The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research

Abstract

Substance use disorders represent a global public health issue. This mental health disorder is hypothesized to result from neurobiological changes as a result of chronic drug exposure and clinically manifests as inappropriate behavioral allocation towards the procurement and use of the abused substance and away from other behaviors maintained by more adaptive nondrug reinforcers (e.g. social relationships, work). The dynorphin/kappa-opioid receptor (KOR) is one receptor system that has been altered following chronic exposure to drugs of abuse (e.g. cocaine, opioids, alcohol) in both laboratory animals and humans; implicating the dynorphin/KOR system in the expression, mechanisms, and treatment of substance use disorders. KOR antagonists have reduced drug self-administration in laboratory animals under certain experimental conditions, but not others. Recently, several human laboratory and clinical trials have evaluated the effectiveness of KOR antagonists as candidate pharmacotherapies for cocaine or tobacco use disorder to test hypotheses generated from preclinical studies. KOR antagonists failed to significantly alter drug use metrics in humans suggesting translational discordance between some preclinical drug selfadministration studies and consistent with other preclinical drug self-administration studies that provide concurrent access to an alternative nondrug reinforcer (e.g. food). The implications of this translational discordance and future directions for examining the therapeutic potential of KOR agonists or antagonists as candidate substance use disorder pharmacotherapies are discussed. Preclinical Evaluation of Candidate Substance Use Disorder TreatmentsSubstance use disorders (SUDs; i.e. drug addiction) are an insidious and global public health issue. This complex and multi-faceted mental health disorder is most commonly modeled in the laboratory using a drug self-administration (SA) procedure to provide an opportunity to measure volitional drug intake. Both preclinical and human laboratory drug SA procedures have made significant contributions to improving our understanding of psychoactive compounds for more than 50 years. In general, preclinical drug SA procedures are used to address two main categories of scientific questions. One category is for abuse liability assessment of psychoactive compounds for potential scheduling as controlled substances by the Drug Enforcement Agency, and there are already excellent reviews on the utility of drug SA procedures (Ator and Griffiths 2003;Carter and Griffiths 2009). The other category is for understanding the expression, mechanisms, and treatment of drug-taking behavior as a

Effects of Kappa Opioid Receptor Agonists on Fentanyl vs. Food Choice in Male and Female Rats: Contingent vs. Non-Contingent Administration

“…Acute, non-contingent administration of U50488 or nalfurafine failed to selectively decrease fentanyl choice and decreased overall rates of operant behavior. These findings suggest KOR agonists would not be effective as standalone treatments for substance use disorders (see (Banks 2020)) and are in agreement with a report of acute enadoline treatment failing to selectively affect cocaine-versus-money choice in human volunteers (Walsh et al 2001a). Previous works have highlighted the importance of evaluating behavioral selectivity of treatment effects of candidate substance use disorder treatments (Czoty et al 2016; Haney and Spealman 2008; Mello and Negus 1996), arguing that such measures increase the potential for preclinical-to-clinical translation.…”

‘Not at all what I had expected’: Discontinuing treatment with extended-release naltrexone (XR-NTX): A qualitative study

“…Another explanation suggests a synergic effect of NTX and BUP. Research has suggested that the kappa opioid receptor system has a role in mood disorders (Banks, 2020;Chavkin & Koob, 2016;Crowley & Kash, 2015;Tejeda & Bonci, 2019;Wee & Koob, 2010). Studies have proposed that prolonged opioid use, and thus continued exposure to mu agonists, can result in kappa receptor system overdrive (Banks, 2020;Chavkin & Koob, 2016).…”

“…Research has suggested that the kappa opioid receptor system has a role in mood disorders (Banks, 2020;Chavkin & Koob, 2016;Crowley & Kash, 2015;Tejeda & Bonci, 2019;Wee & Koob, 2010). Studies have proposed that prolonged opioid use, and thus continued exposure to mu agonists, can result in kappa receptor system overdrive (Banks, 2020;Chavkin & Koob, 2016). This overdrive may lead to dysphoric mood states, which may be part of a prolonged abstinence reaction, symptoms which may be further increased by naltrexone mu opioid receptor blockade (Rothman, 1992;Rothman et al, 1991).…”

Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System

“…DYN is derived from pro-dynorphin (PDYN) and is the only endogenous ligand with a high affinity for KOR. Among specific KOR agonists used in preclinical research ( Banks, 2020 ), we can cite salvinorin A, the active principle of Salvia divinorum ( Roach and Shenvi, 2018 ) and the synthetic analogue U50,488 ( Karkhanis et al, 2017 ).…”

“…Naltrexone, as naloxone, is a non-selective mu (µ, MOR), delta (δ, DOR), and kappa (κ, KOR) opioid receptor antagonist, approved for the treatment of alcohol and opioid use disorders ( Sudakin, 2016 ), and is actually tested (in co-treatment with buprenorphine), in a phase 2 clinical trial, to treat alcohol use disorder comorbid with PTSD (NCT03852628, 2019). Interestingly, the pharmacological industry was prompted to develop KOR antagonists to treat stress-induced relapse of cocaine, alcohol, and tobacco ( Carroll and Carlezon, 2013 ; Banks, 2020 ). To our knowledge, a pharmacological strategy aiming selective KOR antagonism has not yet been explored to treat SUD/PTSD comorbidity.…”