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Papers: 18 Apr 2020 - 24 Apr 2020

Animal Studies

2020 Apr 10


Heat shock protein 90 inhibitors block the anti-nociceptive effects of opioids in mouse chemotherapy-induced neuropathy and cancer bone pain models.


Stine C, Coleman DL, Flohrschutz AT, Thompson AL, Mishra S, Blagg BS, Largent-Milnes TM, Lei W, Streicher JM
Pain. 2020 Apr 10.
PMID: 32301839.


Heat shock protein 90 (Hsp90) is a ubiquitous signal transduction regulator, and Hsp90 inhibitors are in clinical development as cancer therapeutics. However, there have been very few studies on the impact of Hsp90 inhibitors on pain or analgesia, a serious concern for cancer patients. We previously found that Hsp90 inhibitors injected into the brain block opioid-induced anti-nociception in tail flick, paw incision, and HIV neuropathy pain. This study extended from that initial work to test the cancer-related clinical impact of Hsp90 inhibitors on opioid anti-nociception in cancer-induced bone pain (CIBP) in female BALB/c mice and chemotherapy-induced peripheral neuropathy (CIPN) in male and female CD-1 mice. Mice were treated with Hsp90 inhibitors (17-AAG, KU-32) by the intracerebroventricular, intrathecal, or intraperitoneal routes, and after 24 hours pain behaviors were evaluated following analgesic drug treatment. Hsp90 inhibition in the brain or systemically completely blocked morphine and oxymorphone anti-nociception in CIPN; this effect was partly mediated by decreased ERK and JNK MAPK activation and by increased protein translation, was not altered by chronic treatment, and Hsp90 inhibition had no effect on gabapentin anti-nociception. We also found that the Hsp90 isoform Hsp90α and the co-chaperone Cdc37 were responsible for the observed changes in opioid anti-nociception. In contrast, Hsp90 inhibition in the spinal cord or systemically partially reduced opioid anti-nociception in CIBP. These results demonstrate that Hsp90 inhibitors block opioid anti-nociception in cancer-related pain, suggesting that Hsp90 inhibitors for cancer therapy could decrease opioid treatment efficacy.