Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain

Abstract

Recent advances in developing opioid treatments for pain with reduced side effects have focused on the signaling cascades of the μ-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 four previous articles. First, in four cell models of MOR signaling, we found that Hsp90 inhibition for 24 h with the inhibitor 17--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 model using CD-1 mice with an intracerebroventricular injection of 17-AAG for 24 h. 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 naive 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 gray and caudal brain stem. We tested these signaling changes by inhibiting ERK in the above-mentioned 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.

A Novel Mu-Delta Opioid Agonist Demonstrates Enhanced Efficacy With Reduced Tolerance and Dependence in Mouse Neuropathic Pain Models

“…The mouse tail flick test was performed as described in our earlier work, 22 with 52°C water and a 10 second cutoff time to prevent tissue damage. SRI-22141 (0.32-10 mg/kg) or morphine (10 mg/kg) was delivered by the subcutaneous (sc) route and tail flick latencies recorded over a time course.…”

“…For a subset of experiments, naloxone was delivered by the intraperitoneal (30 mg/kg, ip), intrathecal (10 nmol, it), or intracerebroventricular (10 nmol, icv) route, or naltrindole (10 mg/kg) by the ip route, prior to SRI-22141 injection by the sc route and measurement as above. The procedures for it and icv injections are described in 22 .…”

Targeting the Hsp90-Cdc37-client protein interaction to disrupt Hsp90 chaperone machinery

“…This chaperone machinery has been regarded as prime importance to cancer survival with its effort on assistance of general protein folding and prevention of protein misfolded or unfolded actions. Hsp90, the famous heat shock protein, is the key factor for this chaperone machinery and allows cancer cells to adapt to severe stress [ 55 , 81 ]. In the past decade, tremendous efforts have been made to develop Hsp90 inhibitors as anticancer agents [ 2 , 82 , 83 ].…”

“…Therefore, the tumor cells, rather than normal cells, have increasing dependency on the Cdc37 level. Moreover, as the recognizer of client protein being tied to the Hsp90 chaperone system, Cdc37 is primarily and specifically interacted with the kinase protein, whereas Hsp90 is widely associated with many classes of client proteins (transcription factors, steroid hormone receptors, and kinases) [ 55 ]. The absence of Cdc37 can only disrupt the interactions with kinase clients but not the interactions with non-kinase clients [ 20 , 56 ].…”

2-Methoxyestradiol and Its Combination with a Natural Compound, Ferulic Acid, Induces Melanoma Cell Death via Downregulation of Hsp60 and Hsp90

“…To this date, there are no studies about the role of Hsp90 in anticancer mode of action of FA. Nonetheless, it was hypothesized that antidepressant-like effect of FA is associated with activation of MAPK kinases pathway and Hsp90 [95,96].…”