Tumor necrosis factor receptor type-1 in sensory neurons contributes to induction of chronic enhancement of inflammatory hyperalgesia in rat
Tumor necrosis factor receptor type-1 in sensory neurons contributes to induction of chronic enhancement of inflammatory hyperalgesia in rat
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DOI：
10.1046/j.1460-9568.2003.02626.x
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发表时间：
2003-05-01
影响因子：
3.4
通讯作者：
Levine, JD
中科院分区：
文献类型：
--
作者：
Parada, CA;Yeh, JJ;Levine, JD
角叉菜胶诱导的炎性疼痛持续数小时到数天会产生一种蛋白激酶C epsilon(PKCepsilon)依赖的“预激”状态，持续数周，在此期间，注射前列腺素E-2可诱导痛敏，与PGE(2)诱导的正常“非预激”大鼠的痛敏相比，这种痛敏显著增强并延长。在本研究中，我们证明，虽然抑制前列腺素合成和拮抗β(2)-肾上腺素能受体显著减轻角叉菜胶引起的痛敏，但这些干预并不影响痛觉过敏的启动。另一种角叉菜胶致炎症的介导物肿瘤坏死因子-α(大鼠重组；rrTNFpha)单独引起痛敏和预激，鞘内注射PKCepsilon反义寡核苷酸可分别减弱和预防这两种作用。用沙利度胺或大鼠多克隆抗肿瘤坏死因子α抗体抑制肿瘤坏死因子α可减轻角叉菜胶引起的痛觉过敏，并阻止启动。鞘内注射反义肿瘤坏死因子受体-1(TNFR1)可减少向感觉神经元外周终末转运的TNFR1水平，并减弱角叉菜胶和rTNFpha诱导的启动作用。用反义TNFR1治疗的动物，卡拉胶或rrTNFα诱导的急性痛敏反应保持不变。我们的结果表明，启动状态的产生不需要产生痛敏反应，而在急性炎症过程中产生的TNFpha可以作用于感觉神经元，通过激活神经元的PKCepsilon来诱导痛敏启动。
Carrageenan-induced inflammatory pain lasting hours to days produces a protein kinase C epsilon (PKCepsilon)-dependent 'primed' state lasting several weeks, during which time injection of prostaglandin E-2 induces hyperalgesia which is markedly enhanced and prolonged compared to PGE(2) -induced hyperalgesia in normal 'unprimed' rats. In the present study, we demonstrate that while inhibition of prostaglandin synthesis and antagonism of beta(2) -adrenergic receptors markedly attenuated the hyperalgesia induced by carrageenan, these interventions did not affect hyperalgesic priming. Tumor necrosis factor-alpha (rat recombinant; rrTNFalpha), another mediator of carrageenan-induced inflammation, alone produced hyperalgesia and priming, which were attenuated and prevented, respectively, by intrathecal administration of antisense to PKCepsilon. Inhibition of TNFalpha with thalidomide or a rat polyclonal anti-TNFalpha antibody attenuated carrageenan-induced hyperalgesia and prevented priming. Intrathecal administration of antisense to tumour necrosis factor receptor type-1 (TNFR1) reduced the level of TNFR1 transported toward the peripheral terminals of sensory neurons, and attenuated both carrageenan- and rrTNFalpha-induced priming. Acute hyperalgesia induced by carrageenan or rrTNFalpha remained intact in animals treated with TNFR1 antisense. Our results demonstrate that the generation of the primed state does not require production of hyperalgesia and that TNFalpha, which is generated during acute inflammation, can act on sensory neurons to induce hyperalgesic priming by activating neuronal PKCepsilon.