The Role of the Kappa-Opioid Receptor in Stress and Substance Use Disorder

Introduction

Substance use disorder affects around 31 million people worldwide (WHO 2018) and is one of the United States’ top health problems (Cleck 2008). The major challenge in treating substance use disorders is that many times drug use and relapse is precipitated by stress, and the precise mechanisms that link the two have not yet been fully elucidated (Cleck 2008). In this paper, I explore how the dynorphin/kappa-opioid receptor (DYN/KOR) system may contribute to the interplay between stress and addiction. In particular, I summarize evidence from recent studies indicating that the KOR, a member of the opioid neuromodulatory system, plays a central role in stress and addiction and represents a promising pharmacological target for treatment. Although stress-induced escalation or reinstatement of drug use poses a serious health risk in the United States and worldwide, there are still very few medications that are able to effectively intervene in the cycle of addiction, especially in preventing the relapse of drug use. Therefore, it is important to continue investigating molecular mechanisms to identify therapeutic targets for treatment.

Proposed Mechanisms

The KOR is a G-protein coupled receptor that is part of a family of receptors that make up the endogenous opioid system of the brain, which has been implicated in substance abuse disorders (Karkhanis 2017). These receptors are found throughout various brain regions such as the ventral tegmental area (VTA), nucleus accumbens (NAc), bed nucleus of the stria terminalis (BNST), and central amygdala (CeA) (Karkhanis 2017). The presence of KORs in key brain regions such as the VTA and the NAc that also make up the mesolimbic dopamine (DA) reward pathway could contribute in part to the interaction between stress and addiction (Cleck 2008). The DYN/KOR system is believed to exert effects on other neurotransmitter systems, such as the dopaminergic system, and one proposed theory is through decreasing the release of DA in the NAc (Karkhanis 2016). Chronic stress causes the release of corticotrophin-releasing hormone (CRH), which then stimulates an increase in levels of DYN that then bind to KORs located presynaptically on DA neuron terminals, thereby suppressing DA release in the NAc and increasing ethanol intake in rats (Karkhanis 2016). In addition to this effect on DA, it has also been proposed that when bound by its endogenous ligand, DYN, the KOR can have multiple downstream effects such as activating the Gi/o pathway (Karkhanis 2017). It has been shown that activation of this Gi signaling cascade within BLA CAMKII??? neurons, which in turn inhibit the excitatory signaling within this brain region, is sufficient to reinstate nicotine preference in rats (Nygard 2016). There is some dissention, however, because some rodent studies have found that optogenetically inhibiting the BLA actually decreases cue-induced cocaine-seeking behavior (Stefanik 2013). However, the discrepancy between these studies could be due to a difference in the involvement of KORs in stress-induced as opposed to cue-induced drug seeking. Further studies are required to better understand region and behavior-specific differences in the influence of these mechanisms on drug addiction.

Effect of KORs on Modulating Drug Consumption

The DYN/KOR system has been implicated in having a critical role in promoting the initial use of drugs, as well as escalating current drug use. A study by Karkhanis et al. (2016) showed that rats that undergo adolescent social isolation exhibit increased ethanol intake as adults compared to group-housed rats. This effect of an early-life stressor is thought to be due to an upregulation of the DYN/KOR system, which enhances KOR function. This subsequently establishes a hypodopaminergic state at baseline along with an increase in evoked DA release and uptake in the NAc, potentiating the associated effects of ethanol (Karkhanis 2016). Administration of the KOR antagonist nor-BNI reduced this observed increased ethanol intake in socially isolated rats as well as decreased the hypodopaminergic baseline state, suggesting that KOR activation drives this stress-induced reward seeking (Karkhanis 2016).

Researchers have also investigated the effects of the DYN/KOR system in facilitating stress-provoked drug relapse. Administration of the KOR agonist U50,488 to rats, which has been shown to also induce a physiological stress response, causes a reinstatement of alcohol seeking (Lí? 2017). This effect was associated with increased neuronal activity in the BNST, and this region-specific KOR activity was shown to be both necessary and sufficient in the reinstatement of alcohol-seeking relapse (Lí? 2017). Moreover, administration of a KOR antagonist is correlated with a reduction in drug reinstatement. Pretreatment with the KOR antagonist nor-BNI prevented stress-reinstated nicotine conditioned place preference in rats (Nygard 2016). Additionally, KOR and DYN knockout mice that did not express either the receptors or ligand in the BLA also did not exhibit stress-induced nicotine reinstatement (Nygard 2016). This provides further evidence for the necessity of the DYN/KOR system in reinstating drug use and identifies a specific brain region in which this effect is significant.

One shortcoming with the present research in the field is that many studies have been conducted only in male rodents or humans. However, there is evidence that there are important sex differences in the long-term effects of stress on KORs (Laman-Maharag 2017). First, it has been shown that males and females differ in their sensitivity to various doses of KOR ligands, however a consensus has not yet been reached on the exact differences in sensitivity, and why we observe these differences (Laman-Maharag 2017). Additionally, stress and treatment with the KOR agonist U50,488 has been shown to increase neuronal activity, as measured by quantifying levels of the early growth response 1 (ERG1) gene, in the NAc in female California mice but to reduce activity in males (Laman-Maharag 2017). Sex differences like these could affect the efficacy of treatments administered to females if they are developed solely based on the known circuitry and responses in males. In order to thoroughly examine the mechanisms and design effective therapeutic treatments, it is thus necessary to include females in these studies and to thoroughly investigate sex differences.

Taken altogether, these studies support the role of KORs in the stress-provoked enhancement or reinstatement of drug intake in rodent models. More research is needed to determine the mechanisms by which the KOR elicits responses in each specific brain region, and whether it influences behavior differently in a region-dependent manner.

Therapeutic Drugs

There is growing interest in the role of KOR antagonists as potential substance use disorder treatments. A promising therapeutic avenue currently being pursued is the use of the selective KOR antagonist CERC-501, also known as Opra Kappa, in treating stress-induced reinstatement of alcohol seeking. The previously developed and most commonly used KOR antagonist, nor-binaltrophimine (nor-BNI) was determined to not be optimal for use of humans due to its long duration of action and delayed onset of function (Domi 2018, Reed 2018). Another KOR antagonist investigated, JDTic, was also determined to be unsuitable due to side effects of tachycardia during clinical trials (Buda 2015). Unlike nor-BNI and JDTic, CERC-501 has been shown to be suitable for medical administration and further study in human subjects via oral administration (Domi 2018, Reed 2018). CERC-501 was able to suppress stress-induced reinstatement of alcohol seeking in rats that had previous chronic ethanol exposure (Domi 2018). However, in a clinical trial examining the effect of CERC-501 on cocaine-dependent individuals, a 10 mg dose of CERC-501 caused no substantial changes with regard to depression or drug craving in a stress-minimized environment (Reed 2018). Further studies are warranted to determine whether this lack of effect could be due to the low-stress environment the participants were placed in, their low baseline scores of craving or dysphoria, or whether there are other factors at play that affect CERC-501’s efficacy in humans. Additionally, the exact mechanism by which CERC-501 exerts its effect has not yet been described, and further studies are needed to elucidate this. Ultimately, CERC-501 shows promising potential for future development as a therapeutic treatment for alcohol use disorders driven by stress.

Conclusions and Future Directions

In conclusion, the DYN/KOR system looks like a promising avenue for further therapeutic research. There are still many gaps in knowledge and much is still unknown about the interaction between this system, stress, and the cycle of drug use and addiction. Future studies examining specific neurobiological mechanisms and downstream effects of blocking or activating the KOR will be useful in understanding how therapeutic agents targeting the DYN/KOR system could potentially be used to treat patients with addiction. One possible avenue for researchers to examine is whether there is an effect of estrogen on the DYN/KOR system that influences the effect of an agonist or antagonist on the receptor and explains the noted sex differences. Another avenue of future research could be to investigate the effects on drug addiction when agonists and antagonists are administered in various brain regions, and whether the specific pathways involved are the same or different depending on the type of stressor the animal is subjected to. Finally, as drugs like CERC-501 become determined to be safe to administer in humans, it would be interesting to see more clinical trials that examine the effect of these drugs in preventing stress-related drug relapse in humans. Further investigation into the DYN/KOR system’s mechanisms and how it interacts with stress will be very valuable in designing more specific drugs that can help treat people unable to escape the vicious cycle of substance abuse.

Works Cited

  1. Buda, J. J., Carroll, F. I., Kosten, T. R., Swearingen, D., & Walters, B. B. (2015). A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability and Pharmacokinetics of Single, Escalating Oral Doses of JDTic. Neuropsychopharmacology,40(9), 2059-2065. doi:10.1038/npp.2015.27
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  4. Karkhanis, A. N., Rose, J. H., Weiner, J. L., & Jones, S. R. (2016). Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System. Neuropsychopharmacology,41(9), 2263-2274. doi:10.1038/npp.2016.21
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  9. Reed, B., Butelman, E. R., Fry, R. S., Kimani, R., & Kreek, M. J. (2018). Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence. Neuropsychopharmacology,43(4), 928-928. doi:10.1038/npp.2017.245
  10. Stefanik, M. T., & Kalivas, P. W. (2013). Optogenetic dissection of basolateral amygdala projections during cue-induced reinstatement of cocaine seeking. Frontiers in Behavioral Neuroscience, 7. doi:10.3389/fnbeh.2013.00213
  11. WHO (2018). Management of Substance Abuse Facts and Figures, https://www.who.int/substance_abuse/facts/en/
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