In major depression, increased kappa and mu opioid receptor levels are associated with immune activation

2020 ◽  
Vol 32 (2) ◽  
pp. 99-108 ◽  
Author(s):  
Hussein Kadhem Al-Hakeim ◽  
Suhaer Zeki Al-Fadhel ◽  
Arafat Hussein Al-Dujaili ◽  
Michael Maes
Keyword(s):  
Opioid Receptor ◽  
Immune Activation ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Receiver Operating Curve ◽  
Primary Immune Response ◽  
Mu Opioid ◽  
Simultaneous Activation ◽  
Drug Free ◽  
Inflammatory System

AbstractObjective:This study was carried out to delineate differences between major depressive disorder (MDD) and healthy controls in dynorphin and kappa opioid receptor (KOR) levels in association with changes in the β-endorphin – mu opioid receptor (MOR) and immune-inflammatory system.Methods:The present study examines dynorphin, KOR, β-endorphin, MOR, interleukin (IL)-6 and IL-10 in 60 drug-free male participants with MDD and 30 age-matched healthy males.Results:Serum dynorphin, KOR, β-endorphin and MOR are significantly higher in MDD as compared to controls. The increases in the dynorphin/KOR system and β-endorphin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, β-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls with a bootstrapped (n = 2000) area under the receiver operating curve of 0.972. The dynorphin/KOR system is significantly decreased in depression with comorbid nicotine dependence.Conclusion:Our findings suggest that, in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and β-endorphin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by (a) exerting immune-regulatory activities attenuating the primary immune response and (b) modulating reward responses and mood as well as emotional and behavioural responses to stress.

scholarly journals In Major Depression, Increased Serum Dynorphin and Kappa Opioid Receptor Levels are Positively Associated with Mu Opioid Receptor Levels and Immune Activation and Are Attenuated by Nicotine Dependence

2019 ◽  
Author(s):  
Hussein Al-Hakeim ◽  
Suhaer Al-Fadhel ◽  
Arafat Hussein Al-Dujaili ◽  
Michael Maes
Keyword(s):  
Major Depression ◽  
Nicotine Dependence ◽  
Opioid Receptor ◽  
Immune Activation ◽  
Kappa Opioid Receptor ◽  
Receiver Operating Curve ◽  
Kappa Opioid ◽  
Mu Opioid ◽  
Beta Endorphin ◽  
Opioid Systems

Background: There is now evidence that immune and opioid systems show functional reciprocal relationships and that both systems may participate in the pathophysiology of major depression (MDD). Objective: The present study was carried out to delineate differences between MDD patients and healthy controls in dynorphin and kappa opioid receptor (KORs) in association with levels of β-endorphins and mu opioid receptors (MORs), interleukin-6 (IL-6) and IL-10. Method: The present study recruited 60 drug-free male participants with MDD aged 24-70 year and 30 age-matched healthy males as control group and measured serum levels of dynorphin, KOR, β-endorphin, MOR, IL-6 and IL-10. Results: Serum dynorphin, KOR, β-endorphin and MOR are significantly increased in MDD as compared with controls. The increases in the dynorphin/KOR system and β-endorhin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, β-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls, whereby both opioid peptides and cytokines show a bootstrapped (n=2000) area under the receiver operating curve of 0.972. KOR and the dynorphin/KOR system are both significantly decreased in depressed subjects with comorbid nicotine dependence. Conclusion: Our findings suggest that in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and β-endorhin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by a) exerting immune regulatory activities attenuating the primary immune response; and b) modulating reward responses and mood as well as emotional and behavioral responses to stress.

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

scholarly journals IL-10 is associated with increased mu-opioid receptor levels in major depressive disorder

2019 ◽  
Vol 57 ◽  
pp. 46-51 ◽  
Author(s):  
Suhaer Zeki Al-Fadhel ◽  
Hussein Kadhem Al-Hakeim ◽  
Arafat Hussein Al-Dujaili ◽  
Michael Maes
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Opioid Receptor ◽  
Regulatory System ◽  
Mu Opioid Receptor ◽  
Endogenous Opioids ◽  
Major Depressive ◽  
Mu Opioid ◽  
Male Patients ◽  
Drug Free

AbstractObjective:Activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) and aberrations in endogenous opioids play a role in the pathophysiology of major depressive disorder (MDD). There are no studies which examined the associations between both systems in MDD. The aim of the present study was to examine the relation between β-Endorphin (β-EP), Endomorphin-2, and their mu-opioid receptor (MOR) as well as interleukin (IL)-6 and IL-10, an anti-inflammatory cytokine, in MDD patients.Method:The study included 60 depressed drug-free male patients and 30 matched controls. Serum β-EP, Endomorphin-2, MOR, IL-6 and IL-10 levels were measured using ELISA techniques.Results:The results revealed a significant increase in serum β-EP, MOR, IL-6 and IL-10 in MDD patients versus healthy controls. MOR levels were strongly associated with IL-10 levels. There were no significant correlations between endogenous opioids and IL-6 and IL-10.Conclusion:The results show that MOR levels may function as a possible component of the CIRS whilst there is no evidence that β-EP and EM-2 may modify the IRS. The significant correlation between MOR levels and IL-10 may be explained through central activation of the HPA-axis and increased B-cell numbers expressing MOR as a response to cytokine over-secretion in MDD.

scholarly journals Isolation and Pharmacological Characterization of Six Opioidergic Picralima nitida Alkaloids

2020 ◽  
Author(s):  
Simone Creed ◽  
Anna Gutridge ◽  
Malaika Argade ◽  
Madeline Hennessy ◽  
J. Brent Friesen ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Biological Evaluation ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Traditional Use ◽  
Pharmacological Characterization ◽  
Thermal Nociception ◽  
Mu Opioid ◽  
Opioid Receptor Agonist

<p>The seeds of the akuamma tree (<i>Picralima nitida</i>) have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography is developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation. Five of these alkaloids, akuammine, pseudo-akuammigine, picraline, akuammicine, and akuammiline, were evaluated against a panel of >40 central nervous system receptors to identify that their primary targets are the opioid receptors. Detailed<i> in vitro </i>investigations revealed one alkaloid as a potent kappa opioid receptor agonist and three alkaloids with micromolar activity at the mu opioid receptor. The mu opioid receptor agonists were further evaluated for analgesic properties but demonstrated limited efficacy in assays of thermal nociception. These findings contradict previous reports of the antinociceptive properties of the akuamma alkaloids and the traditional use of akuamma seeds as analgesics. Nevertheless, their opioid preferring activity does suggest the akuamma alkaloids provide distinct scaffolds from which to develop novel opioids with unique pharmacologically properties and therapeutic utility. <b><br></b></p>

scholarly journals Exploring the putative mechanism of allosteric modulations by mixed-action kappa/mu opioid receptor bitopic modulators

2021 ◽  
Author(s):  
Huiqun Wang ◽  
Danni Cao ◽  
James C Gillespie ◽  
Rolando E Mendez ◽  
Dana E Selley ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Opioid Receptor ◽  
Binding Mode ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Allosteric Site ◽  
Kappa Opioid ◽  
Mu Opioid ◽  
Mixed Action ◽  
Putative Mechanism

The modulation and selectivity mechanisms of seven mixed-action kappa opioid receptor (KOR)/mu opioid receptor (MOR) bitopic modulators were explored. Molecular modeling results indicated that the ‘message’ moiety of seven bitopic modulators shared the same binding mode with the orthosteric site of the KOR and MOR, whereas the ‘address’ moiety bound with different subdomains of the allosteric site of the KOR and MOR. The ‘address’ moiety of seven bitopic modulators bound to different subdomains of the allosteric site of the KOR and MOR may exhibit distinguishable allosteric modulations to the binding affinity and/or efficacy of the ‘message’ moiety. Moreover, the 3-hydroxy group on the phenolic moiety of the seven bitopic modulators induced selectivity to the KOR over the MOR.

scholarly journals 131 A Marionettist Pulling My Strings: A Case of Buprenorphine-induced Chorea

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 282-283
Author(s):  
Dev Patel ◽  
Ishandeep Gandhi ◽  
Faisal Malek ◽  
Camille Olechowski ◽  
Alan R. Hirsch
Keyword(s):  
Basal Ganglia ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Activation ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Mu Opioid ◽  
Palmar Erythema ◽  
History Of

Abstract:Introduction:Choreaform movements provoked by opiates is an infrequent adverse event. Buprenorphine induction of chorea has not heretofore been described. Such a case is presented.METHOD:Case Study: A 38-year-old female presented with a decade long history of alcohol, cocaine, benzodiazepine, and heroin abuse. The patient was insufflating 1.5 grams of heroin daily. On presentation, she was actively withdrawing, scoring 17 on the Clinical Opioid Withdrawal Scale. Urine toxicology screening was positive for opiates, cocaine, and cannabinoids. Buprenorphine 4 mg sublingual was initiated. Within one hour, she observed, “My legs were moving uncontrollably as if I was a marionette.” These dance-like movements were isolated to both legs and gradually resolved after discontinuation of buprenorphine: most of the movements manifested in the first 8 hours, and dissipated over the next 2 days. She did have similar movements after treatment with quetiapine during a previous hospitalization, years earlier.RESULTS:Abnormalities in physical examination: General: goiter, bilateral palmar erythema. Neurological examination: Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test: 2 (anosmia). Motor Examination: Drift testing: mild right pronator drift. Reflexes: 3+ bilateral lower extremities. Neuropsychiatric Examination: Clock Drawing Test: 3 (abnormal). Animal Fluency Test: 18 (normal). Go-No-Go Test 6/6 (normal).DISCUSSION:Buprenorphine induced chorea could be a result of partial mu-opioid agonism, or kappa and delta receptor antagonism (Burke, 2018; Cowan, 1977). Mu-opioid receptor activation causes increased dopamine turnover in the nigrostriatum, which is responsible for locomotor sensitization (Campos-Jurado, 2017). With the addition of mu-opioid receptor modulation of dopamine release, kappa-opioid receptor alters various neurotransmitters in the basal ganglia, potentiating hyperkinetic movements. Buprenorphine’s choreiformogenic action may be due to kappa-opioid receptors ability to augment neurotransmission in the striatum (Escobar, 2017; Bonnet, 1998). The combination of simultaneous activity of these three opioid receptors may cause chorea, since they act to modulate dopamine, glutamate, and GABA in the direct and indirect pathways within the basal ganglia (Abin, 1989; Cui, 2013; Allouche, 2014; Trifilieff, 2013). This patient’s history of heroin and cocaine use may have caused supersensitization of dopamine receptors (Memo, 1981), provoking hyperkinesia. Involvement of substance-induced sensitization with concurrent kappa-opioid receptor neurotransmitter augmentation in direct and indirect pathways in the basal ganglia may have primed our patient to the development of chorea after buprenorphine administration. Further investigation for the presence of extrapyramidal movements in those undergoing buprenorphine treatment is warranted.

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