Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
Comprehensive Pain and Addiction Center, University of Arizona, Tucson, AZ, USA.
Sci Signal. 2023 Apr 11;16(780):eade2438. doi: 10.1126/scisignal.ade2438.
Opioids and other agonists of the μ-opioid receptor are effective at managing acute pain, but their chronic use can lead to tolerance that limits their efficacy. We previously reported that inhibiting the chaperone protein HSP90 in the spinal cords of mice promotes the antinociceptive effects of opioids in a manner that involved increased activation of the kinase ERK. Here, we found that the underlying mechanism involves the relief of a negative feedback loop mediated by the kinase AMPK. Intrathecal treatment of male and female mice with the HSP90 inhibitor 17-AAG decreased the abundance of the β1 subunit of AMPK in the spinal cord. The antinociceptive effects of 17-AAG with morphine were suppressed by intrathecal administration of AMPK activators and enhanced by an AMPK inhibitor. Opioid treatment increased the abundance of phosphorylated AMPK in the dorsal horn of the spinal cord, where it colocalized with a neuronal marker and the neuropeptide CGRP. Knocking down AMPK in CGRP-positive neurons enhanced the antinociceptive effects of morphine and demonstrated that AMPK mediated the signal transduction between HSP90 inhibition and ERK activation. These data suggest that AMPK mediates an opioid-induced negative feedback loop in CGRP neurons of the spinal cord and that this loop can be disabled by HSP90 inhibition to enhance the efficacy of opioids.
阿片类药物和 μ 型阿片受体的其他激动剂在治疗急性疼痛方面非常有效，但它们的慢性使用会导致耐受，从而限制其疗效。我们之前曾报道过，在小鼠脊髓中抑制伴侣蛋白 HSP90 可以促进阿片类药物的镇痛作用，其作用机制涉及激酶 ERK 的激活增加。在这里，我们发现其潜在机制涉及由激酶 AMPK 介导的负反馈回路的缓解。鞘内给予 HSP90 抑制剂 17-AAG 可降低小鼠脊髓中 AMPKβ1 亚基的丰度。鞘内给予 AMPK 激活剂可抑制 17-AAG 与吗啡的镇痛作用，而 AMPK 抑制剂则增强其作用。阿片类药物治疗可增加脊髓背角磷酸化 AMPK 的丰度，其与神经元标志物和神经肽 CGRP 共定位。在 CGRP 阳性神经元中敲低 AMPK 可增强吗啡的镇痛作用，并表明 AMPK 介导了 HSP90 抑制与 ERK 激活之间的信号转导。这些数据表明，AMPK 在脊髓 CGRP 神经元中介导阿片类药物诱导的负反馈回路，并且该回路可通过 HSP90 抑制失活以增强阿片类药物的疗效。
