Ossipov Michael H, Bazov Igor, Gardell Luis R, Kowal Justin, Yakovleva Tatiana, Usynin Ivan, Ekström Tomas J, Porreca Frank, Bakalkin Georgy
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA.
J Neurosci. 2007 Aug 1;27(31):8226-37. doi: 10.1523/JNEUROSCI.5126-06.2007.
Chronic pain is maintained in part by long-lasting neuroplastic changes in synapses and several proteins critical for synaptic plasticity are degraded by the ubiquitin-proteasome system (UPS). Here, we show that proteasome inhibitors administered intrathecally or subcutaneously prevented the development and reversed nerve injury-induced pain behavior. They also blocked pathological pain induced by sustained administration of morphine or spinal injection of dynorphin A, an endogenous mediator of chronic pain. Proteasome inhibitors blocked mechanical allodynia and thermal hyperalgesia in all three pain models although they did not modify responses to mechanical stimuli, but partially inhibited responses to thermal stimuli in control rats. In the spinal cord, these compounds abolished the enhanced capsaicin-evoked calcitonin gene-related peptide (CGRP) release and dynorphin A upregulation, both elicited by nerve injury. Model experiments demonstrated that the inhibitors may act directly on dynorphin-producing cells, blocking dynorphin secretion. Thus, the effects of proteasome inhibitors on chronic pain were apparently mediated through several cellular mechanisms indispensable for chronic pain, including those of dynorphin A release and postsynaptic actions, and of CGRP secretion. Levels of several UPS proteins were reduced in animals with neuropathic pain, suggesting that UPS downregulation, like effects of proteasome inhibitors, counteracts the development of chronic pain. The inhibitors did not produce marked or disabling motor disturbances at doses that were used to modify chronic pain. These results suggest that the UPS is a critical intracellular regulator of pathological pain, and that UPS-mediated protein degradation is required for maintenance of chronic pain and nociceptive, but not non-nociceptive responses in normal animals.
慢性疼痛部分是由突触中持久的神经可塑性变化维持的，泛素 - 蛋白酶体系统（UPS）会降解几种对突触可塑性至关重要的蛋白质。在此，我们表明鞘内或皮下注射蛋白酶体抑制剂可预防神经损伤诱导的疼痛行为的发展并使其逆转。它们还能阻断持续给予吗啡或脊髓注射强啡肽A（一种慢性疼痛的内源性介质）所诱导的病理性疼痛。蛋白酶体抑制剂在所有三种疼痛模型中均能阻断机械性异常性疼痛和热痛觉过敏，尽管它们并未改变对照大鼠对机械刺激的反应，但部分抑制了对照大鼠对热刺激的反应。在脊髓中，这些化合物消除了由神经损伤引发的辣椒素诱发的降钙素基因相关肽（CGRP）释放增强和强啡肽A上调。模型实验表明，这些抑制剂可能直接作用于产生强啡肽的细胞，阻断强啡肽的分泌。因此，蛋白酶体抑制剂对慢性疼痛的作用显然是通过慢性疼痛不可或缺的几种细胞机制介导的，包括强啡肽A释放和突触后作用以及CGRP分泌的机制。在患有神经性疼痛的动物中，几种UPS蛋白的水平降低，这表明UPS下调与蛋白酶体抑制剂的作用类似，可抵消慢性疼痛的发展。在用于改变慢性疼痛的剂量下，这些抑制剂并未产生明显或致残的运动障碍。这些结果表明，UPS是病理性疼痛的关键细胞内调节因子，并且UPS介导的蛋白质降解是维持慢性疼痛和伤害性反应所必需的，但对正常动物的非伤害性反应并非必需。
