EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury.
EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury.
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DOI：
10.1016/j.ynpai.2019.100040
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发表时间：
2020-01-01
期刊：
影响因子：
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通讯作者：
Bavencoffe, Alexis G
中科院分区：
文献类型：
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作者：
Berkey, Samantha C;Herrera, Juan J;Bavencoffe, Alexis G
脊髓损伤（SCI）后慢性疼痛与初级伤害感受器的电性亢进（自发的和诱发的）有关。环腺苷单磷酸（cAMP）信号是伤害感受器兴奋性的重要贡献者，cAMP效应物，由cAMP激活的交换蛋白（EPAC）的敲低已被证明可以缓解几种慢性疼痛模型中的疼痛样反应。为了研究EPAC亚型（EPAC1和epac2）在维持慢性疼痛中的潜在不同作用，我们使用了大鼠和小鼠挫伤脊髓损伤（SCI）模型。在大鼠脊髓损伤模型中，EPAC1或2的药理抑制足以逆转脊髓损伤诱导的伤害感受器过度活跃，这表明EPAC1和2信号活性是互补的，两者都是维持过度活跃所必需的。然而，EPAC激活不足以诱导幼稚大鼠的伤害感受器出现类似的过度活跃，我们观察到脊髓损伤后EPAC蛋白表达没有变化。在小鼠脊髓损伤模型中，需要通过药物抑制和基因缺失相结合的方式抑制EPAC两种亚型，才能逆转脊髓损伤诱导的伤害感受器过度活跃。这与我们的发现一致，即EPAC1-/-和EPAC2-/-小鼠在操作性机械冲突测试中都没有受到sci诱导的慢性疼痛的保护。因此，EPAC1和2的活性可能在小鼠伤害感受器中发挥了冗余作用，尽管脊髓损伤后EPAC蛋白表达水平没有相应的变化。尽管这些物种之间存在一些差异，但我们的数据表明EPAC1和EPAC2在维持损伤感受器过度活跃和脊髓损伤后慢性疼痛的机制中都起着重要作用。
Chronic pain following spinal cord injury (SCI) is associated with electrical hyperactivity (spontaneous and evoked) in primary nociceptors. Cyclic adenosine monophosphate (cAMP) signaling is an important contributor to nociceptor excitability, and knockdown of the cAMP effector, exchange protein activated by cAMP (EPAC), has been shown to relieve pain-like responses in several chronic pain models. To examine potentially distinct roles of each EPAC isoform (EPAC1 and 2) in maintaining chronic pain, we used rat and mouse models of contusive spinal cord injury (SCI). Pharmacological inhibition of EPAC1 or 2 in a rat SCI model was sufficient to reverse SCI-induced nociceptor hyperactivity, indicating that EPAC1 and 2 signaling activity are complementary, with both required to maintain hyperactivity. However, EPAC activation was not sufficient to induce similar hyperactivity in nociceptors from naive rats, and we observed no change in EPAC protein expression after SCI. In the mouse SCI model, inhibition of both EPAC isoforms through a combination of pharmacological inhibition and genetic deletion was required to reverse SCI-induced nociceptor hyperactivity. This was consistent with our finding that neither EPAC1-/- nor EPAC2-/- mice were protected against SCI-induced chronic pain as assessed with an operant mechanical conflict test. Thus, EPAC1 and 2 activity may play a redundant role in mouse nociceptors, although no corresponding change in EPAC protein expression levels was detected after SCI. Despite some differences between these species, our data demonstrate a fundamental role for both EPAC1 and EPAC2 in mechanisms maintaining nociceptor hyperactivity and chronic pain after SCI.