Wallace Victoria C J, Blackbeard Julie, Pheby Timothy, Segerdahl Andrew R, Davies Meirion, Hasnie Fauzia, Hall Susan, McMahon Stephen B, Rice Andrew S C
Pain Research Group, Department of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, 369 Fulham Road, London SW10 9NH, UK.
Pain. 2007 Dec 15;133(1-3):47-63. doi: 10.1016/j.pain.2007.02.015. Epub 2007 Apr 12.
A painful neuropathy is frequently observed in people living with human immunodeficiency virus type 1 (HIV-1). The HIV coat protein, glycoprotein 120 (gp120), implicated in the pathogenesis of neurological disorders associated with HIV, is capable of initiating neurotoxic cascades via an interaction with the CXCR4 and/or CCR5 chemokine receptors, which may underlie the pathogenesis of HIV-associated peripheral neuropathic pain. In order to elucidate the mechanisms underlying HIV-induced painful peripheral neuropathy, we have characterised pathological events in the peripheral and central nervous system following application of HIV-1 gp120 to the rat sciatic nerve. Perineural HIV-1 gp120 treatment induced a persistent mechanical hypersensitivity (44% decrease from baseline), but no alterations in sensitivity to thermal or cold stimuli, and thigmotactic (anxiety-like) behaviour in the open field. The mechanical hypersensitivity was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. Immunohistochemical studies reveal: decreased intraepidermal nerve fibre density, macrophage infiltration into the peripheral nerve at the site of perineural HIV-1 gp120; changes in sensory neuron phenotype including expression of activating transcription factor 3 (ATF3) in 27% of cells, caspase-3 in 25% of cells, neuropeptide Y (NPY) in 12% of cells and galanin in 13% of cells and a spinal gliosis. These novel findings suggest that this model is not only useful for the elucidation of mechanisms underlying HIV-1-related peripheral neuropathy but may prove useful for preclinical assessment of drugs for the treatment of HIV-1 related peripheral neuropathic pain.
在感染1型人类免疫缺陷病毒（HIV-1）的人群中，经常会观察到疼痛性神经病变。HIV外壳蛋白糖蛋白120（gp120）与HIV相关的神经疾病发病机制有关，它能够通过与CXCR4和/或CCR5趋化因子受体相互作用引发神经毒性级联反应，这可能是HIV相关外周神经病理性疼痛发病机制的基础。为了阐明HIV诱导的疼痛性外周神经病变的机制，我们对将HIV-1 gp120应用于大鼠坐骨神经后外周和中枢神经系统中的病理事件进行了表征。神经周围给予HIV-1 gp120会导致持续的机械性超敏反应（比基线降低44%），但对热刺激或冷刺激的敏感性以及旷场中的趋触性（焦虑样）行为没有改变。机械性超敏反应对加巴喷丁、吗啡和大麻素WIN 55,212-2的全身治疗敏感，但对阿米替林不敏感。免疫组织化学研究显示：表皮内神经纤维密度降低，巨噬细胞在神经周围HIV-1 gp120部位浸润到外周神经；感觉神经元表型发生变化，包括27%的细胞中激活转录因子3（ATF3）表达、25%的细胞中半胱天冬酶-3表达、12%的细胞中神经肽Y（NPY）表达以及13%的细胞中甘丙肽表达，以及脊髓胶质增生。这些新发现表明，该模型不仅有助于阐明HIV-1相关外周神经病变的机制，而且可能对治疗HIV-1相关外周神经病理性疼痛的药物临床前评估有用。
