Expression of neuron-associated tumor necrosis factor alpha in the brain is increased during persistent pain
Expression of neuron-associated tumor necrosis factor alpha in the brain is increased during persistent pain
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DOI：
10.1053/rapm.2002.31930
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发表时间：
2002-07-01
影响因子：
5.1
通讯作者：
Spengler, RN
中科院分区：
文献类型：
--
作者：
Covey, WC;Ignatowski, TA;Spengler, RN
背景与目的：有证据表明多效性细胞因子肿瘤坏死因子α（TNFα）在持续性疼痛的发病机制中起作用。本研究采用神经性疼痛的慢性缩窄性损伤（CCI）模型，以检测该疼痛模型中中枢神经系统（CNS）和外周的TNFα产生情况。
方法：通过热板试验测量痛觉阈值来评估CCI诱导的痛觉过敏。通过以下方式将痛觉过敏的发展与TNFα水平相关联：使用WEHI - 13变异细胞毒性生物测定法检测坐骨神经、颈脊髓、胸腰段脊髓匀浆以及血浆中的生物活性TNFα；通过原位杂交检测蓝斑切片中TNFα的mRNA。
结果：我们先前已证明，在包含蓝斑的脑干区域，TNFα生物活性随着痛觉过敏的发展而增加，并在痛觉过敏停止的第14天恢复到基线值。在对照大鼠、假手术大鼠和接受CCI的大鼠的血浆、坐骨神经以及颈脊髓和胸腰段脊髓中均检测到TNFα的固有水平。在结扎后第8天，受损坐骨神经中的TNFα水平显著升高，与最大程度的痛觉过敏同时发生，并且在结扎后第14天痛觉过敏减轻时仍保持升高。此外，在结扎后第4天，胸腰段脊髓区域的TNFα活性增加，并在痛觉过敏期间（第8天）以及痛觉过敏消退后（第14天）仍保持升高。TNFα表达的增加是中枢神经系统特定区域所特有的，而不是全身性炎症反应的结果，因为实际上接受CCI的大鼠血浆中的TNFα生物活性是降低的。此外，在结扎后第2、8和14天，在包含蓝斑的脑区域内的神经元中，TNFα特异性mRNA的积累显著增加，与痛觉过敏的发展同时发生。
结论：在与肾上腺素能神经元功能以及疼痛感知调节相关的脑和脊髓区域内TNFα的增加，以及TNFα积累增加的时间进程和分布，支持TNFα在中枢神经系统中对神经性疼痛的发生和维持具有神经调节作用。
Background and Objectives: Evidence implicates the pleiotropic cytokine tumor necrosis factor alpha (TNFalpha) in the pathogenesis of persistent pain. The present study employs a chronic constriction injury (CCI) model of neuropathic pain to examine TNFalpha production in the central nervous system (CNS) and in the periphery in this pain model. Methods: CCI-induced hyperalgesia is assessed by measuring the nociceptive threshold using the hotplate test. The development of hyperalgesia is correlated to levels of TNFalpha by assessing: bioactive TNFalpha in homogenates of sciatic nerves, cervical spinal cord, thoracolumbar spinal cord, as well as in plasma using the WEHI-13 variant cytotoxicity bioassay; and mRNA for TNFalpha in sections of locus coeruleus by in situ hybridization.Results: We have previously demonstrated that TNFa bioactivity in the region of the brainstem containing the locus coeruleus is increased concurrent with the development of hyperalgesia, returning to baseline values by day 14, when hyperalgesia has ceased. Constitutive levels of TNFalpha are demonstrated in the plasma, sciatic nerves, and cervical and thoracolumbar spinal cord of control rats, sham-operated rats, and rats undergoing CCI. Levels of TNFalpha are significantly elevated in the injured sciatic nerve by day 8 postligature placement, concurrent with maximal hyperalgesia, and remain elevated when hyperalgesia has abated at day 14 postligature placement. Additionally, TNFalpha activity is increased in the thoracolumbar region of the spinal cord by day 4 postligature placement and remains elevated during hyperalgesia (day 8), as well as after hyperalgesia has dissipated (day 14). The increase in TNFalpha expression is specific to discrete regions of the CNS, rather than being the result of a systemic inflammatory response, since TNFa bioactivity in plasma is, in fact, decreased in rats undergoing CCI. Additionally, accumulation of mRNA specific for TNFalpha is significantly increased in neurons within a region of the brain containing the locus coeruleus at days 2, 8, and 14 postligature placement, contemporaneous with the development of hyperalgesia.Conclusions: The increases in TNFalpha within regions of the brain and spinal cord that are associated with adrenergic neuron function, as well as with modulation of pain perception, and the time course and distribution of the increases in TNFalpha accumulation support a neuromodulatory role for TNFalpha within the CNS in the development and maintenance of neuropathic pain.