The Role of Dynorphin and the Kappa Opioid Receptor in the Symptomatology of Schizophrenia: A Review of the Evidence

Abstract

Schizophrenia is a debilitating mental illness that affects approximately 1% of the world's population. Despite much research in its neurobiology to aid in developing new treatments, little progress has been made. One system that has not received adequate attention is the kappa opioid system and its potential role in the emergence of symptoms, as well as its therapeutic potential. Here we present an overview of the kappa system and review various lines of evidence derived from clinical studies for dynorphin and kappa opioid receptor involvement in the pathology of both the positive and negative symptoms of schizophrenia. This overview includes evidence for the psychotomimetic effects of kappa opioid receptor agonists in healthy volunteers and their reversal by the pan-opioid antagonists naloxone and naltrexone and evidence for a therapeutic benefit in schizophrenia for 4 pan-opioid antagonists. We describe the interactions between kappa opioid receptors and the dopaminergic pathways that are disrupted in schizophrenia and the histologic evidence suggesting abnormal kappa opioid receptor signaling in schizophrenia. We conclude by discussing future directions.

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

“…Moreover, KOR agonists may exhibit psychotomimic properties while opioid antagonists may ameliorate SCZ symptoms [80]. KOR activation and administration of KOR agonists including salvinorin A may induce hallucinations, anxiety, depression, negative-like symptoms (lack of motivation and social withdrawal), psychomotor retardation, dysphoria and neurocognitive impairments including in attention, working memory and task performance, which are quite similar to the effects of acute ketamine administration [81][82][83].…”

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

“…Moreover, KOR agonists may exhibit psychotomimic properties while opioid antagonists may ameliorate SCZ symptoms (Clark and Abi-Dargham, 2019). KOR activation and administration of KOR agonists including salvinorin A may induce hallucinations, anxiety, depression, negative-like symptoms (lack of motivation and social withdrawal), psychomotor retardation, dysphoria and neurocognitive impairments including in attention, working memory and task performance, which are quite similar to the effects of acute ketamine administration (Land et al, 2008;Nemeth et al, 2010;Shekhar, 2019).…”

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). KORs are also implicated in chronic inflammatory and visceral pain, fatigue, weakness, and autonomic symptoms (Mysels, 2009).…”