Kappa Opioid Receptors: Rekindling the Flame

by Megan Talkington on 8/12/2011

For over 30 years, neurobiologists have flirted with kappa opioid receptors as possible targets for pain treatment in the central nervous system (CNS; Pasternak, 1980). That relationship, however, hasn’t gone nearly as far as the long-term affair with mu opioid receptors, the targets of powerful painkillers including morphine. Kappa receptor agonists progressed into clinical trials in the 1980s, but were abandoned because they caused depression and hallucinations (Pfeiffer et al., 1986). More recently, the focus has shifted to peripheral opioid receptors, with a number of groups working on kappa agonists that never enter the CNS. (For recent reviews, see Vanderah, 2010 and Kivell and Prisinzano, 2010.)

Now, data from Charles Chavkin and colleagues at the University of Washington, Seattle, reveal how central kappa opioid receptors regulate mood, and suggest that the signaling pathways involved are different from those that elicit analgesia. Given the fresh information, targeting kappa opioid receptors in the CNS to treat pain may once again become a workable proposal.

In the paper, published August 11 in Neuron, first author Michael Bruchas, now at Washington University in St. Louis, Missouri, and coworkers report that in mice under stress, kappa receptors regulate the serotonin system in the brain via p38 mitogen-activated protein kinase (p38 MAPK). For alleviating depression and addictive behaviors, then, inhibiting the p38 cascade could be a new route to treatment. For pain therapeutics, the pathway looks like one to carefully avoid.

In previous work, the investigators showed that stress activates p38 MAPK via kappa opioid receptors and leads to depression-like and drug-seeking behaviors (Bruchas et al., 2007). In the new study, Bruchas found that in stressed mice, activation of p38 MAPK specifically in serotonin-producing cells of the dorsal raphe nucleus increased serotonin uptake, leading to a deficit of the neurotransmitter in the brain. In mice lacking p38 MAPK, the stress-induced behavioral effects were abolished, but the animals still showed an analgesic response. The results suggest that kappa receptors require p38 MAPK activation to create aversive behaviors, but not analgesic effects. “These receptors are not quite as simple as we once thought,” Bruchas told PRF.

Even so, it may be possible to navigate the complex lives of kappa receptors in the CNS. According to an emerging theory—variously called “biased agonism,” “ligand-directed signaling,” or “functional selectivity”—opioid receptors are dynamic molecules, and their distinct conformations activate different signaling pathways. To achieve analgesia without unleashing unwanted side effects, the trick is to find small molecules that selectively stabilize the desired conformations (Whalen et al., 2011). In the case of kappa receptors, potential painkillers would need to be screened based on their ability to turn on analgesic pathways while leaving the serotonergic system untouched. Experiments from the Chavkin team showed that a mutant kappa receptor was able to mediate analgesia without activating p38 or producing aversive behaviors (Land et al., 2009), supporting the idea that small molecules might be able to effect a similar kind of one-sided signaling. “If we can develop kappa agonists that don’t turn on p38, we may have a really nice analgesic,” Bruchas said.

That would represent a whole new way to harness kappa opioid receptors in the central nervous system for pain treatment. “What [the Chavkin lab] has found may allow us to get around the dysphoric effects” that plagued earlier trials, said William Carlezon, Harvard Medical School, Boston, who wrote a commentary accompanying the Chavkin study.

Partial agonists that specifically turn on pain-killing pathways might even have an added benefit, Chavkin speculates. In theory, they could prevent other, endogenous agonists from binding, and thus act as partial antagonists of the p38 MAPK pathway. That, in turn, might allow them to alleviate dysphoric aspects of patients’ pain.

On the other hand, there is a possible pitfall in partial agonists, Carlezon told PRF. A major attraction of kappa opioid receptors as targets for pain-killing medications is that, unlike mu receptor activators such as morphine, kappa activators do not trigger addiction. It is possible, Carlezon said, that activation of the p38 MAPK pathway, by producing aversive effects, is what prevents kappa agonists from being rewarding. If so, kappa agonists biased against the p38 pathway could turn out to be addictive. For that reason, he said, it will be important to carefully evaluate functionally selective compounds for their abuse potential.