Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models.
Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models.
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DOI：
10.4097/kja.d.18.00022
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发表时间：
2019-03
影响因子：
2.9
通讯作者：
Joo JD
中科院分区：
文献类型：
--
作者：
Kim Y;Kwon SY;Jung HS;Park YJ;Kim YS;In JH;Choi JW;Kim JA;Joo JD
三环类抗抑郁药的止痛特性可以归因于几种作用。最近的观察表明，腺苷参与阿米替林的抗伤害作用。A3腺苷受体（A3 AR）是唯一在炎症和癌细胞中过表达的腺苷亚型。本研究旨在探讨A3 AR在阿米替林抗伤害性效应中的作用。通过结扎雄性Sprague-Dawley大鼠的L5和L 6脊神经来诱导脊神经结扎的神经性疼痛。将神经病大鼠随机分为以下三组之一（每组8只）：用生理盐水的神经病性疼痛组、用阿米替林的神经病性疼痛组、以及用阿米替林和3-乙基-5-苄基-2-甲基-4-苯基乙炔基-6-苯基-1，4-（±）-二氢吡啶-3，5-二羧酸酯（MRS）的神经病性疼痛组。阿米替林或生理盐水腹腔内给药，并在阿米替林给药前立即皮下注射A3 AR拮抗剂3-乙基-5-苄基-2-甲基-4-苯基乙炔基-6-苯基-1，4-（±）-二氢吡啶-3，5-二羧酸酯（MRS-1191）。细胞外信号调节激酶P44/42（ERK 1/2），环磷酸腺苷反应元件结合蛋白（CREB）和促炎细胞因子的水平进行了评估，使用免疫印迹或逆转录聚合酶链反应。阿米替林可增加神经病大鼠的机械性缩足阈。磷酸化ERK 1/2和磷酸化CREB蛋白的水平，和脊髓神经结扎产生的促炎细胞因子的阿米替林管理显着降低。然而，在阿米替林给药前使用MRS-1191不仅降低了机械性异常性疼痛的阈值，而且增加了信号蛋白和促炎细胞因子水平，阿米替林降低了这些水平。本研究的结果表明，阿米替林的抗伤害性作用涉及ERK 1/2和CREB信号蛋白的抑制，A3 AR激活也影响炎症反应的缓解。
The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory and cancer cells. This study was performed to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline. Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague-Dawley rats. The neuropathic rats were randomly assigned to one of the following three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and 3-ethyl-5-benzyl- 2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS) group. Amitriptyline or saline was administered intraperitoneally and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191), an A3AR antagonist, was injected subcutaneously immediately before amitriptyline administration. The level of extracellular signal-regulated kinase P44/42 (ERK1/2), cyclic AMP response element-binding protein (CREB), and proinflammatory cytokines were assessed using immunoblotting or reverse-transciption polymerase chain reaction. Amitriptyline increased the mechanical withdrawal threshold of the neuropathic rats. The level of phospho-ERK1/2 and phospho-CREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline administration not only reduced the threshold of mechanical allodynia, but also increased the signaling protein and proinflammatory cytokine levels, which were reduced by amitriptyline. The results of this study suggest that the anti-nociceptive effect of amitriptyline involves the suppression of ERK1/2 and CREB signaling proteins, and A3AR activation also affects the alleviation of the inflammatory response.
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影响因子：
3.3
作者：
Katz, N. K.;Ryals, J. M.;Wright, D. E.
通讯作者：
Wright, D. E.
影响因子：
3.6
作者：
Joo, Jin D.;Choi, Jin W.;Jeon, Yeon S.
通讯作者：
Jeon, Yeon S.
影响因子：
5
作者：
Esser, MJ;Sawynok, J
通讯作者：
Sawynok, J
影响因子：
5
作者：
Mabley, J;Soriano, F;Szabó, C
通讯作者：
Szabó, C
影响因子：
2.9
作者：
Kwon, So-Young;Yeom, Jae Hwa;Joo, Jin-Deok
通讯作者：
Joo, Jin-Deok