Treatments for pain or addiction targeting the κ-opioid receptor often cause hallucinogenic side effects. To understand this, cryo-electron microscopy mapped the receptor's structure with various G-proteins and compounds. These detailed maps uncovered molecular controls for G-protein binding and drug selectivity, showing distinct preferences. This clarifies opioid action, establishing a foundation for developing safer, pathway-selective therapies.
Ketamine, used for treatment-resistant depression and severe pain, acts primarily by blocking the N-methyl-D-aspartate receptor, but its therapeutic and abuse-related effects may involve additional targets. Structural evidence shows that ketamine and its analog phencyclidine (PCP) can directly bind to and activate human opioid receptors. The study identifies key molecular motifs involved in this binding and efficacy modulation, and also reveals the structure of the ligand-free state of the κ opioid receptor. Ketamine exhibits more dynamic binding than PCP at the orthosteric site, which may explain its distinct pharmacology. These findings indicate that opioid receptors are important for understanding ketamine's clinical versatility.