Opioidergic Signaling-A Neglected, Yet Potentially Important Player in Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is one of the most common skin diseases, the prevalence of which is especially high among children. Although our understanding about its pathogenesis has substantially grown in recent years, and hence, several novel therapeutic targets have been successfully exploited in the management of the disease, we still lack curative treatments for it. Thus, there is an unmet societal demand to identify further details of its pathogenesis to thereby pave the way for novel therapeutic approaches with favorable side effect profiles. It is commonly accepted that dysfunction of the complex cutaneous barrier plays a central role in the development of AD; therefore, the signaling pathways involved in the regulation of this quite complex process are likely to be involved in the pathogenesis of the disease and can provide novel, promising, yet unexplored therapeutic targets. Thus, in the current review, we aim to summarize the available potentially AD-relevant data regarding one such signaling pathway, namely cutaneous opioidergic signaling.

Keywords: atopic dermatitis (AD); cutaneous barrier; inflammation; itch; keratinocyte; mast cell; nociceptin/orphanin FQ (NOP) receptor; opioid; skin; µ-opioid receptor (MOR); δ-opioid receptor (DOR); κ-opioid receptor (KOR).

Figure 1

Overview of the major opioid receptors and their most important exogenous ligands mentioned in the text. Affinity data are obtained from the IUPHAR Guide to Pharmacology database (accessed on 5 December 2021) or (in case of PK20) from Ref [82]. When available, affinities for the human receptors are shown. If such data were not available, animal data are given (indicated by yellow fonts). Bold characters highlight apparently selective compounds (i.e., compounds that have no other targets according to the said database). Note that, unlike the other opioid receptors, ζ (OGF) receptor is normally expressed in the nuclear envelope. Upon binding OGF, it translocates to the nucleus, where it directly regulates gene expression [79]. Please note that we only provide affinity but not efficacy data of the substances.

Figure 2

Overview of the origin and receptor affinity of the most important endogenous opioids. The color code indicates the relevant targets of each molecule. When one molecule can activate more than one receptor, the order of the colors from the left to the right represents the order of the affinity toward each receptor. For example, the order of colors in case of “β-endorphin” (black-blue-green) indicates that its affinity is the highest to human MOR, it is less to DOR, and even less to KOR. Affinity data are obtained from the IUPHAR Guide to Pharmacology database (accessed on 5 December 2021) and from Ref [83]. Importantly, lack of a specific color does not necessarily mean lack of the respective binding, but rather lack of experimental evidence of the said binding. Please note that we only provide affinity but not efficacy data of the substances.

Figure 3

Overview of the expression patterns and “AD-relevant” roles of the major opioid receptors in human epidermal keratinocytes and PBMCs. DOR, KOR, and MOR are involved in the regulation of the proliferation/differentiation balance of the epidermal keratinocytes, as well as in influencing immune responses. (Question marks indicate conflicting data/unclear effects.)

Figure 4

Overview of the “AD-relevant” effects of selected modulators of the key opioid receptors. Note that most of the above compounds are not selective (for details, see Figure 2) but can rather concentration dependently activate/antagonize multiple opioid receptors. The color code indicates the relevant targets of each molecule. When one molecule can activate or antagonize more than one receptor, the order of the colors from the left to the right represents the order of the affinity toward each receptor. For example, the order of colors in the case of “Naltrexone” (black-green-blue) indicates that its affinity is highest with human MOR, it is less with KOR, and even less with DOR. Affinity data are obtained from the IUPHAR Guide to Pharmacology database (accessed on 5 December 2021) as well as from Ref [121] (in the case of KORA 5a). Importantly, lack of a specific color does not necessarily mean lack of the respective binding but rather lack of experimental evidence of the said binding. Please note that we only provide affinity but not efficacy data of the substances. This is especially important in the case of Nalbuphine, since it can simultaneously activate KOR, and, as a partial agonist, suppress full agonist-induced MOR and DOR signaling.

Figure 5

Hypothesized contribution of β-endorphin and IL-13-induced upregulation (or impaired activation-induced downregulation) of MOR to the pathogenesis of AD. Blue background marks external factors, internal contributors are highlighted with yellow background, whereas green background indicates that stress can be the consequence of internal and external causes as well. As shown on the figure, β-endorphin appears to be a common point in multiple AD-relevant pathways. Although there is a continuous β-endorphin-mediated activation, at least in a subset of the AD patients, MOR does not downregulate, most likely because of the presence of IL-13 and/or certain external factors (e.g., BCM7). This may lead to pathologically prolonged MOR activity further skewing the immune response toward T_h2 polarization, and possibly disturbing differentiation of epidermal keratinocytes, as well as maturation/degranulation of cutaneous MCs. However, it should also be noted that certain data argue for a different working hypothesis. Indeed, as mentioned in the main text, certain reports argue that expression pattern of MOR alters in certain AD patients, i.e., MOR becomes intracellular in the keratinocytes of the lesional skin, which leaves MOR on the sensory neurons without competition for the ligand (β-endorphin), leading to overactivation of the said neuronal receptors [193,240,247]. (Question marks indicate hypothesized effects.)