Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain
Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain
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DOI：
10.1073/pnas.1510137112
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发表时间：
2015-07-21
影响因子：
11.1
通讯作者：
Hammock, Bruce D.
中科院分区：
文献类型：
--
作者：
Inceoglu, Bora;Bettaieb, Ahmed;Hammock, Bruce D.
尽管在了解神经病理性疼痛的机制方面进行了密集的努力并取得了进展，但在治疗方法上取得的成功有限。最近发现的一种非通道、非神经递质的疼痛治疗靶点是酶溶环氧化物水解酶(SEH)。SEH降解天然的止痛脂介质--环氧脂肪酸(EpFAs)，因此它的抑制作用使这些生物活性介质稳定。在这里，我们展示了EpFAs在糖尿病引起的神经病理性疼痛中的作用，并定义了一种先前未知的疼痛机制，该机制受内质网(ER)压力的调节。内质网应激的激活首次在I型糖尿病大鼠的外周神经系统中被量化。我们证明，疼痛和内质网应激的标志都可以被化学伴侣逆转。接下来，我们确定EpFAs是内质网应激途径的上游调节器。内质网应激的化学诱导剂总是导致疼痛行为，而这种行为可被化学伴侣和sEH抑制剂逆转。诱导痛行为的快速发生、阻滞剂的同样快速逆转以及糖尿病周围神经系统(PNS)内质网应激的自然发生，证明了内质网应激通路在调节伤害性感受系统的兴奋性中起着重要作用。了解内质网应激在疼痛产生和维持中的作用，为将这一系统用于治疗目的开辟了道路。
Despite intensive effort and resulting gains in understanding the mechanisms underlying neuropathic pain, limited success in therapeutic approaches have been attained. A recently identified, non-channel, nonneurotransmitter therapeutic target for pain is the enzyme soluble epoxide hydrolase (sEH). The sEH degrades natural analgesic lipid mediators, epoxy fatty acids (EpFAs), therefore its inhibition stabilizes these bioactive mediators. Here we demonstrate the effects of EpFAs on diabetes induced neuropathic pain and define a previously unknown mechanism of pain, regulated by endoplasmic reticulum (ER) stress. The activation of ER stress is first quantified in the peripheral nervous system of type I diabetic rats. We demonstrate that both pain and markers of ER stress are reversed by a chemical chaperone. Next, we identify the EpFAs as upstream modulators of ER stress pathways. Chemical inducers of ER stress invariably lead to pain behavior that is reversed by a chemical chaperone and an inhibitor of sEH. The rapid occurrence of pain behavior with inducers, equally rapid reversal by blockers and natural incidence of ER stress in diabetic peripheral nervous system (PNS) argue for a major role of the ER stress pathways in regulating the excitability of the nociceptive system. Understanding the role of ER stress in generation and maintenance of pain opens routes to exploit this system for therapeutic purposes.