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Comments
Howard Fields, University of California San Francisco
This is a very thorough study
This is a very thorough study that examines a group of structurally related mu opioid agonists and provides data that respiratory depression and analgesia can be differentially affected by changes that shift post-binding signaling: Compounds with greater activation of beta-arrestin are much more likely to cause respiratory depression at any given analgesic dose. The dose ranges used seem to be clinically relevant, making this a potentially important data set that could be used to develop safer mu opioid agonists.
Ru-Rong Ji, Duke University Medical Center
The Cell paper focused on the
The Cell paper focused on the acute effects of the novel opioid agonists, which are very impressive. However, the chronic effects of these compounds on hyperalgesia, tolerance, and dependence are unclear. As a scaffold protein, beta-arrestin2 not only regulates opioid receptors and other GPCRs but also regulates TRP channels and NMDA receptors. Inhibition of beta-arrestin2 will cause hyperactivation of NMDA receptors in the spinal cord. So, the chronic or delayed effects of these opioid biased agonists remain to be investigated.