• Yixin Zhang, Peilan Zhou, Zhen Wang, Ming Chen, Fenghua Fu, and Ruibin Su.
• State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.
• Life Sci. 2020 Jul 1; 252: 117676.

AimsMany μ-opioid receptor (MOR)-associated proteins can regulate the MOR signaling pathway. Using a bacterial two-hybrid screen, we found that the C-terminal of the MOR associated with heat shock protein 90 isoform β (Hsp90β). Here, we explored the effect of Hsp90β on MOR signaling transduction and function.Main MethodsThe interaction of Hsp90β with MOR was detected by co-immunoprecipitation and immunofluorescence. The effects of Hsp90β on MOR signaling induced by opioids were studied in vitro and in vivo. The effects of the Hsp90β inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) on morphine tolerance and dependence were studied via a hot plate test and CPP test.Key FindingsHsp90β, instead of Hsp90α, interacted with the MOR in HEK293 cells and SH-SY5Y cells, and the interaction was augmented after morphine pretreatment. The interaction of Hsp90β and MOR increased the inhibition of cAMP and decreased PKA activity under opioid treatment. The functional Hsp90β-MOR complex also promoted the phosphorylation and internalization of the MOR induced by DAMGO in MOR-CHO cells. 17-AAG blocked Hsp90β-MOR interactions and decreased the effect of Hsp90β on the MOR signal transduction. In C57BL/6 mice, 17-AAG decreased morphine-induced acute anti-nociception in the hot plate test, with an increase in phosphorylated PKA and phosphorylated JNK and a decrease in phosphorylated CREB and phosphorylated ERK in murine brains. Chronic morphine treatment induced tolerance, and dependence was inhibited by 17-AAG co-administration.SignificanceHsp90β is a positive co-regulator of the MOR via the activation of a G-protein-dependent and β-arrestin-dependent pathway. Hsp90β has the potential to improve the pharmacologic profile of existing opiates. It is conceivable that in future clinical treatments, the Hsp90β inhibitor, 17-AAG, could decrease the tolerance and dependence in cancer patients induced by opioids.Copyright © 2020 Elsevier Inc. All rights reserved.

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