The Endogenous Opioid System in Schizophrenia and Treatment Resistant Schizophrenia: Increased Plasma Endomorphin 2, and κ and μ Opioid Receptors are Associated with Interleukin-6

Abstract

Background: Activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) play a key role in SCZ and treatment resistant SCZ. There are only few data on immune and endogenous opioid system (EOS) interactions in SCZ and treatment resistant SCZ.Aim of the study: We examined serum β-endorphin, endomorphin-2 (EM2), mu-opioid (MOR) and kappa-opioid (KOR) receptors, and interleukin (IL)-6 and IL-10 in 60 non responders to treatment (NRTT), 55 partial RTT (PRTT) and 43 normal controls.Results: Serum EM2, KOR, MOR, IL-6 and IL-10 were significantly increased in SCZ as compared with controls. β-endorphin, EM2, MOR and IL-6 were significantly higher in NRTT than in PRTT. There were significant correlations between IL-6, on the one hand, and β-endorphin, EM2, KOR, and MOR, on the other, while IL-10 was significantly correlated with MOR only. A large part of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation and formal thought disorders was explained by the combined effects of EM2 and MOR with or without IL-6 while increased KOR was significantly associated with all symptom dimensions. Increased MOR, KOR, EM2 and IL-6 were also associated with neurocognitive impairments including in episodic, semantic and working memory and executive functions.Conclusion: The EOS contributes to SCZ symptomatology, neurocognitive impairments and a non-response to treatment. In SCZ, EOS peptides/receptors may exert CIRS functions, whereas increased KOR levels may contribute to the pathophysiology of SCZ and EM2 and KOR to a non-response to treatment.

Depression, anxiety, and chronic fatigue symptoms in acute rheumatoid arthritis are associated with immune-inflammatory, autoimmune, endogenous opioid system and lactosylceramide signaling pathways: a nomothetic network approach

“…[107][108][109] EOS peptides and receptors are secreted during immune activation, and most of them act as CIRS compounds. 26,52,105 In the current study, we observed that lactosylceramide levels significantly increased in RA compared to controls and were marginally associated with the common phenome core extracted from the PP and RA disease activity data. Some ceramides, including CD17, are significantly elevated in depressed patients.…”

“…52 Activation of immune-inflammatory pathways is likely responsible for circulating levels of β-endorphin and other EOS markers (such as MOR and KOR) during inflammatory conditions. 105,106 Successive expression of chemokines and adhesion molecules, primarily CXCR2 ligands, L and P selectins, α4/β2 integrins, and intercellular adhesion molecule 1 orchestrate the recruitment of opioid-containing leukocytes from the circulation to the site of inflammation. [107][108][109] EOS peptides and receptors are secreted during immune activation, and most of them act as CIRS compounds.…”

Chronic Fatigue Syndrome and Fibromyalgia-Like Symptoms Are an Integral Component of the Phenome of Schizophrenia: Neuro-Immune and Opioid System Correlates

“…Recently, we reviewed that the EOS may contribute to schizophrenia symptomatology and neurocognitive impairments (Moustafa et al, 2020). For example, KOR activators or agonists have psychotomimic properties and may induce hallucinations and negative-like symptoms, neurocognitive deficits and psychomotor retardation (Clark & Abi-Dargham, 2019;Land et al, 2008;Nemeth et al, 2010;Shekhar, 2019).…”

“…Chen et al, 2015;Heinke, Gingl, & Sandkühler, 2011). On the other hand, β-endorphin and MOR have antinoceptive effects and may exert CIRS activities by suppressing the primary immune response in schizophrenia (Moustafa et al, 2020). Future research should examine the EOS in ME/CFS and fibromyalgia to delineate the role of those opioids.…”

“…We also reported that the endogenous opioid system (EOS) may contribute to the symptomatology and neurocognitive impairments in schizophrenia through increased levels of mu-opioid (MOR) and kappa-opioid (KOR) receptors, and endomorphin-2 (EM2) (Moustafa et al, 2020). There are few papers suggesting that the EOS may play a role in the pathophysiology of ME/CFS.…”