Role of kappa‐opioid and mu‐opioid receptors in pruritus: Peripheral and central itch circuits

Abstract

Modern genetic approaches in animal models have unveiled novel itch‐specific neural pathways, emboldening a paradigm in which drugs can be developed to selectively and potently target itch in a variety of chronic pruritic conditions. In recent years, kappa‐opioid receptors (KORs) and mu‐opioid receptors (MORs) have been implicated in both the suppression and promotion of itch, respectively, by acting on both the peripheral and central nervous systems. The precise mechanisms by which agents that modulate these pathways alleviate itch remains an active area of investigation. Notwithstanding this, a number of agents have demonstrated efficacy in clinical trials that influence both KOR and MOR signalling. Herein, we summarize a number of opioid receptor modulators in development and their promising efficacy across a number of chronic pruritic conditions, such as atopic dermatitis, uremic pruritus and beyond.

Discovery and Binding Mechanism of Pyrazoloisoquinoline-Based Novel β-Arrestin Inverse Agonists of the Kappa-Opioid Receptor

“…In regard to peripheral effects, KOR antagonists have been reported to promote pruritus by acting on both the peripheral and CNS due to an imbalance of KOR and MOR. 24 In fact, the KOR agonist nalfurafine, the only approved KOR targeted drug, is used as an antipruritic medication in Japan. 25 Although the mechanism of antipruritic effects of KOR activation has been suggested to be independent of the β-arrestin pathway, 26,27 β-arrestin inverse agonist 7q may lead the pruritus side effects since it showed a high binding affinity at KOR in the binding assay using the radiolabeled KOR antagonist.…”

“…Nevertheless, further studies such as the brain PK study would be needed for the evaluation of practical physicochemical property of the compound to apply for CNS targeted drug discovery since PAMPA is an artificial membrane system. In regard to peripheral effects, KOR antagonists have been reported to promote pruritus by acting on both the peripheral and CNS due to an imbalance of KOR and MOR . In fact, the KOR agonist nalfurafine, the only approved KOR targeted drug, is used as an antipruritic medication in Japan .…”

Arsenic exposure and pruritus: Evidence from observational, interventional, and mendelian randomization studies

“…Abbreviations: AS3MT, gene encoding arsenite methyltransferase; DMA, dimethylated arsenic; MMA, monomethylated arsenic; NRS, numerical rating scale; OR, odds ratio; PRS, polygenic risk score through a distinct pathway in the nervous system known as the "itch pathway". [11][12][13] However, the triggers that activate MOR and increase β-endorphin in pruritus have not been fully explored.…”

“…One potential mechanism for the relationship between β‐endorphin and pruritus is through the activation of mu‐opioid receptors. μ‐opioid receptors (MOR), known as playing a critical role in pain modulation, 10 have also been found to be involved in itch perception since itch sensation is transmitted through a distinct pathway in the nervous system known as the “itch pathway” 11–13 . However, the triggers that activate MOR and increase β‐endorphin in pruritus have not been fully explored.…”

Pruritus Is Associated with an Increased Risk for the Diagnosis of Autoimmune Skin Blistering Diseases: A Propensity-Matched Global Study

“…Free nerve endings of nonmyelinated C-type nerve fibers that are located at the dermo-epidermal junction and within the epidermis are assumed to regulate pruritus [ 11 ]. Further, there is also evidence of histamine-independent itch-specific fibers in the skin, such as G-protein-coupled receptors, kappa-opioid receptors, and mu-opioid receptors [ 12 ]. More recently investigated receptors include the interleukin (IL)-31RA and oncostatin-m-specific receptor (OSMR), in addition to the transient receptor potential cation channel subfamily V member 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1), thymic stromal lymphopoietin protein receptor (TSLPR), protease-activated receptor 2 (PAR-2), neurokinin 1 receptor (NK1R), Trk, and histamine (H) 1R and H4R, as well as mas-related G-protein-coupled receptors (MRGPRs) [ 13 , 14 , 15 , 16 , 17 ] that play a role in pruritus mechanisms ( Figure 1 ).…”