Non-Neuronal Kappa Opioid Pathway Profiling in the Skin of Different Chronic Pruritus–Associated Dermatoses

Abstract

Recent studies argue for an important role of peripheral opioidergic signaling including cutaneous pathways in inflammation, neurons and itch ( Ádám et al., 2022 Ádám D Arany J Tóth KF Tóth BI Szöllősi AG Oláh A Opioidergic Signaling—A Neglected, Yet Potentially Important Player in Atopic Dermatitis. Int J Mol Sci. MDPI. 2022; Google Scholar ). Signal transduction induced by synthetic opiates and endogenous opioid peptides takes place via three types of opioid receptors (OR), the μ-OR (MOR), δ-OR (DOR) and the κ-OR (KOR) ( Tominaga et al., 2007 Tominaga M, Ogawa H, Takamori K. Possible Roles of Epidermal Opioid Systems in Pruritus of Atopic Dermatitis. Journal of Investigative Dermatology. Elsevier Masson SAS; 2007;127(9):2228–2235 Available from: https://linkinghub.elsevier.com/retrieve/pii/S0022202X15335387 Google Scholar ). A specific agonist/receptor combination is usually preferred for activation of the signaling cascade, e.g. morphine/MOR and dynorphin/KOR ( Snyder et al., 2018 Snyder LM, Chiang MC, Loeza-Alcocer E, Omori Y, Hachisuka J, Sheahan TD, et al. Kappa Opioid Receptor Distribution and Function in Primary Afferents. Neuron. Elsevier Inc.; 2018;99(6):1274-1288.e6 Available from: https://doi.org/10.1016/j.neuron.2018.08.044 Google Scholar ). The nervous system is the predominant site of opioid receptor expression including their endogenous agonists (Rogers 2020). However, these can also be found in non-neuronal peripheral cells of the skin ( Kupczyk et al., 2017 Kupczyk P Reich A Hołysz M Gajda M Wysokińska E Kobuszewska A et al. Opioid receptors in psoriatic skin: Relationship with itch. Acta Derm Venereol. 2017; 97: 564-570 Crossref PubMed Scopus (30) Google Scholar ). So far, little is known about the cutaneous expression and function of endogenous opioid peptides and their receptors. This includes the κ-opioidergic system, which is in the current focus of the itch research and already resulted in the first approved peripherally acting KOR agonist difelikefalin. ( Fishbane et al., 2020 Fishbane S Jamal A Munera C Wen W Menzaghi F A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. New England Journal of Medicine. 2020; 382: 222-232 Crossref PubMed Scopus (0) Google Scholar ; Inan et al., 2019 Inan S Huerta A Jensen L Dun N, Cowan A. Nalbuphine, a kappa opiod receptor agonist and mu opioid receptor antagonist attenuates pruritus, decreases IL-31, and increases IL-10 in mice with contact dermatitis. Eur J Pharmacol. 2019; : 864 Google Scholar ) . Interestingly, OPRK1 expression found to be reduced in lesional pruritic skin areas compared to non-lesional, non-pruritic skin areas in patients, with keratinocytes as predominant expression site. Based on these data, itch induced by a cutaneous imbalance in KOR expression with stable expression of MOR has been discussed, forcing the importance of KOR ( Kupczyk et al., 2017 Kupczyk P Reich A Hołysz M Gajda M Wysokińska E Kobuszewska A et al. Opioid receptors in psoriatic skin: Relationship with itch. Acta Derm Venereol. 2017; 97: 564-570 Crossref PubMed Scopus (30) Google Scholar ; Phan et al., 2012 Phan NQ Lotts T Antal A Bernhard JD Ständer S Systemic kappa Opioid receptor agonists in the treatment of chronic pruritus: A literature review. Acta Derm Venereol. 2012; 92: 555-560 Crossref PubMed Scopus (100) Google Scholar ). Therefore, we investigated the KOR, MOR and dynorphin expression in skin biopsies from patients with chronic pruritus-associated inflammatory skin diseases with different pathophysiology and different epidermal pathology. We selected the entities of atopic dermatitis (AD), psoriasis (PSO), chronic nodular prurigo (CNPG), lichen planus (LP), mastocytosis (MAST) and healthy controls.