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Heat shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK Mitogen Activated Protein Kinase (MAPK) mechanism in mouse brain.

Heat shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK Mitogen Activated Protein Kinase (MAPK) mechanism in mouse brain.
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Lei W, Mullen N, McCarthy S, Brann C, Richard P, Cormier J, Edwards K, Bilsky EJ, Streicher JM,


Lei W, Mullen N, McCarthy S, Brann C, Richard P, Cormier J, Edwards K, Bilsky EJ, Streicher JM, (click to view)

Lei W, Mullen N, McCarthy S, Brann C, Richard P, Cormier J, Edwards K, Bilsky EJ, Streicher JM,

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The Journal of biological chemistry 2017 04 27() pii 10.1074/jbc.M116.769489

Abstract

Recent advances in developing opioid treatments for pain with reduced side effects have focused on the signaling cascades of the mu opioid receptor (MOR). However, few such signaling targets have been identified for exploitation. To address this need, we explored the role of Heat shock protein 90 (Hsp90) in opioid-induced MOR signaling and pain, which has only been studied in 4 previous papers. First, in 4 cell models of MOR signaling, we found that Hsp90 inhibition for 24 hours with the inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) had different effects on protein expression and opioid signaling in each line, suggesting that cell models may not be reliable for predicting pharmacology with this protein. We thus developed an in vivo model using CD-1 mice with intracerebroventricular (icv) injection of 17-AAG for 24 hours. We found that Hsp90 inhibition strongly blocked morphine-induced anti-nociception in models of post-surgical and HIV neuropathic pain, but only slightly blocked anti-nociception in a naïve tail flick model, while enhancing morphine-induced precipitated withdrawal. Seeking a mechanism for these changes, we found that Hsp90 inhibition blocks ERK MAPK activation in the periaqueductal grey (PAG) and caudal brain stem. We tested these signaling changes by inhibiting ERK in the above pain models, and found that ERK inhibition could account for all of the changes in anti-nociception induced by Hsp90 inhibition. Taken together, these findings suggest that Hsp90 promotes opioid-induced anti-nociception by an ERK mechanism in mouse brain, and that Hsp90 could be a future target for improving the therapeutic index of opioid drugs.

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