On January 21, Gavril Pasternak gave a talk on the promise of mu opioid receptor splice variants as a path to safer opioid therapies for pain. After his talk, there was a panel discussion featuring:
- Bryan Roth, University of North Carolina at Chapel Hill, US
- Lynn Webster, PRA Health Sciences, Salt Lake City, Utah, US
- Charles Inturrisi, Weill Cornell Medical College, New York, US (moderator)
Watch the webinar recording below (and see written summary here).
Here is a summary of Pasternak’s talk:
Despite the acknowledged effectiveness of mu opioids in managing severe pain, their side effects such as respiratory depression, physical dependence, reward behavior, and addiction adversely impact their utility. Clinicians have long appreciated the subtle differences among mu opioids in their patients. The cloning of the mu opioid receptor and its gene, Oprm1, revealed a complexity not previously appreciated, with over 20 different splice variants generated from the gene that can be classified by their protein structure. Most are full-length G protein-coupled receptors, with their classical 7 transmembrane (7TM) domains. The other two classes are truncated proteins with either 1 or 6 transmembrane domains (1TM or 6TM). Genetic models established that drugs such as morphine and methadone act through these 7TM receptors. In contrast, several opioids have been synthesized that produce analgesia solely through the 6TM receptors. These compounds can be potent in thermal, mechanical, neuropathic, and inflammatory pain models while lacking respiratory depression, physical dependence, and reward behavior. Thus, many of the adverse properties of traditional opioids are associated with the full-length 7TM receptors and can be avoided by 6TM-specific agents. In addition to these two categories of mu opioids, there is another group, represented by buprenorphine, that depends upon both the 7TM and the 6TM variants for its pharmacological profile. Finally, within all these classes of mu receptor variants, it may be possible to further restrict a number of undesirable actions by biasing the functional activation pattern of the receptor. Thus, the future for safer, potentially less abusable opioid analgesics looks bright.
“Safer Opioid Analgesics: It’s All in the Telling of the Tail” is the 11th in a new series of PRF webinars supported by Genentech and MedImmune, with additional site support from other PRF sponsors. All webinars and other site content on PRF are editorially independent; all editorial decisions are made solely by the PRF editors. See previous PRF webinars here.