Fairbanks Carolyn A, Peterson Cristina D, Speltz Rebecca H, Riedl Maureen S, Kitto Kelley F, Dykstra Jaclyn A, Braun Patrick D, Sadahiro Masato, Salton Stephen R, Vulchanova Lucy
Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA Experimental and Clinical Pharmacology Graduate Program, University of Minnesota, Minneapolis, MN, USA Comparative and Molecular Biosciences Graduate Program, University of Minnesota, St. Paul, MN, USA Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, USA.
Pain. 2014 Jul;155(7):1229-1237. doi: 10.1016/j.pain.2014.03.012. Epub 2014 Mar 21.
VGF (nonacronymic) is a granin-like protein that is packaged and proteolytically processed within the regulated secretory pathway. VGF and peptides derived from its processing have been implicated in neuroplasticity associated with learning, memory, depression, and chronic pain. In sensory neurons, VGF is rapidly increased following peripheral nerve injury and inflammation. Several bioactive peptides generated from the C-terminus of VGF have pronociceptive spinal effects. The goal of the present study was to examine the spinal effects of the peptide TLQP-21 and determine whether it participates in spinal mechanisms of persistent pain. Application of exogenous TLQP-21 induced dose-dependent thermal hyperalgesia in the warm-water immersion tail-withdrawal test. This hyperalgesia was inhibited by a p38 mitogen-activated protein kinase inhibitor, as well as inhibitors of cyclooxygenase and lipoxygenase. We used immunoneutralization of TLQP-21 to determine the function of the endogenous peptide in mechanisms underlying persistent pain. In mice injected intradermally with complete Freund adjuvant, intrathecal treatment with anti-TLQP-21 immediately prior to or 5hours after induction of inflammation dose-dependently inhibited tactile hypersensitivity and thermal hyperalgesia. Intrathecal anti-TL21 administration also attenuated the development and maintenance of tactile hypersensitivity in the spared nerve injury model of neuropathic pain. These results provide evidence that endogenous TLQP-21 peptide contributes to the mechanisms of spinal neuroplasticity after inflammation and nerve injury.
VGF（无首字母缩写词）是一种类颗粒蛋白，在调节性分泌途径中进行包装和蛋白水解加工。VGF及其加工衍生的肽与学习、记忆、抑郁和慢性疼痛相关的神经可塑性有关。在感觉神经元中，外周神经损伤和炎症后VGF会迅速增加。从VGF的C末端产生的几种生物活性肽具有伤害感受性脊髓效应。本研究的目的是研究肽TLQP-21的脊髓效应，并确定它是否参与持续性疼痛的脊髓机制。在温水浸尾甩尾试验中，外源性TLQP-21的应用诱导了剂量依赖性热痛觉过敏。这种痛觉过敏被p38丝裂原活化蛋白激酶抑制剂以及环氧化酶和脂氧合酶抑制剂所抑制。我们使用TLQP-21的免疫中和来确定内源性肽在持续性疼痛潜在机制中的功能。在皮内注射完全弗氏佐剂的小鼠中，在炎症诱导前或诱导后5小时鞘内注射抗TLQP-21剂量依赖性地抑制触觉超敏反应和热痛觉过敏。在神经性疼痛的 spared nerve injury模型中，鞘内注射抗TL21也减弱了触觉超敏反应的发展和维持。这些结果提供了证据，表明内源性TLQP-21肽在炎症和神经损伤后脊髓神经可塑性机制中起作用。
