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Dynorphin, Dysphoria, and Dependence: the Stress of Addiction

The hypothesis that the dynorphin-kappa opioid receptor system may be a key component of the neuroplasticity associated with stress-induced mood disorders and the ‘dark side’ of addiction (withdrawal-negative affect stage) continues to gain preclinical and clinical experimental support. The endogenous kappa opioid peptides derived from prodynorphin encode the dysphoric, anxiogenic, and cognitive disrupting responses to behavioral stress exposure (Bruchas et al, 2010; Carroll and Carlezon, 2013). Drugs of abuse are also profound activators of the brain stress systems, and dynorphin release following a binge of consumption contributes to the dysphoric and anhedonic responses experienced during withdrawal (Koob et al, 2014). Behavioral studies using rodents in multiple laboratories have now consistently demonstrated that kappa antagonists do not block the ‘euphoric-like’ effects of drugs but rather block the stress-induced potentiation of drug reward, block stress-induced reinstatement of drug seeking behavior, and block escalation of drug consumption in long-access models (Whitfield et al, 2015). We predict that kappa antagonists will promote stress resilience and disrupt the addiction cycle by reducing the dysphoria-driven cravings that trigger a subsequent round of drug seeking.

However, very exciting preclinical findings too often fail to deliver on their promises, particularly in CNS drug development, which is notoriously expensive and difficult. Progress is being made with a kappa antagonist (LY2456302) developed by Eli Lilly scientists, which passed initial safety testing and has been licensed for development by Cerecor (Lowe et al, 2014). Another key to this translational effort will be the further development of selective kappa opioid PET imaging in normal and affected human subjects, which is still at a nascent stage. A more ‘out of the box approach’ is to take advantage of “creative” pharmacology. Buprenorphine is not only a mu partial agonist, but is a potent kappa antagonist having antidepressant activity (Karp et al, 2014). A recent open label clinical trial by Alkermes demonstrated that the nonselective KOR antagonist buprenorphine when combined with a mu opioid antagonist significantly reduced depressive symptoms in a population of individuals having treatment resistant depression (E. Ehrich, Kappa-2015 conference proceedings). Dr Andrew Saxon (Seattle, VA) also reported results from the NIDA-funded CURB study, which showed that while cocaine consumption was not significantly reduced by buprenorphine combined with a long acting mu antagonist, secondary analysis of the data from cocaine-using subjects showed a highly significant reduction in nicotine and ethanol use. Additional, recent findings in the dynorphin-kappa domain reported at the ‘3rd Conference on the Therapeutic Potential of Kappa Opioids in Pain and Addiction’ can be found at (http://depts.washington.edu/nidactr/kappatherapeutics2015.html).

Human laboratory studies are an efficient means of bridging the gap between preclinical studies and clinical trials, and we encourage additional validations using more selective kappa antagonists, nevertheless, these early findings are provocative. In summary, the initial results using animal models of psychiatric diseases followed by early validation in human trials support the prediction that individuals unable to control their drug consumption because of overwhelming feelings of dysphoria or anxiety during the abstinence phase, may find kappa antagonists helpful by promoting stress resilience.

FUNDING AND DISCLOSURE

The authors declare no conflict of interest.

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Acknowledgements

This work is supported by United States Public Health Service Grants from the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism.

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Correspondence to Charles Chavkin.

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Chavkin, C., Koob, G. Dynorphin, Dysphoria, and Dependence: the Stress of Addiction. Neuropsychopharmacol 41, 373–374 (2016). https://doi.org/10.1038/npp.2015.258

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