When the κ-subtype of opioid receptor was first distinguished, there was tremendous interest in developing analgesics that would provide pain-relief without activating the reward pathways stimulated by morphine-like μ-opioids. A nonaddictive opioid has been a holy grail of medicinal chemistry ever since Friedrich Serturner isolated morphine from opium in 1804. Selective κ-agonists were developed, but quickly found to produce different problems including dysphoria, diuresis, and constipation. In addition, their maximal analgesic effects were weaker than μ-opioids in rodents. But interest in κ-opioids as therapeutic tools did not completely die; Shippenberg and colleagues found that κ-agonists reduced the rewarding effects of co-administered addictive drugs; κ-opioid analgesia using pentazocine was seen as an alternative for pain control in people with a risk of drug abuse; and κ-agonists entered clinical trials for the treatment of pain and itch (see Millan, 1990).

Although enthusiasm for agonists waned, interest in κ-antagonists as therapeutic tools got a boost when Carlezon and colleagues showed their activity in the forced swim assay, predictive of antidepressant activity (Mague et al, 2003). Following on that study, we reported that κ-antagonism blocked stress-induced potentiation of cocaine reinforcement (McLaughlin et al, 2003). Numerous studies have replicated and extended those findings showing the utility of κ-antagonists to block stress-induced reinstatement of extinguished cocaine- and ethanol-seeking, block μ-opioid and cannabinoid withdrawal signs, and block the aversive effects of nicotine. All these effects of κ-antagonists can be attributed to block of the actions of endogenous dynorphins, which are κ-selective opioid peptides released during the stress response (Land et al, 2008). Consistent with the dysphoric effects of κ-agonist drugs and natural κ-opioids isolated from the plant Salvia divinorum, endogenous dynorphins encode a component of the anxiogenic and dysphoric responses to stressful experience.

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account
Continue with Google
Continue with ORCiD