18.1. INTRODUCTION

The sensation of itch is difficult to define but is generally accepted as an unpleasant cutaneous sensation, leading to the desire to scratch. It has clear survival value as it has been conserved across many mammalian species through different evolutionary pathways. There are many different manifestations of itch or other related sensations, such as tingling, crawling, or irritation. Some of these more diffuse sensations are initiated in the central nervous system (CNS), but most originate from the periphery, in particular, the skin. Cutaneous itch has many different causes and triggers, and it is crucial to understand that the interactions between the peripheral nonmyelinated, sensory C-fibers and different skin cells is the initial step for the initiation of the itch sensation in skin. Numerous skin cells are involved in this nerve–skin interaction, ranging from keratinocytes, melanocytes, Merkel cells, Langerhans cells to various dermal cells such as mastocytes, endothelial cells, fibroblasts, and cells in skin appendages. In previous publications we proposed the existence of a keratinocyte-nerve “unit,” consisting of very fine and superficial nerve fibers in the epidermis connecting to keratinocytes that may be specialized in function. These keratinocytes could act as sensors and send signals either to other keratinocytes or to the epidermal C-fibers. The interaction between different cell systems in the epidermis might be crucial for the initiation of various peripheral sensations such as pain, itching, burning, tickling, and tingling. All these sensations have very distinct functions, but most of these sensation qualities do not require an immediate reflex mechanical withdrawal reaction such as the stimulation of dermal myelinated A-delta fibers with conduction of deep, well-defined injuries. Sensations such as itching, not well localized pain burning, tickling or tingling are danger signals that do not require an immediate withdrawal action but rather notify of a danger that needs to be removed by swiping or scratching. This clearly implies that the skin has very sophisticated mechanisms to sense different levels of danger and to react in different ways.

The brain provides a conscious realization that there is a sensation of itch, after which we will react by rubbing or scratching to remove the noxious stimulus. The itch signal from the periphery will be modulated during its journey through the peripheral nerves, dorsal root ganglia and spinal cord to the higher centers in the brain. Inflammation of the skin as well as constant stimulation of the peripheral nerve system will modify signals emanating from the skin and in transmission of these signals to the CNS; indeed, the threshold and the irritability of the nerve fibers will change under the influence of various cytokines, growth factors, neuropeptides, and neurotransmitters. The different perceptions of itch and pain seem to have very distinct pathways in the CNS. The removal of pain is not a prerequisite for induction of itch (Liu et al. 2011). It is very difficult to separate the peripheral events in itch and pain from the processes in the CNS, but it is clear that these various sensations can be modulated at every level of transduction (Sun and Chen 2007). The events in the periphery appear to be equally important as mechanisms occurring in the CNS, and this is especially true for the involvement of the opioid receptor system in modulation of sensory function both in the periphery and CNS. While the opioid system, and in particular its influence on pain, has been well studied in the CNS, very little is known about the role of opioid receptors in skin, and in addition we are at the infancy of understanding the nerve systems in the skin.

The goal of this chapter is to describe the role of the opioid receptor system in the induction and regulation of the peripheral components of pain and itching mechanisms, with strong focus on itch. Also discussed are possibilities of treating very cumbersome sensations (itch, pain, and tingling) that have been peripherally induced by topical applications of opioids, with the intention of limiting the side effects generated by opioidergic activity within the CNS.

18.2. OPIOID RECEPTORS IN SKIN

Opioid receptors are G-protein coupled receptors that mediate the effects not only by endogenous opioid peptides but also by exogenous opiate alkaloids such as morphine. The opiate receptor system consists of three major receptor types with corresponding endogenous ligands; the µ-(mu opioid receptor [MOR]/Oprm1) with endorphins, κ-(kappa opioid receptor [KOR]/Oprk1) with dynorphins, and δ-(delta opioid receptor [DOR]/Oprd1) with enkephalins. These endogenous ligands are not, however, exclusively specific for the corresponding receptor, for example, endorphins cross-react between KOR and DOR and the enkephalins between DOR and MOR. Some of the ligands can act as agonists on one receptor type and show antagonist activity on others.

In general terms the opioid receptor system has been strongly related to the CNS, particularly in the context of pain. More recently, however, there is growing evidence that the opioid receptor system can also produce potent and specific analgesic effects outside the CNS. In addition, emerging research has shown that opioid receptors are not only involved in the sensation of pain and itch; these receptors also influence inflammation, proliferation, differentiation, and apoptosis of various cells in skin. Opioid receptors are clearly present on peripheral nerve fibers located in the dermis and epidermis, around hair follicles (Bigliardi et al. 2009), bone, joint tissue, and in dental pulp (Sehgal et al. 2011). Coggeshall et al. (1997) reported MOR expression in 29% to 38% of cutaneous unmyelinated sensory axons, and the existence of MOR on peripheral nerve fibers in skin was later confirmed by several other groups (Stander et al. 2002; Bigliardi-Qi et al. 2004).

Opioid peptides are involved in pathophysiologic responses to stress and inflammation, and they can act on the peripheral nerve system by decreasing the excitability of sensory nerves and/or inhibiting release of proinflammatory cytokines and neuropeptides (Sehgal et al. 2011). Opioid receptors are not only present in neuronal cells and tissue but also in immune cells (macrophages and neutrophils), gastrointestinal system, and various skin cells, such as melanocytes, hair follicle epithelium, fibroblasts, and keratinocytes (Bigliardi et al. 2009).

Over the years, several different opioid ligands have been found in human skin, such as beta-endorphin (Wintzen et al. 2001; Kauser et al. 2004), enkephalins (Zagon et al. 1996; Schulze et al. 1997; Nissen and Kragballe 1997; Tachibana and Nawa 2005), and dynorphins (Tominaga et al. 2007). Bigliardi-Qi et al. (1999) reported for the first time the presence of MOR in human skin cells. During the following years the existence of MOR in nonneuronal cells in human skin was confirmed by the same and other groups (Bigliardi et al. 2002; Stander et al. 2002; Bigliardi and Bigliardi-Qi 2004; Bigliardi-Qi et al. 2005; Kauser et al. 2003), with DOR (Bigliardi-Qi et al. 2006; Bigliardi et al. 2009) and KOR (Tominaga et al. 2007; Bigliardi et al. 2009) being found subsequently. Bigliardi et al. (2009) have shown by real-time polymerase chain reaction that MOR expression in ectoderm-derived skin cells (keratinocytes and melanocytes) is higher than DOR expression. By contrast, mesoderm-derived fibroblasts express higher levels of DOR than of MOR. The distinct expression of opioid receptors in various skin cells suggests differing roles for these receptor systems in skin physiology and pathology. Functionally, DOR, and to a lesser extent MOR, are involved in skin differentiation and homeostasis and profoundly modulate wound healing (Bigliardi et al. 2003, 2009; Bigliardi-Qi et al. 2006). Wound healing is often accompanied by strong itch sensation, which is a major problem in burn wounds, and this pruritus is histamine independent (Cheng et al. 2011). This could suggest a leading role for the opioid system in itch.

18.3. OPIOID RECEPTORS IN SKIN DISEASES

Several publications describe the regulation of opioid receptor expression in various skin disorders associated with pruritus. Bigliardi et al. (2007) measured the expression of MOR in epidermis of patients with pruritic, chronic atopic dermatitis with a specific antibody (Diasorin) (Bigliardi-Qi et al. 2005; Bigliardi et al. 2007). A significant downregulation and internalization of the MOR expression by these antibodies was observed; in addition, in situ hybridization revealed a distinct distribution pattern of the mRNA for MOR in patients with chronic atopic dermatitis. In atopic dermatitis the mRNA for MOR is concentrated in the subcorneal layer of the epidermis, and in normal skin it is more highly expressed in the suprabasal layer.

Other groups have made different observations on the distribution of MOR in skin of patients with atopic dermatitis. There was no apparent difference in MOR (Stander et al. 2002; Tominaga et al. 2007) and KOR (Tominaga et al. 2007) expression measured by immunohistochemistry in patients with atopic dermatitis compared to healthy volunteers. KOR expression was, however, downregulated in skin of atopic dermatitis, and PUVA treatment resulted in a downregulation of MOR and a restoration of KOR (Tominaga et al. 2007).

Similar discrepancies were found with MOR in psoriasis and prurigo nodularis; Bigliardi et al. (2000) observed a significant downregulation of MOR immunoreactivity in lesional skin of psoriasis (Bigliardi-Qi et al. 2000), prurigo nodularis (Bigliardi and Bigliardi-Qi 2004) and chronic nonhealing wounds (Bigliardi et al. 2003). The nonlesional skin of patients with plaque psoriasis and also in acute wounds shows similar MOR expressions as normal skin. However, alternative studies showed MOR immunoreactivity in skin of patients with psoriasis (Stander et al. 2002; Taneda et al. 2011) and Prurigo nodularis (Stander et al. 2002) as not differing from normal skin.

There are several possibilities to explain the different results on expression of MOR in atopic dermatitis. First, Bigliardi et al. (2005) selected patients with chronic atopic dermatitis, and, second, they used different polyclonal antibodies against MOR (Diasorin) than Staender (Biotrend), and Tominaga/Taneda (Santa Cruz). In addition, the permeabilization of the cells could result in different staining patterns. Bigliardi et al. (2005) describe in their earlier publication an internalization of the MOR in atopic dermatitis. With certain staining protocols the internalized receptor, which has no functional activity, will be stained as well. Finally, all the analyses of the MOR expression in the papers of Bigliardi et al. (2004), and Bigliardi-Qi (2005) were done by confocal microscopy with less background and three-dimensional reconstruction. Nevertheless, regardless of the reasons for the different staining pattern for opioid receptors in the skin, further studies are required to elucidate the exact role the opioid receptor system in pruritic skin diseases.

18.4. PERIPHERAL µ-OPIOID RECEPTORS (MOR) AND ITCH

The MOR system has been used for centuries to treat chronic and acute pain, and it is still one of the most effective antinociceptive treatment strategies. The side effects can be numerous and debilitating such as constipation, nausea, sedation, and pruritus. The prevalence of pruritus depends on the opioid used and the method of administration and may be influenced by genetic factors. Pruritus occurs in 2% to 10% of the patients treated systemically with opioids (Reich and Szepietowski 2010). The highest prevalence for opioid-induced pruritus is associated with intrathecal administration of morphine with neuroaxial itching mostly around the nose and upper parts of the face. Systemically applied MOR antagonists are successfully used in the treatment of various dermatologic and systemic diseases, such as chronic urticaria, prurigo nodularis, mycosis fungoides, and postburn itch (Phan et al. 2010), with several reports existing related to atopic dermatitis (Brune et al. 2004; Malekzad et al. 2009) and cholestatic pruritus. There are even some controlled trials with the opioid antagonists naltrexone and naloxone in cholestatic pruritus (Bergasa et al. 1995; Bergasa 2004). MOR antagonists are not, however, currently recommended in the treatment of uremic pruritus (Phan et al. 2010). The question remains connected to the use of systemic applications of naloxone or naltrexone. Are the antipruritic effects of naloxone and naltrexone purely restricted to the CNS or does the opioid receptor system in the skin also modulate itch sensation?

The first question was whether the MOR system is really active in the peripheral nervous system or if the effects are purely related to the CNS. The following discussion should shed some light on this topic. Akiyama et al. (2010) published a mouse model that could distinguish between topical nociceptive or pruritogenic stimulation. The opioid antagonist naloxone did not affect the pain component (wiping activity) after capsaicin treatment, but it significantly reduced the already low level of capsaicin-evoked scratching behavior. These results from the mouse cheek model are consistent with human observations that capsaicin induces a burning pain, eventually also leading to itch, but can induce an initial itch response in some individuals. Histamine- and touch-evoked scratching was inhibited by the MOR antagonist naltrexone (Akiyama et al. 2012). In this study the pruritogens were applied locally on cheek skin of mice and the MOR antagonists were applied subcutaneously suggesting a peripheral action, although additional effects through CNS could not be excluded.

There are, however, several clear indications that opioid receptors, especially MOR, are involved in the peripheral induction and modulation of itch sensation. Methylnaltrexone is a peripherally restricted, relatively potent MOR antagonist with moderately good selectivity for MOR versus KOR and no effects at DOR (Goodman et al. 2007). Methylnaltrexone does not cross the blood–brain barrier and has been FDA approved for the treatment of opioid-induced constipation without affecting the analgesic effects (Holzer 2012). Interestingly, clinical and laboratory studies performed during the development of methylnaltrexone have indicated that this drug also influences nausea, vomiting, and pruritus (Phan et al. 2010). Orally administered methylnaltrexone has been shown to decrease morphine-induced itching in one small, double-blind randomized, placebo-controlled study (Yuan et al. 1998), strongly challenging the theory that opioid related itching is purely related to CNS. Further studies are required to elucidate the role of peripherally active MOR antagonists on opioid induced side effects and pruritus mechanisms. New compounds such as Alvimopan (Goodman et al. 2007) are in the pipeline and will lead to further studies.

Yamamoto and Sugimoto (2010) have shown that intradermal injection of MOR agonists DAMGO (very specific) and loperamide elicits dose-dependent scratching behavior in mice, while the intradermal injection of specific DOR agonist (DPDPE) and KOR agonist (U-50488H) does not. This scratching behavior was inhibited by peripherally restricted naloxone-methionine, and therefore the authors concluded that MOR plays a primary role in peripheral pruritus. This conclusion is directly supported by other studies performed by the group of Bigliardi et al. (2007). Topically applied naltrexone has been shown to be effective in the treatment of pruritus in patients with atopic dermatitis (Bigliardi et al. 2007). The double-blind, placebo-controlled, crossover trial on 40 patients demonstrated clearly that cream containing naltrexone had an overall 29.4% better effect compared with placebo. The formulation containing naltrexone required a median of 46 minutes to reduce the itch symptoms to 50% (placebo 74 min). After careful analysis of the patient’s data, another important observation was made. Atopic dermatitis patients with chronic pruritus (>6 weeks) had a significant 45% alleviation of the pruritus by the topical naltrexone formulation using visual analogue scale (VAS) measurements compared with placebo (n = 24). Reduction of pruritus by topically applied naltrexone in atopic dermatitis patients with acute pruritus (<6 weeks), however, was not significant (7%, n = 15). This indicates clearly that the influence of various modulators of itch change over time in patients with the same pruritic dermatologic disorder. Clinical experience demonstrates that antihistamines might work in acute flare-ups of pruritus in atopic dermatitis, but they are often ineffective in chronic pruritus in patients with atopic dermatitis. The same clinical study (Bigliardi et al. 2007) has confirmed previous results (Bigliardi-Qi et al. 2005) that the significant downregulation of MOR expression is especially pronounced in chronic pruritic skin disorders with long-lasting history of pruritus. Treatment of the chronic pruritic skin disorders for 2 weeks with topically applied naltrexone resulted in increase of epidermal MOR staining (Bigliardi et al. 2007). The regulation of the epidermal opioid receptor correlated clearly with the clinical assessment and indicates a role of the MOR in epidermis in modulation of the peripheral components of itch sensation.

There are animal models also suggesting that MOR is involved in the modulation of itch sensation in chronic, but not acute skin disorders. Miyamoto et al. (2002) described a new dry skin pruritus mouse model, which correlates to a chronic atopic dermatitis with marked increase of trans epidermal water loss (TEWL), epithelial hypertrophy, and spontaneous scratching. Subcutaneous administered opioid antagonists (naloxone and naltrexone) significantly suppressed spontaneous scratching in mice with dry skin dermatitis. There was no change of scratching behavior in mast cell-deficient mice, suggesting that the role of mast cells and histamine is not relevant in this dry skin itch model (Miyamoto et al. 2002). Experiments using MOR knockout mice (Bigliardi-Qi et al. 2007) have shown that these mice reveal a phenotype of significantly thinner epidermis with higher density of epidermal nerve fibers stained by PGP 9.5 compared to wild-type mice. This suggests that MOR has effects on skin homeostasis and also cutaneous innervation. In addition, Bigliardi-Qi et al. (2007) decided to induce the dry skin dermatitis model described by Miyamoto on these mice, on the basis of the observations from the clinical study that topically applied naltrexone affected primarily pruritus in chronic atopic dermatitis. The histological analysis of the skin revealed that the epidermal hypertrophy, induced by the dry skin dermatitis, was significantly less developed in MOR knockout mice than in wild-type mice. Behavioral experiments also demonstrated that MOR knockout mice scratch significantly less after induction of dry skin dermatitis than wild-type mice, and this was not due to T-cell induced inflammation and independent of mast cell counts in the dermis. In conclusion, there are various indications that the MOR system in skin plays an important role in skin homeostasis, epidermal nerve fiber regulation, and most importantly, in the initiation and modulation of itch sensation in skin.

Naltrexone and naloxone have antagonistic effects on all opioid receptors and therefore a discussion is necessary on whether the peripheral effects of methylnaltrexone or naltrexone alone on pruritus are purely by blockage of MOR or if KOR is also involved in peripheral components of itch sensation. New data with dogs using new and highly selective MOR antagonists (3-Azabicyclo [3.1.0] hexane compounds) that produced rapid and dramatic reduction in pruritic behavior in dogs with flea allergy dermatitis add new evidence that pruritus in skin is mostly linked to MOR (Lunn et al. 2012) rather than the other opioid receptors.

18.5. PERIPHERAL κ-OPIOID RECEPTORS (KOR) AND ITCH

There are few reports linking KOR and its ligand dynorphin to pruritic skin diseases, such as atopic dermatitis. KOR immunostaining was downregulated in the epidermis of atopic dermatitis and in lesional skin of patients with pruritic psoriasis. PUVA therapy did not change KOR levels, but it increased the expression of KOR ligand dynorphin A (Tominaga et al. 2007). However, a recent study has shown no significant correlation between atopic dermatitis and pruritus in 211 patients with atopic dermatitis by analysis of pro-dynorphin promoter polymorphism (Greisenegger et al. 2009). These results show that the role of KOR in pruritic skin diseases is still under debate and further studies on patients with chronic pruritus have to follow.

In general, the exact role of KOR in the pathogenesis of pruritus is still unknown, and there are some data from animal and human studies that can shed some light into this topic. The density of free nerve endings in the epidermis is higher in KOR knockout mice compared to wild-type mice. In addition, scratching behavior of KOR knockout mice with dry skin dermatitis is reduced compared to wild-type mice. Using the dry skin model with chronic itch the MOR and KOR knockout mice behaved in a similar manner. Interestingly, the same KOR deficient animals showed no obvious alteration in the perception of thermal or mechanical pain, to the contrary of MOR knockout mice (Gaveriaux-Ruff and Kieffer 2002). Disruption of the KOR gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective KOR agonist U-50488 and attenuates morphine withdrawal (Simonin et al. 1998). These observations are in accordance to reports indicating a role of KOR in visceral pain.

However, in other more CNS-related itch models and in controlled human studies the KOR agonists have an antipruritic activity, in contrast with pruritogenic activity of MOR agonists. In addition, application of peripherally restricted KOR agonist ICI 204,448 inhibited chloroquin-induced pruritus in mice (Inan and Cowan 2004). This suggests that KOR also has action against pruritus in the periphery and that the opioid receptor system generally has very distinct effects on the different types of pruritus.

KOR agonists are used in the treatment of uremic pruritus, prurigo nodularis, paraneoplastic, and cholestatic pruritus (Phan et al. 2012). Nalfurafine hydrochloride (TRK 820 or Remitch^®) is a KOR agonist with partial MOR and DOR agonism and has been shown to be effective in placebo-controlled studies against uremic pruritus. This drug has approval in the Japanese market for treatment of pruritus during hemodialysis. Another ligand with agonistic activity on KOR and antagonistic activity on MOR is Butophanol. This drug has been shown to be highly effective in the treatment of intractable pruritus (Dawn and Yosipovitch 2006; Lim et al. 2008), but has also demonstrated induction of pruritus (Bernstein and Grinzi 1981). With all of these observations and treatments it is literally impossible to separate peripheral KOR effects from activity within the CNS. Some authors postulate that the itch sensation in the periphery and CNS are the results of an imbalance between MOR and KOR activity; indeed, it is widely accepted that KOR signaling suppresses itch, while MOR signaling can stimulate itch. If KOR signaling was truly itch suppressive, however, one would expect enhanced scratching behavior in KOR-KO mice rather than a reduction. KOR- and MOR-KO mice do not differ in their scratching behavior after induction of dry skin dermatitis (Bigliardi-Qi et al. 2007). An obvious explanation of this finding is not clear, but pharmacological effects of putative agonists or antagonists in in vitro binding assays do not reflect the functional in vivo situation, or that in vivo there are compensatory mechanisms masking the actual functional effects of knockout of the respective opioidergic receptors. Alternatively, the different in vivo models used may not be directly comparable; moreover, KOR agonists have been clinically tested on acute forms of itching, while KOR- and MOR-KO mice studies have used a chronic form of itching (i.e., a dry skin itch model) (Bigliardi et al. 2009).

18.6. PERIPHERAL δ-OPIOID RECEPTORS (DOR) AND ITCH

As with KOR, the role of DOR in pruritus is poorly understood. In DOR-deficient animals, analgesia induced by the two agonists DPDPE and deltorphin was either abolished, reduced, or maintained, depending on the nociceptive assay and route of administration (Zhu et al. 1999). The observation that activity of DOR agonists remains prevalent in DOR-deficient animals, and that the activity of the same compounds in MOR-deficient mice is decreased, strongly suggests cross-reactivity of agonists between DOR and MOR in vivo. Results from DOR agonists therefore are complex and should be placed into context in combination with MOR effects. There are, however, a few reports linking endogenous DOR ligands to certain types of pruritus, for example. Hemodialysis patients with pruritus revealed significant higher opioid levels in plasma compared to hemodialysis patients without pruritus and normal controls. The increased opioid level was mainly restricted to increased plasma enkephalins (DOR) and not β-endorphin (MOR) or dynorphin (KOR) (Odou et al. 2001). Thornton and Losowsky (1988) found increased plasma levels of the DOR agonists methenkephalin and leu-enkephalin in patients with primary biliary cirrhosis. Other actions of DOR in skin are completely unknown except for profound effects on wound healing, skin homeostasis and skin differentiation (Bigliardi-Qi et al. 2006).

18.7. CONCLUSIONS

One of the major questions concerning opioid receptors and itch sensation will always be the relative involvement of the opioid receptor systems in the periphery versus the CNS. The most likely explanation is that it is a mixture between both settings, and this leads to the obvious challenge of dissecting out the different effects. Normal itch sensation is obviously initiated in the periphery, in particular the skin as a sensory organ, and is then transmitted by slow-conducting, nonmyelinated, sensory C-fibers through the DRG into the spinal cord and eventually to the brain. In the brain we will perceive the real or conscious sensation of itch. The signal underlying itch is open to alteration, suppression, and modulation in all the different components of this pathway. The exact interactions of the opioid receptor system and the involvement of other receptor systems can only be elucidated by developing new in vitro coculture models of skin and nerve (Pereira et al. 2010) and comparing them to new animal models as described by Akiyama and Carstens (Akiyama et al. 2012), while keeping a close watch over emerging clinical observations and trial data.

Most of the current papers describe the KOR system as itch suppressing and the MOR system as itch stimulating; however, the itch intensity of KOR- and MOR-knockout mice in response to dry skin dermatitis did not differ (Bigliardi-Qi et al. 2007). Several explanations could account for this discrepancy. The in vitro pharmacological effects of putative opioid agonists or antagonists may not reflect the in vivo situation, especially at the level of keratinocytes and peripheral nerve fibers. Alternatively, the different in vivo models might not be directly comparable. This is especially true for different species and different types or modalities of pruritus such as chronic versus acute pruritus or that induced by various pruritic stimuli. Topically applied naltrexone works mostly on chronic itch and not on acute itch in patients with atopic dermatitis (Bigliardi et al. 2007). It seems that acute itching is mainly related to stimulations by histamine, prostaglandins, leucotrienes, proteinases, CGRP, SP, or KOR agonists, while MOR seems to be more effective in chronic itch sensations. Future studies are needed to prove if this is due to changes of receptors and/or endogenous ligands in skin, in particular, in or on keratinocytes or peripheral cutaneous C-fibers, and what role the keratinocyte-nerve unit plays in the peripheral induction of itch sensations.

Another explanation for diverse reactions to opioid ligands in pain and itch treatments will be genetic variants of opioid receptors in different species and even individuals. There are several new indications for the importance of genetics in responses to opioids. Studies of twins have shown significant heritability for respiratory depression, nausea, drug disliking, or even pruritus (Angst et al. 2012). In addition, the pruritus related to application of opioid ligands seems to be linked to single nucleotide polymorphisms, such as for SNP A118 (Wei et al. 2008; Sia et al. 2008; Tsai et al. 2010). Most of the authors have concluded that these SNP variations are responsible for changed susceptibility to central pruritus. This may not be the full story, and further studies are needed to examine the role of genetic variations such as SNPs in the threshold for induction of peripheral itch sensations, especially in pruritic skin diseases such as atopic dermatitis.

Opioids are not only involved in the sensations of pain or itch. There are various indications that peripheral opioids are also involved in wound healing and anti-inflammatory responses (Rachinger-Adam et al. 2011). These effects are closely linked to pain and itch sensations, and more and more evidence is evolving toward the idea of the peripheral opioids being crucial in the regulation of inflammation, wound healing, and unpleasant itch or pain sensations. Targeting these opioids by topical or peripheral treatments will lead to novel strategies without the well-known and dreadful side effects on the CNS (Bigliardi et al. 2009; Reich and Szepietowski 2012).

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