SYSTEMIC ISOFORM-SELECTIVE HEAT SHOCK PROTEIN 90 INHIBITORS IMPROVE THE THERAPEUTIC INDEX OF MORPHINE

Abstract

Opioids like morphine are the benchmark for treating severe acute pain; however, severe side effects including respiratory depression and addiction limit their viability. One approach to improve opioid therapy focuses on a dose-reduction strategy by amplifying opioid analgesia without boosting side effects, so that less opioid can be given. To this end, we tested the hypothesis that targeting spinal cord heat shock protein 90 (hsp90) with isoform-selective inhibitors given IV could boost opioid pain relief without altering side effects, enabling a dose-reduction strategy. We tested this hypothesis with the novel Grp94-selective inhibitor KUNG65 and the novel Hsp90β-selective inhibitor KUNB106, given at a 1mg/kg dose IV in male and female CD-1 mice, followed by a 24hr treatment time, then analysis of opioid antinociception and side effects. We found that systemic (IV) KUNG65 treatment resulted in a 1.9 fold increase in morphine potency to relieve tail flick pain with similar findings for KUNB106, consistent with our earlier studies injecting inhibitors directly into the spinal cord. We also found that both KUNG65 and KUNB106 boosted morphine potency in paw incision pain. Additionally, we found that KUNG65 and KUNB106 injection could rescue established morphine tolerance in the tail flick assay. These results support our hypothesis that isoform-selective Hsp90 inhibitors can selectively engage Hsp90 in the spinal cord when given systemically, resulting in improved opioid antinociception and side effects. These results strongly suggest that Hsp90 isoform-selective inhibitors could be a powerful new tool to improve opioid therapy through a dose-reduction strategy, and further show that this effect can be achieved through a translationally relevant dosing route.