Heat Shock Protein 90 Inhibitors Block Opioid Anti-Nociception In Chemotherapy-Induced Peripheral Neuropathy And Cancer-Induced Bone Pain In Mice
AuthorStine, Carolyn Ann
AdvisorStreicher, John M.
MetadataShow full item record
PublisherThe University of Arizona.
AbstractHeat shock protein 90 (Hsp90) is a ubiquitous signal transduction regulator, and Hsp90 inhibitors are currently in clinical development for use as cancer therapeutics. However, there have been no studies on the impact of Hsp90 inhibitors on pain or analgesia, a serious concern for cancer patients. We previously found that Hsp90 inhibitors block opioid-induced anti-nociception in the brain in paw incision and HIV neuropathic pain models through an ERK mechanism. This study investigated the effects of Hsp90 inhibitors on opioid anti-nociception in cancer-induced bone pain (CIBP) and chemotherapy-induced peripheral neuropathy (CIPN). Mice were treated with Hsp90 inhibitors (17-AAG, KU-32) by the intracerebroventricular, intrathecal, or intraperitoneal routes, and 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 activity and was not altered by chronic treatment. Additionally, Hsp90 inhibition had no effect on gabapentin-induced anti-nociception. Furthermore, we found the alpha isoform of Hsp90 to be responsible for these effects in the brain. These results demonstrate that Hsp90 inhibitors can block opioid anti-nociception in cancer-related pain, suggesting that Hsp90 inhibitors for cancer therapy could negatively impact opioid treatment efficacy.