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.

中文翻译：

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抑制脊髓中的 Hsp90 通过激活 ERK-RSK 通路增强吗啡的镇痛作用。

尽管有许多不良副作用，但吗啡和其他阿片类药物通常用于治疗疼痛。调节 μ-阿片受体 (MOR) 信号是潜在改善阿片类药物治疗的一种方法。在小鼠中，伴侣蛋白 Hsp90 介导大脑内的 MOR 信号传导。在这里，我们发现在脊髓中特异性抑制 Hsp90 可增强吗啡对小鼠的镇痛作用。鞘内而非全身给药 Hsp90 抑制剂 17-AAG 或 KU-32 可增强吗啡抑制小鼠对热刺激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 磷酸化并增加脊髓背角中激酶 RSK 的丰度，脊髓背角富含初级传入感觉神经元。在鞘内抑制 ERK、RSK 或蛋白质合成后，Hsp90 抑制的累加效应被消除。这种机制位于 MOR 下游，定位于脊髓并被 Hsp90 抑制，可能用于提高疗效并可能减少阿片类药物治疗的副作用。