6; Table. 1). Dermal mast cells act in close interaction with nerve fibres and contain substances which act as direct and indirect mediators of itch. Accordingly, topical or systemic administration of neuronal receptor agonists or antagonists as well as mast cell mediating agents proved efficacy next to conventional therapies such as topical or systemic glucocorticosteroids or UV-light therapy (Table. 2).

Table 1.   Neuroreceptors on sensory nerve fibres and their role in cutaneous nociception
NeuroreceptorLigandFunction
  1. TRPV, transient receptor potential vanilloid 1; PAR, proteinase-activated receptor-2.

Induction of nociception
 Histamine receptors: H1-H4HistaminePruritus (H1 and H4 receptor), neurogenic inflammation; sensitised by bradykinine, prostaglandins
 TRPV1Noxious heat (>42°C), protons, capsaicin, anandamide Heat, burning pain, burning pruritus, noxious heat, sensitized by NGF, galanin, bradykinin
 PAR-2Tryptase, trypsinPruritus, neurogenic inflammation
 Endothelin A/B receptorEndothelinPruritus, burning pain
Suppression of nociception
 TRPM8 (on Aδ-fibres)Cold (8–28°C), menthol, icilinCold
 TRPA1 (ANKTM1)Noxious cold (<17°C), wasabi, horseradish, mustardPain induced by cold, burning
 Cannabinoid receptors: CB1, CB2Cannabinoids
CB1: anandamide
CB2: PEA
Suppression of itch, pain and neurogenic inflammation, release of opioids
Table 2.   Modern antipruritic therapies: neurophysiological basis and efficacy
TherapyTargetEffective in pruritus of (diagnosis)
Topical therapies: general measures
 Cold, menthol, icilinTRPM8 (CMR1), ANKTM1Reduction of pruritus of any kind for a short time
 Anaesthetics, e.g. PolidocanolSuppress activity of voltage-dependent sodium channelsReduction of pruritus of any kind for a short time period
Topical therapies: special symptomatic therapies
 Capsaicin cream
0.025–0.1%, 3–6 times daily
Vanilloid receptor subtype 1 (TRPV1)Localised forms of pain in pruritus such as notalgia paraesthetica, PUVA-itch and pain, postherpetic neuralgia, brachioradial pruritus, aquagenic pruritus, pruritus in lichen planus and prurigo nodularis
 Palmidrol (PEA) -containing cream, twice dailyCannabinoid receptors (CB1, CB2)Uraemic pruritus, pruritus of unknown origin, lichen simplex, prurigo nodularis, localised pruritus
 Calcineurininhibitors pimecrolimus 1%, tacrolimus 0.1%TRPV1Prurigo nodularis, Pruritus in AD, chronic irritative hand dermatitis, rosacea, graft-versus-host disease, lichen sclerosus; genitoanal pruritus, pruritus of unknown origin
Systemic therapies
 H1 antihistaminesH1 receptorsUrticaria, mastocytosis, urticarial drug-reaction, combination of antihistamines: AD, prurigo nodularis, pruritus of multifactorial origin in elderly patients
 H1-Antihistamine KetotifeneH1 receptors, mast cell stabilization?Renal pruritus, urticaria
 H2-Blocker
Cimetidine
H2-receptorsSevere forms of polycythaemia vera, Hodgkin′s diseases
 Leukotriene receptor-antagonist MontelukastLeucotriene D4 receptorAD, urticaria, urticaria factitia, aquagenic pruritus
 Cyclosporin ASuppression of IL-2AD, prurigo nodularis
 Anticonvulsants
Gabapentin, Pregabalin
e.g. Nerve membrane stabilisation by blockade of calcium channelsBrachioradial pruritus, notalgia paraesthetica, meralgia paraesthetica, small fibre neuropathy, hydroxyethyl starch (HES)-induced pruritus, renal pruritus, diabetic pruritus
 Mu-opioid receptor antagonists: naltrexone, nalmefene, naloxoneMu-opioid receptor on spinal cord neuronsCholestatic pruritus, chronic urticaria, atopic dermatitis, prurigo nodularis, pruritic mycosis fungoides, HES-induced pruritus.
 Antidepressant: amitriptyline, clomipramine, doxepin, mirtazapine Interfere with the presynaptic re-uptake of neurotransmitters such as serotonin and noradrenalinePrurigo nodularis and chronic pruritus of unknown origin
 Antidepressant: serotonin re-uptake inhibitor paroxetine, fluvoxamineInterfere with the presynaptic re-uptake of serotoninPrurigo nodularis and chronic pruritus of unknown origin

The vanilloid capsaicin

The vanilloid receptor subtype 1 (VR1/TRPV1) is a non-selective heat-activated cation channel that is activated by vanilloids (e.g. capsaicin), endogenous cannabinoid anandamide, increase in temperature within a noxious range (above 42°C) and protons (pH below 5.9) (10,11). Vanilloid receptor activation leads to depolarisation and release of secretory granules containing neuropeptides such as substance P (SP) or calcitonin gene-related peptide (CGRP) (12). Repeated stimulation of the receptor, e.g. by application of capsaicin for several days induces desensitisation of nerve fibres, inhibition of neuropeptide accumulation and suppression of painful and pruritic sensations. Capsaicin is a full ligand at the TRPV1 and proves antipruritic efficacy in clinical application since decades. Capsaicin (e.g. in a prescription using the liquid extract or over the counter [OTC] cream) can be applied topically in varying concentrations of 0.025–0.1% (three to six times daily) in mostly localised forms of pain and pruritus such as notalgia paraesthetica, PUVA-itch and pain, postherpetic neuralgia, brachioradial pruritus, aquagenic pruritus and prurigo nodularis (13).

The cannabinoid N-palmitoylethanolamin

Endogenous and synthetic cannabinoids are known for their psychotic and analgesic potency upon systemic administration. Recently, both cannabinoid receptors CB1 and CB2 were found to be expressed on cutaneous sensory nerve fibres, mast cells and keratinocytes (14–16). It was demonstrated that during inflammation, CB1 expression in primary afferent neurons and transportation to peripheral axons are increased and contributes thereby to enhanced antihyperalgesic efficacy of locally administered CB1 agonist (17). In addition, injections of the CB2 agonist N-palmitoylethanolamin (PEA) may inhibit experimental nerve growth factor (NGF)-induced thermal hyperalgesia (18). First pilot trials with PEA-containing cream could relieve pruritus in haemodialysis (19,20), prurigo nodularis and lichen simplex (21). These preliminary data show that topically applied cannabinoid agonists may be an interesting future concept of antipruritic therapy. The antinociceptive effects are believed to be mediated in part by opioid and vanilloid mechanisms and not directly by the activation of cannabinoid receptors. For example, it was shown that the CB1 agonist anandamide binds to the TRPV1 receptor (11) and that topical cannabinoids directly inhibit TRPV1 functional activities via a calcineurin pathway (22). Moreover, it was demonstrated that the antinociceptive effects of CB2 agonists can be prevented by the MOR antagonist naloxone (23,24). Interestingly, the cannabinoid agonist AM1241 stimulates β-endorphin release from rat skin tissue and from cultured human keratinocytes (25). On summing up, cannabinoid receptors seem to exert a central role in cutaneous nociception mediating direct and indirect effects and therefore represent interesting targets for the development of new neurochemical antinociceptive therapies.

Cold, menthol, icilin

Cold, menthol and icilin activate two cold receptors, TRPM8 (CMR1) and ANKTM1 (8,9), on a subset of nociceptive sensory neurons. It was demonstrated that cooling the skin by lowering the skin temperature results in relief of experimentally induced itch (7). A similar effect can be achieved by menthol although the skin temperature was not decreased leading to application of menthol creams (3% to 5%) (7). However, both cold and menthol reduce acute and chronic pruritus only for several minutes. Icilin is a relatively new developed substance, and its antipruritic efficacy in chronic pruritus is still in research.

Calcineurin inhibitors

Topical calcineurin inhibitors have been successfully introduced in the treatment of AD. In addition to relief of skin lesions, significant antipruritic effects could also be observed. The only clinically relevant side-effect is initial burning and stinging itch with consequent rapid amelioration of pruritus. This resembles neurogenic inflammation induced by activation of the TRPV1 receptor by capsaicin. Recent animal studies raised indirect evidence that calcineurin inhibitors may bind to the TRPV1 on cutaneous nerve fibres (26,27): topical application of pimecrolimus and tacrolimus was followed by an initial release of SP and CGRP from primary afferent nerve fibres in mouse skin. Upon clinical use, pruritic dermatoses such as chronic irritative hand dermatitis, rosacea, graft-versus-host disease and lichen sclerosus were also treated successfully with pimecrolimus or tacrolimus as well as genitoanal pruritus and prurigo nodularis (28).

H1-antihistamines

For a long time, antihistamines have been the only antipruritic therapy available in various types of pruritus. Histamine is stored in mast cells and keratinocytes while H1 receptors are present on cutaneous sensory nerve fibres (29). Furthermore, most of the known itch mediators are potent mast cell and thereby histamine liberators leading to pruritus. Next to antihistaminergic effects, antihistamines can modulate immunological mechanisms such as reducing mediator release and expressing adhesion molecules, regulating the release of cytokines, chemokines and consequently inflammatory cells recruitment (30–37). In urticaria, mastocytosis and urticarial drug-reactions, H1-antihistamines exhibit a clear effect on the histamine-induced triple response of neurogenic inflammation (erythema, wheal and flare) by competitive binding to H1 receptors on nerve endings. In other pruritic diseases, especially AD, low dosages of H1-antihistamines do not show high efficacy but high dosages of antihistamines may be more effective. According to own experiences, a combination of antihistamines, e.g. azelastine, levocetirizine and fexofenadine (each twice daily) showed antipruritic effects in patients with AD, prurigo nodularis and pruritus of multifactorial origin in elderly patients (5). Varying results concerning antipruritic efficacy in inflammatory skin diseases may be explained by the fact that the affinity of antihistamines depends on cutaneous pH changes (38).

H2-blockers

The H2-receptor blocker cimetidine, developed for the treatment of gastrointestinal ulcera, was described to mediate histamine-independent (39) antipruritic effects. Case reports demonstrated the use of high-dosage cimetidine (1 g/day: 200–200–200–400 mg) in severe pruritus caused by Hodgkin’s lymphoma and polycythaemia vera (4,40,41).

Leukotriene receptor antagonists

The role of leukotrienes in the pathogenesis of pruritus is speculative, although there is some evidence hinting to their relevance. Intradermal-injected leukotriene B4 is able to provoke scratching in mice (42). Additionally, a correlation of nocturnal itch and high-urinary leukotriene B4 levels was found (43) suggesting that leukotrienes may contribute to severe pruritus at night in AD. Leukotriene receptor-antagonists such as zafirlukast, zileuton and montelukast block cysteinyl leukotriene receptors. Most commonly, montelukast, a leukotriene D4 receptor antagonist, is approved for asthma therapy. Montelukast also proved clinical efficacy in urticaria and urticaria factitia (28,44,45). According to own experiences, patients suffering from aquagenic pruritus experience improvement when treated with montelukast. Zafirlukast and zileuton have been demonstrated to suppress pruritus in AD patients (46–48).

Cyclosporin A

Several interleukins, i.e. IL-2, IL-4, and IL-6 are known to account for the elicitation of itch. Just recently, IL-31 was discovered to play a role in pruritus of AD (49). Interestingly, not only animal studies (49) but also blood and genetical investigations in humans suggest an important role of IL-31 in the pathogenesis of atopic and non-atopic eczema (50,51). IL-2 is also claimed to be a potent inducer of pruritus because when high doses of recombinant IL-2 were applied in cancer therapy, itching and redness of the skin were frequently observed (52). IL-2 elicited itch in experimental skin-prick testing (53) by activating a subpopulation of cutaneous C-fibres that are chemosensitive to histamine, bradykinin and capsaicin (54). Bradykinin thereby seems to enhance the effect of IL-2-induced pruritus on sensory nerve fibres (55). Consequently, the suppression of IL-2 produces significant antipruritic effects. Cyclosporin A (CyA), a cyclic polypeptide with potent immunosuppressive effects, has been reported to have itch-relieving effects in various diseases including AD. In a randomized study, CyA demonstrated significant reduction of itch (56). After discontinuation, pruritus recurred immediately suggesting that CyA represents a symptomatic and non-causal therapy of pruritus. Moreover, CyA is effective in very pruritic AD as well as prurigo nodularis of various origins.

Targeting pruritus elicitation in the central nervous system

The itch sensation is transmitted by cutaneous afferences to extracutaneous peripheral nerves running via the dorsal root ganglion to the spinal cord. On the spinal level, neurons of the spinothalamic tract projecting to the thalamus were found to be selectively excited by histamine and thus probably participate in the transmission of pruriceptive information (57,58). PET studies in humans showed activation of several brain areas including thalamus and the primary sensory cortex after histamine prick tests (59). Recent studies demonstrated that pruritus-transmitting spinal cord neurons express pruritus-specific receptors (e.g. gastrin-releasing peptide receptor) (60) and run separately from pain neurons to the brain. However, pain afferences may communicate and interact with pruritus neurons. For example, upon scratching and inducing moderate pain sensation, pruritus transmission is inhibited. These observations led to the introduction of several centrally acting substances for treating severe pruritus.

Anticonvulsants: gabapentin and pregabalin

Gabapentin is an anticonvulsive with additional analgetic properties. By direct action at the spinal cord, it is speculated to hinder the transmission of nociceptive sensations to the brain and thereby also suppresses pruritus. The exact mechanisms are still discussed but are possibly based on a nerve membrane stabilisation by blockade of postsynaptic calcium channels or inhibition of the synthesis of neurotransmitters. Gabapentin can be recommended as second choice therapy, e.g. in renal or diabetic pruritus (61,62). In forms of neuropathic pruritus such as brachioradial pruritus, notalgia paraesthetica, meralgia paraesthetica, small fibre neuropathy or hydroxyethyl starch (HES)-induced pruritus, it may be used as therapy of choice (63). The new substance pregabalin displays similar effects upon use as an analgetic agent with better side effect profile. The substance is a GABA analogue which selectively binds to the α2–δ subunit of neuronal voltage-gated calcium channels. Pregabalin modulates the presynaptic release of excitatory neurotransmitters such as glutamate and noradrenalin. Further, pregabalin reduces the SP-related activation of glutamate receptors (AMPA receptors) on noradrenergic synapses, total transmitter release and finally neuronal activity (64,65). As a result, neuronal hyperexcitability is reduced that explains the clinical efficacy of pregabalin. According to own clinical experiences, gabapentin showed stronger antipruritic effects than pregabalin.

Mu-opioid receptor antagonists: naltrexone, nalmefene, naloxone

Opioid receptor antagonists were originally developed for the treatment of heroin dependence and for symptom reversal of postanaesthetic depression, narcotic overdose and opioid intoxication. Clinical and experimental observations have demonstrated that pruritus can be evoked or intensified by endogenous or exogenous opioids (66,67). This phenomenon can be explained by activation of spinal opioid receptors, mainly MORs on pain transmitting neurons which induce analgesia often in combination with pruritus. Reversing this effect by mu-opioid antagonists results thereby in inhibition of pruritus. Several studies showed antipruritic effects of MOR antagonists such as naltrexone, nalmefene and naloxone. Placebo-controlled studies demonstrated efficacy of nalmefene in cholestatic pruritus, chronic urticaria and AD (68–70). Case reports and large uncontrolled studies showed significant reduction of pruritus by naltrexone in prurigo nodularis, pruritic mycosis fungoides and hydroxyethyl-starch induced pruritus (71). However, initial side effects as well as high therapy cost lead to second line use of in chronic pruritus.

Antidepressants and antiserotoninergic substances

Antidepressants directly influence central pruritus perception by so far unknown mechanisms. It is speculated that they interfere in the neuronal re-uptake of neurotransmitters such as serotonin and noradrenalin and thereby reduce pruritus perception. Accordingly, tricyclic (e.g. amitriptyline, clomipramine, doxepin) and tetracyclic (e.g. mirtazapine) antidepressants were applied with some success in chronic pruritus or prurigo nodularis (5). Doxepin has additional antihistaminergic effects and is therefore frequently preferred. In the meantime, modern preparations are available which have similar effects but a better side effect profile. The selective serotonin re-uptake inhibitor (SSRI) paroxetine was reported to have antipruritic effects in polycythemia vera, psychogenic pruritus and paraneoplastic pruritus in single patients (72–74). In an own study, 68% of the patients suffering from chronic pruritus experienced a significant antipruritic effect upon treatment with paroxetine and fluvoxamine (Barbara Böckenholt and Sonja Ständer, unpublished data). The underlying mechanism of the antipruritic effect is not yet clarified. In the CNS, SSRI target Na+/Cl dependent transporters (synonym: neurotransmitter sodium symporters) on synaptic membranes. These transporters convey released neuromediators, i.e. serotonin, into presynaptic cell bodies after they were released. The inhibition of this mechanism results in increased serotonin concentration acting on postsynaptic receptors. It was speculated that the antipruritic effect of SSRI is due to a down-regulation of 5-HT3 receptors upon continuous stimulation of the receptors. Another hypothesis focuses on the effect of SSRI on opioid receptors. Recent animal studies demonstrated that the antinociceptive effect of paroxetine was significantly inhibited by naloxone, an opioid receptor antagonist, suggesting the involvement of opioidergic mechanisms (75). Interestingly, direct targeting of specific serotonin receptors by serotonin agonists such as ondansetron, tropisetron or granisetron did not show any antipruritic effects in controlled trials (76–78).

Outlook on future therapies

The cutaneous and central neurobiology of pruritus is complex and underlies a regulation of variable, stress-vulnerable mechanisms. Accordingly, the therapies and underlying mechanisms mentioned here represent only part of the complex network of neuronal interactions. Other neuromediators induce a peripheral or central sensitization of nerve fibres contributing to chronification of pruritus. For example, neurotrophins and their receptors play an important role in cutaneous nerve development and reconstruction after injury. They are released by non-neuronal, inflammatory cells such as eosinophilic granulocytes. After binding to specific receptors on the peripheral nerve endings, they are transported along the axon on the cell bodies in the dorsal root ganglia where they regulate expression of a variety of proteins involved in neuronal growth and sensitivity. In addition, one of the neurothrophins, NGF, may lead to sensitisation of peripheral neuroreceptors such as histamine and capsaicin (TRPV1) receptor (79). It was demonstrated that NGF is overexpressed in prurigo nodularis and AD. Moreover, it was speculated that NGF and its receptors contribute to the neurohyperplasia of the disease (80,81). Accordingly, substances targeting NGF could be a future option for treating prurigo nodularis or AD preventing the chronification of pruritus.

A decade ago, the PAR-2 was described to be present on cutaneous sensory nerve fibres. It is activated by mast cell mediators such as tryptase (82). Activation leads to induction of pruritus and neurogenic inflammation comparable to effects induced upon histamine release from mast cells (83,84). In AD, PAR-2 was enhanced on primary afferent nerve fibres in lesional skin suggesting that this receptor is involved in the pathophysiology of pruritus in AD (85). Accordingly, PAR-2 antagonists should be effective in suppression of peripheral induced pruritus, but these substances do not yet exist for therapeutical use. Other recently discovered substances inducing peripheral pruritus may represent targets of new antipruritic drugs such as IL-31. Also targeting neuropeptides such as SP by NK1-antagonists were successful in pilot studies (Sonja Ständer and Thomas A. Luger, unpublished observation). Especially in severe forms of chronic pruritus, e.g. renal pruritus and aquagenic pruritus, new effective therapies are essential because current therapy modalities are not sufficient in the long run. In summary, treatment of chronic pruritus is a challenge and demands knowledge of modern therapies acting directly at neuronal structures in the skin or in the CNS. Identifying the origin of pruritus and early start of a specific therapy preventing the chronification of this symptom has high priority and is of greatest importance.

Competing interest’s statements

None of the authors have a conflict of interest.

Ancillary