Kappa-Opioid Receptor Antagonism: A Mechanism for Treatment of Relief Drinking?

Abstract

Of recreational users of alcohol, 15% at some point go on to develop a pattern of alcohol seeking and taking that continues despite adverse consequences—that is, alcohol addiction or simply alcoholism. This proportion is not much different from what is seen with other drugs of abuse, but more than half of all Americans $12 years old report being current drinkers. As a result, in the United States, 12 million people have a current diagnosis of alcoholism, accounting for a greater disease burden than all illicit drugs combined. Few evidencebased treatments are currently available for these patients. Efficacy of existing treatments is limited further by the heterogeneity of alcoholism. Optimal clinical management of these patients ultimately requires personalized approaches that match treatments to pathophysiologically relevant individual characteristics. Some of these characteristics are clearly genetic, but personalized therapies also need to take in account neuroadaptations that develop over time as a result of alcohol use itself. Research over the past decade has demonstrated that the motivational mechanisms driving alcohol use undergo a shift over the course of the addictive process. In initial stages of alcohol use, positively reinforcing, or rewarding, properties of alcohol dominate. These are mediated partly by alcohol-induced release of endogenous opioids that activate mu opioid receptors, a mechanism targeted by the U.S. Food and Drug Administration–approved opioid antagonist naltrexone. However, with increased duration of brain alcohol exposure and dependence, alcohol consumption becomes increasingly driven by negatively reinforcing actions of alcohol. During this stage, negative emotional states emerge in the absence of alcohol. Because these can be temporarily alleviated by resuming alcohol intake, they introduce a novel, powerful incentive for alcohol consumption—often called the “dark side of addiction.” There are currently no clinically approved medications targeting this type of “relief drinking.” Antagonists for corticotropin-releasing factor receptor 1 (CRF1) have been pursued for some time for their potential in this regard, but along the way, other neurochemical mechanisms have emerged that seem to hold similar promise. In one of the most exciting developments, Walker and Koob (1) discovered that intracerebroventricular administration of the kappa opioid receptor (KOR) antagonist norbinaltorphimine selectively suppresses dependence-induced escalation of alcohol consumption in a manner similar to CRF1 antagonists. In this issue of Biological Psychiatry, Kissler et al. (2) provide an