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Inhibition of Heat Shock Protein 90 in the Spinal Cord Strongly Promotes Morphine Anti Nociception by Increasing ERK MAPK Activation
Author(s) -
Duron David Isaiah,
Lei Wei,
Blagg Brian,
Streicher John
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.684.14
Subject(s) - mapk/erk pathway , nociception , opioid , spinal cord , medicine , morphine , pharmacology , heat shock protein , opioid receptor , anesthesia , receptor , signal transduction , chemistry , biochemistry , gene , psychiatry
Hundreds of millions of individuals suffer from acute and chronic pain in the United States alone. The current gold standard of treatment for patients with moderate to severe pain is the use of opioid analgesics. Although the efficacy of these medications is often superior to other options in the clinic, their use is significantly limited due to their side effects and potential for abuse. Recent progress in the research of opioid receptor signaling has shown that manipulation of opioid signaling by biased agonists or other means can improve the therapeutic profile of opioids; however, the field is limited by a lack of understanding of the opioid signaling complex. We have previously shown that inhibition of the chaperone protein Heat shock protein 90 (Hsp90) in the brain strongly blocks opioid anti‐nociception by blocking ERK activation. Here we demonstrate a reversed effect in the spinal cord in that intrathecal (i.t.) injections of the Hsp90 inhibitors 17‐AAG or KU‐32 in CD‐1 mice strongly increase morphine anti‐nociception in paw incision and tail flick pain. Seeking a mechanism for these changes, we found that i.t. Hsp90 inhibition strongly increased ERK activation in the spinal cord in response to opioids, which is opposite of what is observed in the brain, and also implies that Hsp90 acts to repress opioid‐stimulated ERK signaling in the spinal cord. By combining Hsp90 inhibition with the ERK inhibitor U0126 in the spinal cord, we found that ERK inhibition fully reversed the effects of Hsp90 inhibition while having no effect on its own, supporting the hypothesis that increased ERK signaling in spinal cord is responsible for the effects of Hsp90 inhibition. We also performed experiments with systemic and combined i.c.v. and i.t. Hsp90 inhibitor to demonstrate that Hsp90 inhibition in the brain dominates over other circuits when all are inhibited. This data implies that signaling localization within the pain circuit could be key for the targeting of proteins to modify the therapeutic index of opioid analgesics like morphine. These results also suggest that spinal Hsp90 inhibitors could be used as an opioid dose‐reduction strategy which could preserve analgesic efficacy while reducing side effects. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .