Blockade of Kappa Opiate Receptors Blocks Proneness to Relapse in Addiction
George Koob, the new director of the National Institute for Alcohol Abuse and Alcoholism (NIAAA), showed that animals with extended access to self-administered abuse substances like cocaine or morphine will escalate the amount of drug they self-administer. When the drug is no longer available starting after a delay of one to two weeks, the number of times they press a lever in the presence of a cue previously associated with drug availability progressively increases over a period of one to two months (even through no drug is available). This is called incubation and reflects a measure of “craving” or relapse potential.
This incubation effect, or increasing degree of craving for a drug, is also seen clinically in people who are heavy drug users and then achieve abstinence or are incarcerated and have a period of forced abstinence. As the duration of abstinence increases, they experience an increased proneness to relapse.
Dynorphin is a psychomimetic opiate peptide that is produced in the brain and causes anxiety and dysphoria when it is given to humans. While opiates like morphine and heroin that produce euphoria and antipain effects act at a mu opiate receptor, dynorphin acts at a kappa opiate receptor. Chronic cocaine use gradually increases levels of dynorphin in the brains of addicts and also increases kappa receptors, thus converting what is often initially a euphoric drug experience into an anxiety-producing and dysphoric one.
If kappa receptors are blocked, the incubation effects during abstinence described above do not occur, and presumably addicts would be less relapse-prone. No kappa antagonist is currently available for human use, but if one combines buprenorphine (a mixed opiate agonist/antagonist) with naloxone or naltrexone (which selectively block the mu opiate receptors), one would in effect have a kappa receptor antagonist. Koob showed that this drug combination could prevent the incubation effects in abstinent animals. Further study might lead to advances in the treatment of addition in humans.
