The role of kappa opioid receptors in immune system – An overview (2023)

European Journal of Pharmacology

Volume 933,

15 October 2022

, 175214

Author links open overlay panel, , ,

Abstract

Opioids are one of the most effective anti-nociceptive agents used in patients with cancer pain or after serious surgery in most countries. The endogenous opioid system participates in pain perception, but recently its role in inflammation was determined. κ-opioid receptors (KOP receptors), a member of the opioid receptor family, are expressed in the central and peripheral nervous system as well as on the surface of different types of immune cells, e.g. T cells, B cells and monocytes. In this review, we focused on the involvement of KOP receptors in the inflammatory process and described their function in a number of conditions in which the immune system plays a key role (e.g. inflammatory bowel disease, arthritis, subarachnoid hemorrhage, vascular dysfunction) and inflammatory pain. We summed up the application of known KOP ligands in pathophysiology and we aimed to shed new light on KOP receptors as important elements during inflammation.

Introduction

Opioids are effective in pain relief as well as prevention of its recurrence. Conversely, opioid therapy can adversely affect many organs, including the gastrointestinal (GI), cardiovascular, immune, endocrine and central nervous systems.

The mechanism of opioids action is based on their interactions with opioid receptors located on the cell membrane. Four types of opioid receptors (μ - MOP, δ – DOP, κ – KOP and NOP) and different families of the endogenous agonists (endorphins, enkephalins, dynorphins or nociceptin) constitute the endogenous opioid system (EOS) (Liang et al., 2016). Endogenous opioids are formed by a proteolytic cleavage of precursors. The precursor of endorphins is proopiomelanocortin (POMC), preproenkephalin (PENK) is the precursor of leucine (Leu)- and methionine (Met)-enkephalins, dynorphins are produced from preprodynorphin (PDYN), whereas prepronociceptin is a precursor form of nociceptin (Benarroch, 2012). It should be noted that endogenous opioid peptides do not bind specifically to one type of the opioid receptors, but they exert some affinity for other opioid receptors as well (Table 1).

Endogenous opioid peptides are produced in the central nervous system (CNS), enteric neurons, endocrine and immune cells as well as in various glands throughout the body, i.e. pituitary and adrenal glands. Opioid peptides, which are released by immune cells, interact with opioid receptors located on the primary afferent neurons (Joseph et al., 2010).

Many years of research have shown that expression of the opioid receptors is increased during inflammation. So far, literature provided evidence about the role of MOP, DOP and NOP receptors in this field, their involvement has been confirmed in in vitro experiments and numerous animal models, including inflammatory bowel diseases (IBD), arthritis or vascular inflammation (Iwaszkiewicz et al., 2013; Liang et al., 2016; Philippe et al., 2003).

IBD is a chronic immune-mediated disorder, which is divided into two main types: Crohn's disease (CD) and ulcerative colitis (UC), whose detailed etiology is not well known. A 6-7-fold increase in MOP receptor expression was observed in the ileum and colon collected from patients with CD and a 30-fold increase in mRNA MOP receptor in the colon in patients with UC as compared to healthy controls (Philippe et al., 2006). Moreover, DOP receptor expression at mRNA and protein level was increased in the myenteric and submucosal preparations of the inflamed intestine (Pol et al., 2003). In turn, modulation of NOP receptors activity with small molecules has been recognized as a potential approach to treat inflammatory bowel diseases (Alt et al., 2012). Research to date provides an information about the action and role of three opioid receptors, however, another member of this family, namely KOP receptor, is poorly characterized. KOP receptors are expressed in different types of cells (Fig. 1). Stress-induced KOP receptor activation may enhance the analgesic response and modulate depression (Carlezon et al., 2006; McLennan et al., 2008). Furthermore, peripherally restricted KOP receptor agonists selectively reduce pain and itching, as well as mechanical hypersensitivity (Snyder et al., 2018). Nevertheless reports concerning KOP receptor are limited, therefore, in this review, we focused on the involvement of this receptor in the inflammation and pain (Fig. 2).

Recent advances in laboratory techniques have enabled for development of KOP receptor ligands as anti-nociceptive and anti-inflammatory agents. Some of drugs occur naturally and have been used in the traditional medicine and can be obtained from plants i.e. Salvia divinorum (Jones et al., 2016). Selected KOP receptor ligands have been characterized in preclinical and clinical studies and summarized in Table 2.

Section snippets

Kappa opioids receptors affect the immune cells

Response to harmful stimuli such as pathogens, toxic compounds or damaged cells leads to activation of multiple signaling pathways combined with a release of inflammatory cytokines. Inflammation is characterized by the activation of immune and non-immune cells that protect the host by eliminating pathogens and promoting cell/tissue repair and regeneration. Therefore, activation of the immune system is essential to restore homeostasis. Current state of the art suggests that inflammation may

Inflammatory bowel diseases

KOP receptors, localized in the GI tract, are expressed on myenteric and submucosal plexus neurons (Bagnol et al., 1997; Gray et al., 2006). All opioid receptors are expressed by interstitial cells of Cajal where MOP receptor co-localizes with DOP or KOP receptors in the rat GI tract (Gray et al., 2006). In the human colon, KOP receptors are located in excitatory and inhibitory motoneurons (Galligan and Akbarali, 2014).

Some studies indicated the involvement of KOP receptors during intestinal

Inflammatory pain

Pain is an increasingly common problem, affecting a large percentage of the population. In 2019 20.4% of adults in the United States suffered from chronic pain, and in 7.4% of them the pain limited their daily activities or work (referred to as high intensity chronic pain) (Zelaya et al., 2020). Additionally, more than 50% of the Danish patients with arthritis reported a clinically significant pain (Rifbjerg-Madsen et al., 2017). Nowadays, exact mechanisms underlying the pain are still unclear.

Conclusions

KOP receptors are localized on immune cells, e.g. lymphocytes, macrophages, NK cells, and constitute a potential target in inflammatory diseases. Several studies have confirmed the positive effects of KOP receptor modulation in IBD, subarachnoid hemorrhage, joint inflammation and vascular dysfunction.

Current state of knowledge indicates that activation or inhibition of KOP receptors may play a crucial role in pharmacotherapy. The modulation of inflammation by KOP receptors may occur in two

(Video) Therapeutic Potential of Kappa Opioids in Pain And Addiction

Author contribution

AS and MZ provided the overall concept and framework of the manuscript; AS reviewed current knowledge in the field of paper; AS and MZ wrote the manuscript; JF, WM and MZ revised critically the manuscript. All authors read and approved the final version of the manuscript.

Declaration of competing interest

The authors declare no conflict of interest.

Acknowledgements

Supported by grants from National Science Center #UMO-2019/35/D/NZ7/02830 to MZ and Medical University of Lodz #503/1-156-04/503-11-001-19-00 to JF.

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    FAQs

    What is the role of the kappa opioid receptor? ›

    Kappa opioid receptors (KORs) play a critical role in modulating dopamine, serotonin, and glutamate release in the central nervous system. Dynorphin is a peptide neurotrans- mitter processed from its precursor prodynorphin and is the endogenous ligand of the KOR (5).

    Read More ›
    What do Kappa and Delta opioid receptors do? ›

    Similar to mu opioid receptors, kappa and delta opioid receptors reside in the periphery, the dorsal root ganglion, the spinal cord, and in supraspinal regions associated with pain modulation. Both delta and kappa opioid agonists have been shown to activate pain inhibitory pathways in the central nervous system.

    Read More ›
    What are the effects of kappa opioid receptor agonist? ›

    However, MOA use results in a plethora of well-described side-effects; these include nausea, vomiting, constipation, respiratory depression, addiction, tolerance, and sedation.

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