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Heat shock protein 90 inhibitors block the antinociceptive effects of opioids in mouse chemotherapy-induced neuropathy and cancer bone pain models
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Final Accepted Manuscript
Author
Stine, CarrieColeman, Deziree L.
Flohrschutz, Austin T.
Thompson, Austen L.
Mishra, Sanket
Blagg, Brian S.
Largent-Milnes, Tally M.
Lei, Wei
Streicher, John M.
Affiliation
Univ Arizona, Coll Med, Dept PharmacolIssue Date
2020-04-10Keywords
Heat shock protein 90Opioids
Cancer
Pain
Chemotherapy-induced peripheral neuropathy
Cancer-induced bone pain
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LIPPINCOTT WILLIAMS & WILKINSCitation
Stine, Carriea; Coleman, Deziree L.a; Flohrschutz, Austin T.a; Thompson, Austen L.a; Mishra, Sanketb; Blagg, Brian S.b; Largent-Milnes, Tally M.a; Lei, Weia,c; Streicher, John M.a,* Heat shock protein 90 inhibitors block the antinociceptive effects of opioids in mouse chemotherapy-induced neuropathy and cancer bone pain models, PAIN: August 2020 - Volume 161 - Issue 8 - p 1798-1807 doi: 10.1097/j.pain.0000000000001886Journal
PAINRights
Copyright © 2020 International Association for the Study of Pain.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
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 antinociception 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 antinociception in cancer-induced bone pain in female BALB/c mice and chemotherapy-induced peripheral neuropathy 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 after analgesic drug treatment. Heat shock protein 90 inhibition in the brain or systemically completely blocked morphine and oxymorphone antinociception in chemotherapy-induced peripheral neuropathy; 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 antinociception. We also found that the Hsp90 isoform Hsp90 alpha and the cochaperone Cdc37 were responsible for the observed changes in opioid antinociception. By contrast, Hsp90 inhibition in the spinal cord or systemically partially reduced opioid antinociception in cancer-induced bone pain. These results demonstrate that Hsp90 inhibitors block opioid antinociception in cancer-related pain, suggesting that Hsp90 inhibitors for cancer therapy could decrease opioid treatment efficacy.Note
12 month embargo; published 01 August 2020ISSN
0304-3959PubMed ID
32701840Version
Final accepted manuscriptae974a485f413a2113503eed53cd6c53
10.1097/j.pain.0000000000001886
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