Investigation of the Role of Wnt/Delta‐Catenin Signaling in Regulating Opioid Pain Relief After Heat Shock Protein 90 Inhibition

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Opioid receptors are important regulators of pain, and opioid drugs like morphine are used in a wide variety of clinical settings throughout the world. In spite of their clear utility and efficacy concerning the treatment of pain, the addictive nature of opioids limits their use as an option for the treatment of chronic pain. This illustrates the great medical and social need to improve opioid therapy, both enhancing analgesia and reducing side effects like addiction. More recently, we showed that Heat shock protein 90 (HSP90), a molecular chaperone that participates in a vast array of critical molecular processes in the cell, has been implicated as an important modulator of opioid‐induced pain relief within the spinal cord. We found that inhibition of HSP90 improved the therapeutic index of opioids, boosting pain relief and reducing side effects. In an effort to elucidate the molecular pathways responsible for these benefits, we performed proteomic analysis of spinal cord tissue from male and female CD‐1 mice treated with intrathecal Vehicle or 17‐AAG (0.5 nmol, 24 hrs), an HSP90 inhibitor. We found that the signaling molecule delta‐catenin2 was reduced by 27.6% by 17‐AAG treatment in spinal tissue. Since delta‐catenin2 stabilizes and enables Wnt signaling, this suggests that Wnt signaling is also reduced by HSP90 inhibition. As Wnt has been shown to promote pain, this fits with our model that suppressed Wnt/Catenin signaling could enhance opioid pain relief after HSP90 inhibition. We thus report here our efforts to test this hypothesis by using a Wnt activator (AMBMP) and Wnt inhibitor (JW74) combined with 17‐AAG and morphine in a mouse tail flick pain model; we also report our efforts to confirm molecular Wnt signaling changes in spinal cord by Western Blot and qPCR for Wnt itself along with established Wnt signaling targets VEGF‐A and LEF1. Together these studies will establish a new mechanistic node linking HSP90 to the regulation of opioid pain relief in the spinal cord. This will enhance our basic science understanding of this system and could lead to novel therapeutic targets.