Abstract
The kappa opioid receptor (KOR) and its endogenous ligands dynorphins (DYN) have been implicated in the development or symptomatology of a variety of neuropsychiatric disorders. This review covers a brief history of the development of KOR agonists and antagonists, their effects in healthy volunteers, and the potential role of DYN/KOR dysfunction in schizophrenia and major depressive disorder from a translational perspective. The potential role of DYN/KOR dysfunction in schizophrenia is based on several lines of evidence. Selective KOR agonists induce affective states in healthy volunteers with similarities to the symptoms of schizophrenia. Studies have shown increased DYN in patients with schizophrenia, although the data have been mixed. Finally, meta-analytic data have shown that opioid antagonists are associated with reductions in the symptoms of schizophrenia. The potential role of DYN/KOR dysfunction in major depressive disorder is also based on a combination of preclinical and clinical data. Selective KOR agonists have shown pro-depressive effects in human volunteers, while selective KOR antagonists have shown robust efficacy in several preclinical models of antidepressant activity. Small studies have shown that nonselective KOR antagonists may have efficacy in treatment-resistant depression. Additionally, recent clinical data have shown that the KOR may be an effective target for treating anhedonia, a finding relevant to both schizophrenia and depression. Finally, recommendations are provided for translating preclinical models for schizophrenia and major depressive disorder into the clinic.
Highlights
The kappa opioid receptor (KOR) and its endogenous ligands dynorphins (DYN) (Chavkin and Goldstein 1981; Chavkin et al 1982) have been implicated in the development or symptomatology of a variety of neuropsychiatric disorders including schizophrenia, depression, anxiety, and substance use disorders (Browne and Lucki 2019; Callaghan et al 2018; Clark and Abi-Dargham 2019; Jacobson et al 2020; Koob and Volkow 2010; Li et al 2016; Lutz and Kieffer 2013; Zhang et al 2007)
It is proposed that selective KOR antagonists could be more effective, as off- target effects on the mu opioid receptor (MOR) may limit the efficacy of nonselective KOR antagonists in treating the negative symptoms
As schizophrenia is a heterogeneous disorder, it is possible that DYN/KOR dysfunction affects a subpopulation of patients who might benefit most from therapeutic targeting of this system
Summary
The kappa opioid receptor (KOR) and its endogenous ligands dynorphins (DYN) (Chavkin and Goldstein 1981; Chavkin et al 1982) have been implicated in the development or symptomatology of a variety of neuropsychiatric disorders including schizophrenia, depression, anxiety, and substance use disorders (cocaine, alcohol, opiate, and nicotine) (Browne and Lucki 2019; Callaghan et al 2018; Clark and Abi-Dargham 2019; Jacobson et al 2020; Koob and Volkow 2010; Li et al 2016; Lutz and Kieffer 2013; Zhang et al 2007). In preclinical models selective KOR agonists including U50488 (Vonvoigtlander et al 1983) and U69593 (Lahti et al 1985) have been shown to produce depressivelike and anxiogenic effects on a number of behavioral screening tests for depression It was during the development of new analgesics when the first selective KOR agonists were tested in humans. 10 min after an acute injection of the selective KOR agonist enadoline a healthy volunteer became aggressive during a delusion that the staff were attempting to harm him by conspiring to “ruin his mind” (Walsh et al 2001) These side effects have been reported across a number of clinical trials of synthetic selective KOR agonists including MR 2033/2034 (Pfeiffer et al 1986), enadoline (Hunter et al 1990; Reece et al 1994; Walsh et al 2001), niravoline (Gadano et al 2000), bremazocine (Dortch-Carnes and Potter 2005), and spiradoline (Giuffra et al 1993; Wadenberg 2003). Consistent with this, preclinical studies have shown that low dosages of salvinorin A produce anxiolytic effects (Braida et al 2009) and conditioned place preference in mice (Braida et al 2008)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
