COMMENTARY

Kappa-Opioid Receptor Antagonism: A Mechanismfor Treatment of Relief Drinking?Markus Heilig and Jesse R. Schank

Of recreational users of alcohol, �15% at some point go onto develop a pattern of alcohol seeking and taking thatcontinues despite adverse consequences—that is, alcohol

addiction or simply alcoholism. This proportion is not muchdifferent from what is seen with other drugs of abuse, but morethan half of all Americans $12 years old report being currentdrinkers. As a result, in the United States, �12 million peoplehave a current diagnosis of alcoholism, accounting for a greaterdisease burden than all illicit drugs combined. Few evidence-based treatments are currently available for these patients.Efficacy of existing treatments is limited further by the hetero-geneity of alcoholism. Optimal clinical management of thesepatients ultimately requires personalized approaches that matchtreatments to pathophysiologically relevant individual character-istics. Some of these characteristics are clearly genetic, butpersonalized therapies also need to take in account neuro-adaptations that develop over time as a result of alcohol useitself.

Research over the past decade has demonstrated that themotivational mechanisms driving alcohol use undergo a shift overthe course of the addictive process. In initial stages of alcohol use,positively reinforcing, or rewarding, properties of alcohol dom-inate. These are mediated partly by alcohol-induced release ofendogenous opioids that activate mu opioid receptors, a mechan-ism targeted by the U.S. Food and Drug Administration–approvedopioid antagonist naltrexone. However, with increased durationof brain alcohol exposure and dependence, alcohol consumptionbecomes increasingly driven by negatively reinforcing actions ofalcohol. During this stage, negative emotional states emerge inthe absence of alcohol. Because these can be temporarilyalleviated 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 approvedmedications targeting this type of “relief drinking.” Antagonistsfor corticotropin-releasing factor receptor 1 (CRF1) have beenpursued for some time for their potential in this regard, but alongthe way, other neurochemical mechanisms have emerged thatseem to hold similar promise.

In one of the most exciting developments, Walker and Koob(1) discovered that intracerebroventricular administration of thekappa opioid receptor (KOR) antagonist norbinaltorphimineselectively suppresses dependence-induced escalation of alco-hol consumption in a manner similar to CRF1 antagonists. Inthis issue of Biological Psychiatry, Kissler et al. (2) provide an

From the Laboratory of Clinical and Translational Studies (MH), NationalInstitute on Alcohol Abuse and Alcoholism, National Institutes ofHealth, Bethesda, Maryland; and Department of Physiology andPharmacology (JRS), College of Veterinary Medicine, The Universityof Georgia, Athens, Georgia.

Address correspondence to Markus Heilig, M.D., Ph.D., NIAAA & NIDA, 10Center Drive, 10/1E-5334, Bethesda, MD 20892-1108; E-mail: markus.heilig@mail.nih.gov.

Received Feb 28, 2014; accepted Mar 4, 2014.

0006-3223/$36.00http://dx.doi.org/10.1016/j.biopsych.2014.03.004 Publis

elegant dissection of the underlying neurobiological mechan-isms. They report that both levels of dynorphin (DYN), thecognate ligand for KOR, and G protein signaling by the receptoritself are elevated in the central amygdala (CeA) of animals witha history of dependence. Demonstrating the causal role of theseneuroadaptations, KOR blockade locally within the CeA sup-presses the escalation of alcohol drinking in dependent animals.These effects are selective for animals with a history ofdependence; baseline alcohol intake in nondependent animalsis unaffected. The combined mu opioid receptor antagonist andKOR partial agonist nalmefene, which was approved morerecently for the treatment of alcoholism in the European Union,suppresses both dependence-induced and baseline drinking.These data provide strong support for the notion that KORantagonists merit serious consideration as candidate medica-tions in alcoholism.

The present findings also indicate that overlapping neuroa-daptations may occur in response to alcohol and other addictivedrugs. It has been shown that KOR antagonists selectivelysuppress escalated self-administration that occurs as a result ofextended access to cocaine and heroin (3,4). The extended accessmodel has been proposed to induce neuroadaptations similar tothe neuroadaptations seen with prolonged brain exposure tocycles of alcohol intoxication and withdrawal (i.e., a shift towardnegatively reinforced, “relief”-type motivation for drug taking).This is an area of consistency with the alcohol literature, as Walkerand colleagues (1,5) have repeatedly shown that KOR antagonismsuppresses escalated alcohol self-administration in animals with ahistory of dependence. It is less clear whether KOR signaling playsany role in alcohol reinforcement in the absence of dependence-induced neuroadaptations. In nondependent rats, it has beenreported that KOR inhibition can leave alcohol intake unaffected(1); decrease alcohol intake (6); or, in the Lewis rat strainsusceptible to drug seeking but also to autoimmune disordersand neoplasms, lead to increased alcohol intake (7). In nonde-pendent animals, KOR antagonism was also ineffective in block-ing stress-induced relapse to alcohol seeking (6). Taken together,these data indicate that activity of KOR antagonists to suppressdrug self-administration requires the presence of an upregulateddynorphin/KOR system, occurring as a result of prolonged drugexposure.

The current findings contribute toward a preclinical validationof the KOR as a candidate treatment target in alcohol addiction.However, properly assessing translational potential and identify-ing the optimal clinical application would require additional workthat addresses some important outstanding issues. Key amongthese issues is the role of the KOR system in acute versusprotracted withdrawal. It now seems clear that KOR signalingwithin the CeA can mediate both negative emotionality andescalated alcohol self-administration during acute withdrawal and48 hours after alcohol exposure, as shown in the current study aswell as in other assessments of alcohol withdrawal–inducednegative emotionality (6). It will be important to understandwhether these mechanisms remain engaged and sensitive to KORantagonism in more protracted abstinence. It will also be

BIOL PSYCHIATRY 2014;75:750–751hed by Elsevier Inc on behalf of Society of Biological Psychiatry

Commentary BIOL PSYCHIATRY 2014;75:750–751 751

important to find out why the duration of KOR antagonistaction sometimes appears to vary depending on the behaviorstudied. In findings available so far, suppression of alcohol self-administration by KOR antagonism appears to be relativelyshort-lasting. Some of these observations may reflect a declineof drinking itself over time following alcohol dependency (5),but suppressed alcohol self-administration following two differentKOR antagonists, norbinaltorphimine and JDTic, returned topretreatment levels within 24 hours in another study (6). In con-trast, effects of KOR antagonist on other behaviors, such asanalgesia, have been reported to last for weeks after administra-tion of a single dose (8,9). Finally, an outstanding mechanisticissue is the relationship between KOR and CRF1 signaling independence-induced escalation of alcohol taking. For someaspects of stress effects, it has been postulated that KORactivation is triggered by upstream activation of CRF1 signaling(10), but it is unclear whether this applies to escalated alcoholself-administration.

In conclusion, the elegant findings by Kissler et al. demon-strate that KOR signaling in the CeA is pathologically engagedduring early withdrawal from alcohol and during this time canmediate increased motivation for alcohol reinforcement. It isunclear how long this influence of the DYN/KOR system persistsinto protracted withdrawal. Because the present findings areobtained in Wistar rats, in which the range of genetic variation islimited, it is also important to assess whether geneticallymediated individual differences in the susceptibility to upregulatethe DYN/KOR system as a result of heavy alcohol use exist inother populations. Finally, if therapeutic efficacy of KOR antago-nists can be expected primarily in certain stages of the addictiveprocess and in subpopulations of alcohol-addicted patients inwhich DYN/KOR neuroadaptations are in place as a result ofprolonged alcohol use, finding biomarkers that can identify thesestates and patients would be a critical success factor. If futureresearch efforts can address these issues, the potential of KOR

antagonists to expand the treatment toolkit in alcoholism will bemaximized.

The authors report no biomedical financial interests or potentialconflicts of interest.

1. Walker BM, Koob GF (2008): Pharmacological evidence for a motiva-tional role of kappa-opioid systems in ethanol dependence. Neurop-sychopharmacology 33:643–652.

2. Kissler JL, Sirohi S, Reis DJ, Jansen HT, Quock RM, Smith DG, et al.(2014): The one-two punch of alcoholism: Role of central amygdaladynorphins/kappa-opioid receptors. Biol Psychiatry 75:774–782.

3. Wee S, Orio L, Ghirmai S, Cashman JR, Koob GF (2009): Inhibition ofkappa opioid receptors attenuated increased cocaine intake in ratswith extended access to cocaine. Psychopharmacology 205:565–575.

4. Schlosburg JE, Whitfield TW Jr, Park PE, Crawford EF, George O,Vendruscolo LF, et al. (2013): Long-term antagonism of kappa opioidreceptors prevents escalation of and increased motivation for heroinintake. J Neurosci 33:19384–19392.

5. Walker BM, Zorrilla EP, Koob GF (2011): Systemic kappa-opioid receptorantagonism by nor-binaltorphimine reduces dependence-inducedexcessive alcohol self-administration in rats. Addict Biol 16:116–119.

6. Schank JR, Goldstein AL, Rowe KE, King CE, Marusich JA, Wiley JL, et al.(2012): The kappa opioid receptor antagonist JDTic attenuates alcoholseeking and withdrawal anxiety. Addict Biol 17:634–647.

7. Mitchell JM, Liang MT, Fields HL (2005): A single injection of the kappaopioid antagonist norbinaltorphimine increases ethanol consumptionin rats. Psychopharmacology 182:384–392.

8. Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, et al. (2007):Long-acting kappa opioid antagonists disrupt receptor signaling andproduce noncompetitive effects by activating c-Jun N-terminal kinase.J Biol Chem 282:29803–29811.

9. Carroll I, Thomas JB, Dykstra LA, Granger AL, Allen RM, Howard JL,Pollard GT, Aceto MD, Harris LS (2004): Pharmacological propertiesof JDTic: a novel kappa-opioid receptor antagonist. Eur Journal ofPharmacol 501:111–119.

10. Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (2008): Thedysphoric component of stress is encoded by activation of thedynorphin kappa-opioid system. J Neurosci 28:407–414.

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