Inhibition of heat shock protein 90 in the mouse spinal cord enhances opioid antinociception via the upregulation of dual specificity protein phosphatase 15 (DUSP15) in CGRP neurons
Year: 2026
Type: article
Abstract: In an extended series of studies, we have shown that Heat shock protein 90 (Hsp90) has a novel role in regulating opioid signal transduction and antinociception in both the brain and spinal cord. Inhibition in the spinal cord enhances opioid antinociception, which led to the finding that an isoform-selective Hsp90 inhibitor could improve opioid therapy, both enhancing pain relief and reducing side effects. However, the signaling mechanisms for this activity are still not fully understood. We thus identified Dual Specificity Phosphatase 15 (DUSP15) from an earlier proteomic study as a protein enhanced in the spinal cord after Hsp90 inhibition. Using male and female CD-1 mice, we confirmed that DUSP15 is upregulated in the dorsal horn of the spinal cord after Hsp90 inhibitor (17-AAG) treatment. Using CRISPR and siRNA-mediated knockdown, we showed that DUSP15 was necessary for the enhanced morphine antinociception after Hsp90 inhibitor treatment in both the tail flick and post-surgical paw incision pain models. Using immunohistochemistry (IHC) and behavioral tools, we placed DUSP15 upstream of both ERK MAPK and AMPK in the opioid signaling cascade. We then used IHC to demonstrate that DUSP15 upregulation occurs at least in part in CGRP neurons, and using cell-selective CRISPR, showed that DUSP15 in CGRP neurons is necessary for the enhanced antinociception observed with spinal Hsp90 inhibitor treatment. Together these studies further expand the known mechanisms by which Hsp90 regulates opioid signal transduction and pain relief and provide basic science insight into a potential strategy to improve opioid therapy using Hsp90 inhibitors.
Source: Frontiers in Pharmacology
Institution: University of Arizona
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7222968254