European Journal of Pharmacology
15 October 2022
Author links open overlay panel, , ,
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.
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.
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
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.
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
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.
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.
- C. Alicea et al.
Inhibition of primary murine macrophage cytokine production in vitro following treatment with the K-opioid agonist U50,488H
- Q.S. Auh et al.
Effects of peripheral κ opioid receptor activation on inflammatory mechanical hyperalgesia in male and female rats
(2012)See Alsoκ receptor | Opioid receptors
- D. Bagnol et al.
Cellular localization and distribution of the cloned mu and kappa opioid receptors in rat gastrointestinal tract
- M.R. Bruchas et al.
Long-acting κ opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase
J. Biol. Chem.
- I. Carroll et al.
Pharmacological properties of JDTic: a novel κ-opioid receptor antagonist
Eur. J. Pharmacol.
- N. Cenac et al.
Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2
Am. J. Pathol.
- T. Endoh et al.
Potent antinociceptive effects of TRK-820, a novel κ-opioid receptor agonist
- T. Endoh et al.
Characterization of the antinociceptive effects of TRK-820 in the rat
Eur. J. Pharmacol.
- C. Gavériaux-Ruff et al.
Enhanced humoral response in kappa-opioid receptor knockout mice
- A.C. Gray et al.
Comparison of opioid receptor distributions in the rat ileum
Inhibition of T cell superantigen responses following treatment with the κ-opioid agonist U50,488H
Enhancement of phagocytosis by dynorphin A in mouse peritoneal macrophages
Salvinorin A analogs and other kappa-opioid receptor compounds as treatments for cocaine abuse
Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses
Pharmacol. Biochem. Behav.
Opioids suppress chemokine-mediated migration of monkey neutrophils and monocytes - an instant response
The contribution of activated peripheral kappa opioid receptors (kORs) in the inflamed knee joint to anti-nociception
Novel orally available salvinorin a analog PR-38 protects against experimental colitis and reduces abdominal pain in mice by interaction with opioid and cannabinoid receptors
Endogenous kappa-opioid receptor systems inhibit hyperalgesia associated with localized peripheral inflammation
Inflammation-induced changes in rostral ventromedial medulla mu and kappa opioid receptor mediated antinociception
Functional selectivity of 6′-guanidinonaltrindole (6′-GNTI) at κ-opioid receptors in striatal neurons
J. Biol. Chem.
Evaluation of dynorphin and kappa-opioid receptor level in the human blood lymphocytes and plasma: possible role as a biomarker in severe opioid use disorder
Drug Alcohol Depend.
Salvinorin A attenuates early brain injury through PI3K/Akt pathway after subarachnoid hemorrhage in rat
Naltrexone (NTX) relieves inflammation in the collagen-induced- arthritis (CIA) rat models through regulating TLR4/NFκB signaling pathway
Nociceptin/orphanin FQ inhibition with SB612111 ameliorates dextran sodium sulfate-induced colitis
Eur. J. Pharmacol.
Role of the dynorphin/kappa opioid receptor system in the motivational effects of ethanol
Alcohol Clin. Exp. Res.
Analgesic efficacy of peripheral κ-opioid receptor agonist CR665 Compared to oxycodone in a multi-modal, multi-tissue experimental human pain model: selective effect on visceral pain
Therapeutic potential of kappa opioid agonists
Detection of К-opioid receptor mRNA in immature T cells
Endogenous opioid systems: current concepts and clinical correlations
Detection and function of opioid receptors on cells from the immune system
Clin. Diagn. Lab. Immunol.
Opioid receptors and signaling on cells from the immune system
Asimadoline, a κ-opioid agonist
and Visceral Sensation NIH Public Access
Depressive-like effects of the κ-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats
J. Pharmacol. Exp. Therapeut.
IL-4 induces M2 macrophages to produce sustained analgesia via opioids
Phosphinic derivatives as new dual enkephalin-degrading enzyme inhibitors: synthesis, biological properties, and antinociceptive activities
J. Med. Chem.
Inflammatory responses and inflammation-associated diseases in organs
Local kappa opioid receptor activation decreases temporomandibular joint inflammation
The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a national institutes of health pathways to prevention workshop
Ann. Intern. Med.
Cytokine-mediated inflammatory hyperalgesia limited by interleukin-4
Br. J. Pharmacol.
Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ/AKT/nNOS/NO signaling pathway
Effect of asimadoline, a κ opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome
Aliment. Pharmacol. Ther.
Cellular and oxidative mechanisms associated with interleukin-6 signaling in the vasculature
Int. J. Mol. Sci.
Bremazocine: a κ-opioid agonist with potent analgesic and other pharmacologic properties
CNS Drug Rev.
Topical nalfurafine exhibits anti-inflammatory and anti-pruritic effects in a murine model of AD
J. Dermatol. Sci.
Salvinorin A has antiinflammatory and antinociceptive effects in experimental models of colitis in mice mediated by KOR and CB1 receptors
Inflamm. Bowel Dis.
Salvinorin A inhibits colonic transit and neurogenic ion transport in mice by activating κ-opioid and cannabinoid receptors
Neuro Gastroenterol. Motil.
Methylglyoxal impairs ATP- and UTP-induced relaxation in the rat carotid arteries
European Journal of Pharmacology, Volume 933, 2022, Article 175259
Although methylglyoxal (MGO), a highly reactive dicarbonyl compound, influences the functioning of the vasculature, modulating its effects on vascular reactivity to various substances remains unclear, especially purinoceptor ligands. Therefore, we sought to investigate the direct effects of MGO on relaxation induced by adenosine 5′-triphosphate (ATP) and uridine 5′-triphosphate (UTP) in isolated rat carotid arteries. When carotid arteries were exposed to MGO (420μM for 1h), relaxation induced by acetylcholine or sodium nitroprusside was not affected by MGO. However, ATP- and UTP-induced relaxation was impaired by MGO compared with the control. In both ATP- and UTP-induced relaxation, endothelial denudation, incubation with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine or the selective P2Y purinoceptor 2 (P2Y2) receptor antagonist AR-C118925XX reduced relaxation in both the control and MGO groups, while the differences between the control and MGO groups were eliminated. The cyclooxygenase (COX) inhibitor indomethacin inhibited the differences in ATP/UTP-mediated relaxations between the control and MGO groups. Moreover, N-acetyl-L-cysteine (NAC), an antioxidant, could augment carotid arterial relaxation induced by ATP/UTP in the presence of MGO. MGO increased arachidonic acid-induced contraction, which was suppressed by NAC. Following both ATP/UTP stimulation, MGO increased the release of prostanoids. These results suggest that MGO impaired ATP- and UTP-induced relaxation in carotid arteries, which was caused by suppressed P2Y2 receptor-mediated signaling and reductions in endothelial NO. Moreover, MGO partially contributed to COX-derived vasoconstrictor prostanoids through increased oxidative stress.
NLRP3 inflammasomes: A potential target to improve mitochondrial biogenesis in Parkinson's disease
European Journal of Pharmacology, Volume 934, 2022, Article 175300
Parkinson's disease (PD) is a common neurodegenerative condition for which no approved treatment exists to prevent collective neuronal death. There is ample evidence that mitochondrial dysfunction, reactive oxygen species (ROS), and associated caspase activity underlie the pathology observed. Neurons rely on mitochondrial activity since they have such high energy consumption. Therefore, it is not surprising that mitochondrial alterations favour neuronal degeneration. In particular, mitochondrial dysregulation contributes to PD, based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Also, it is known that inflammatory cytokine-mediated neuroinflammation is the key pathogenic mechanism in neuronal loss. In recent years, the research has focussed on mitochondria being the platform for nucleotide-binding oligomerization domain-like receptors 3 (NLRP3) inflammasome activation. Mitochondrial dysfunction and NLRP3 activation are emerging as critical players in inducing and sustaining neuroinflammation. Moreover, mitochondrial-derived ROS and mitochondrial DNA (mtDNA) could serve as the priming signal for forming inflammasome complexes responsible for the activation, maturation, and release of pro-inflammatory cytokines, including interleukin-1(IL-1) and interleukin-18 (IL-18). The current review takes a more comprehensive approach to elucidating the link between mitochondrial dysfunction and aberrant NLRP3 activation in PD. In addition, we focus on some inhibitors of NLRP3 inflammatory pathways to alleviate the progression of PD.(Video) Opioid receptors and brain function
Inhibition of neuropilin-1 enhances the therapeutic effects of lenvatinib in suppressing cholangiocarcinoma cells via the c-Met pathway
European Journal of Pharmacology, Volume 935, 2022, Article 175290
Neuropilin-1 (NRP-1) participates in the progression of cholangiocarcinoma (CCA) and lenvatinib is an approved tyrosine kinase inhibitor treating several other cancers. Our exploratory study reveals that the inhibitory activities of lenvatinib largely rely on the expression levels of NRP-1 in CCA cells, leading to the present study that aims to investigate whether inhibition of NRP-1 could enhance the effects of lenvatinib in suppressing CCA. By using stable transfected CCA cells depleted of NRP-1 and EG00229, a specific NRP-1 inhibitor, we examined cell proliferation, cell cycle distribution and apoptosis, and detected the expression of key molecules and the involvement of the c-Met pathway. Xenograft mouse models were employed to verify the in vitro results. NRP-1 depletion and EG00229 strengthened lenvatinib in inhibiting the proliferation and promoting the apoptosis of CCA cells, and their additive or synergistic effects were confirmed in animal models. Mechanistically, lenvatinib induced the activation of the c-Met pathway, while either NRP-1 depletion or EG00229 inhibited this activation, which could be stimulated by its ligand hepatocyte growth factor. NRP-1 inhibition resulted in a significant alteration in the expression/activation of downstream pathways and molecules, which are key factors regulating cell proliferation and apoptosis. In conclusion, the present results indicate that the inhibition of NRP-1 enhances the efficacy of lenvatinib via the c-Met pathway, and warrant further studies on the pharmacological utility of EG00229, particularly, in the combination of lenvatinib as a promising adjunct therapeutic strategy for combating CCA.
Non-genomic uterorelaxant actions of corticosteroid hormones in rats: An in vitro and in vivo study
European Journal of Pharmacology, Volume 935, 2022, Article 175346
We aimed to identify the short-term effects of a glucocorticoid (GC) and a mineralocorticoid (MC) on non-pregnant and late pregnant rat uterine contractions to estimate their tocolytic potential.
The in vitro contractility studies were performed with uterine tissues from non-pregnant and 22-day pregnant SPRD rats. The cumulative dose-response of fludrocortisone (FLU) and dexamethasone (DEX) was measured alone or in the presence of steroid receptor antagonist mifepristone (MIF) or spironolactone (SPR). [35S]GTPγS and cAMP immunoassays were carried out to detect the activated G-proteins and cAMP, respectively. The in vivo uterine action of single doses of FLU and DEX was measured by smooth muscle electromyography. The results were statistically analyzed with an unpaired t-test.
FLU and DEX relaxed both pregnant (33 and 34%) and non-pregnant (37 and 34%) uteri in vitro. MIF inhibited the relaxing effect of DEX, especially in the pregnant uterus, but reduced the effect of FLD only in non-pregnant tissues. GTPγS studies showed a MIF-sensitive elevation in activated G-proteins both in pregnant and non-pregnant uteri by DEX, whereas FLU induced activation only in non-pregnant samples. DEX relaxed pregnant and non-pregnant uteri in vivo in a MIF-sensitive way.
DEX can inhibit contractions in the late pregnant uterus in a non-genomic manner, while FLU seems to be ineffective. Its action is mediated by a G-protein-coupled receptor that can be blocked by mifepristone. Further investigations are necessary to determine the required dose and duration of GCs in the therapy of premature birth.
Bergapten attenuates microglia-mediated neuroinflammation and ischemic brain injury by targeting Kv1.3 and Carbonyl reductase 1
European Journal of Pharmacology, Volume 933, 2022, Article 175242
Microglia-mediated neuroinflammation plays a vital role in the pathogenesis of ischemic stroke, which serves as a prime target for developing novel therapeutic agent. However, feasible and effective agents for controlling neuroinflammation are scarce. Bergapten were acknowledged to hold therapeutic potential in restricting inflammation in multiple diseases, including peripheral neuropathy, migraine headaches and osteoarthritis. Here, we aimed to investigate the impact of bergapten on microglia-mediated neuroinflammation and its therapeutic potential in ischemic stroke. Our study demonstrated that bergapten significantly reduced the expression of pro-inflammatory cytokines and the activation of NF-κB signaling pathway in LPS-stimulated primary microglia. Mechanistically, bergapten suppressed cellular potassium ion efflux by inhibiting Kv1.3 channel and inhibits the degradation of Carbonyl reductase 1 induced by LPS, which might contribute to the anti-inflammatory effect of bergapten. Furthermore, bergapten suppressed microglial activation and post-stroke neuroinflammation in an experimental stroke model, leading to reduced infarct size and improved functional recovery. Thus, our study identified that bergapten might be a potential therapeutic compound for the treatment of ischemic stroke.
7-Methoxyisoflavone suppresses vascular endothelial inflammation by inhibiting the expression of endothelial adhesion molecules
European Journal of Pharmacology, Volume 933, 2022, Article 175268
Endothelial cells (ECs) are vital regulators of inflammatory processes, there is the potential for inhibition of EC inflammation to be a therapeutic target in chronic inflammatory diseases. This study aimed to investigate the effect of 7-methoxyisoflavone (7-Mif) on endothelial inflammation. Our results showed that 7-Mif have no cytotoxicity on HUVECs. Pretreatment with 5μM, 10μM and 50μM 7-Mif significantly reduced IL-1β-induced ICAM-1 (28.1%±4.1%, 25.9±2.5% and 32.0%±3.2%, respectively) and VCAM-1 (48.0%±5.6%, 40.1±3.1% and 39.6%±3.1%, respectively) mRNA expression. And pretreatment with 10μM and 50μM 7-Mif significantly reduced IL-1β-induced ICAM-1 (45.1%±4.4% and 33.6±4.4%, respectively) and VCAM-1 (53.0%±3.7% and 53.7±5.1%, respectively) protein levels. Furthermore, pretreatment with 50μM 7-Mif inhibited monocyte-endothelial cell adhesion (50.2%±4.2%). Mechanistically, our results showed that 7-Mif reversed IL-1β-induced NF-κB activation and p65 translocation to the nucleus, therefore inhibiting endothelial cell inflammation. In addition, we confirmed that 7-Mif 10mg/kg and 20mg/kg reduced LPS-induced ICAM-1 (47.3%±1.3% and 39.0%±3.2%, respectively) and VCAM-1 (56.5±2.8% and 47.8±4.3%, respectively) expression and attenuated inflammatory injury in mice. In conclusion, we showed the inhibitory effect of 7-Mif on endothelial inflammation by suppressing the expression of endothelial adhesion molecules and monocyte adhesion. Our data illustrated that 7-Mif could positively regulate the process of endothelial inflammation.
© 2022 Elsevier B.V. All rights reserved.
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).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.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.