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Chaperones put the brakes on opioids
Until alternatives to opioids are developed, keeping opioid doses low but effective may be key to preventing their adverse effects. Duron et al. found that Hsp90 inhibitors injected into the spine of mice enhanced the efficacy of systemically administered opioids. In sensory neuron–rich regions of the spine, the chaperone protein Hsp90 attenuated the activity of a kinase-to-protein synthesis pathway required for the antinociceptive effects of opioids. In mice, blocking Hsp90 in the spine, but not in the brain or periphery, made opioids more effective at dampening sensitivity to heat and touch, suggesting that this approach might be beneficial in patients. Additional observations further suggest that the role of Hsp90 in opioid signaling is tissue specific.
Abstract
Morphine and other opioids are commonly used to treat pain despite their numerous adverse side effects. Modulating μ-opioid receptor (MOR) signaling is one way to potentially improve opioid therapy. In mice, the chaperone protein Hsp90 mediates MOR signaling within the brain. Here, we found that inhibiting Hsp90 specifically in the spinal cord enhanced the antinociceptive effects of morphine in mice. Intrathecal, but not systemic, administration of the Hsp90 inhibitors 17-AAG or KU-32 amplified the effects of morphine in suppressing sensitivity to both thermal and mechanical stimuli in mice. Hsp90 inhibition enabled opioid-induced phosphorylation of the kinase ERK and increased abundance of the kinase RSK in the dorsal horns of the spinal cord, which are heavily populated with primary afferent sensory neurons. The additive effects of Hsp90 inhibition were abolished upon intrathecal inhibition of ERK, RSK, or protein synthesis. This mechanism downstream of MOR, localized to the spinal cord and repressed by Hsp90, may potentially be used to enhance the efficacy and presumably decrease the side effects of opioid therapy.
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