Drilling down to the details of opioid signaling

Despite using opioids for centuries for pain management, we still don’t have a complete understanding of how drugs like morphine and oxycodone actually work. And that’s a problem for patients, who must weather side effects that can range from nausea and constipation to cognitive impairment, addiction, and, at high doses, even death.

When opioid drugs enter the bloodstream, they stimulate "µ-opioid receptors" on the surface of neurons in the brain. These receptors are part of a large class of proteins, called G-protein coupled receptors (GPCRs), which relay signals from outside and into the cell by stimulating partner molecules, called G-proteins, on the inside of the cell. Yet the details of how opiates produce their effects, wanted and unwanted, via GPCRs and G-proteins, have remained elusive.

Recent findings, led in part by Aashish Manglik, MD, PhD, have now revealed how the µ-opioid receptor engages with a particular G-protein as the first molecular step toward quelling pain. The researchers used a technique called cryo-electron microscopy, or cryo-EM, to directly observe an opioid drug activating the receptor, which then activates its G-protein. The study was published on June 13 in Nature.

Manglik is a faculty member in the UCSF School of Pharmacy’s Department of Pharmaceutical Chemistry, and he holds a joint appointment in the School of Medicine's Department of Anesthesia. He carried out this research as a graduate student and Distinguished Fellow at Stanford University.

“We’ve essentially captured this signaling event in the act,” Manglik explained to UCSF News. “These new atomic-level images will hopefully enable us to rationally design compounds that target different aspects of opioid signaling in the brain, with hopes of identifying new, safer painkillers.”

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CryoEM Study Captures Opioid Signaling in the Act (UCSF News Center)