Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
Division of Endocrinology, Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
Sci Signal. 2020 May 5;13(630):eaaz1854. doi: 10.1126/scisignal.aaz1854.
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.
尽管吗啡和其他阿片类药物有许多不良反应，但它们仍被广泛用于治疗疼痛。调节μ-阿片受体（MOR）信号是提高阿片类药物治疗效果的一种方法。在小鼠中，伴侣蛋白 Hsp90 在大脑内介导 MOR 信号。在这里，我们发现特异性抑制脊髓中的 Hsp90 增强了吗啡在小鼠中的镇痛作用。鞘内而非全身给予 Hsp90 抑制剂 17-AAG 或 KU-32 增强了吗啡抑制小鼠对热和机械刺激敏感性的作用。Hsp90 抑制使阿片类药物诱导的激酶 ERK 磷酸化和激酶 RSK 的丰度增加，而 RSK 主要存在于脊髓的背角，其中有大量的初级感觉神经元。鞘内抑制 ERK、RSK 或蛋白质合成后，Hsp90 抑制的附加作用被消除。这种位于脊髓内且受 Hsp90 抑制的 MOR 下游机制，可能被用于增强阿片类药物治疗的疗效，同时降低其副作用。
