Opioid drugs are the gold standard for treating acute and chronic pain, but are limited by negative side effects, including tolerance, constipation, and addiction. New approaches are thus greatly needed to improve opioid therapy and decrease side effects. Our investigations have revealed Heat shock protein 90 (Hsp90) as a critical regulator of opioid receptor signaling, and that inhibition of spinal cord Hsp90 boosts opioid anti-nociception. These findings led us to hypothesize that spinal Hsp90 inhibitor treatment could improve the therapeutic index of opioids, boosting anti-nociception while improving or not altering side effects, enabling a dose-reduction strategy. To test this hypothesis, we injected the Hsp90 inhibitor KU-32 by the intrathecal route into male and female CD-1 mice. We then tested these mice for their response to morphine in a battery of anti-nociception and side effect models. We found that spinal KU-32 treatment increased the anti-nociceptive potency of morphine by 2-4 fold in the tail flick, post-surgical paw incision, and HIV peripheral neuropathy pain models. At the same time, morphine anti-nociceptive tolerance was reduced from 21 fold to 2.9 fold by KU-32 treatment, and established morphine tolerance could be rescued by KU-32 injection. Reward as measured by conditioned place preference and constipation were both unchanged. These results support our hypothesis, and suggest that Hsp90 inhibitors could be a novel approach to improve the therapeutic index of opioids, enable a dose-reduction strategy, and lead to fewer side effects during pain therapy.