Blockade of peripheral and spinal Na+/H+ exchanger increases formalin-induced long-lasting mechanical allodynia and hyperalgesia in rats
Blockade of peripheral and spinal Na+/H+ exchanger increases formalin-induced long-lasting mechanical allodynia and hyperalgesia in rats
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DOI：
10.1016/j.brainres.2012.08.001
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发表时间：
2012-09-26
期刊：
影响因子：
2.9
通讯作者：
Granados-Soto, Vinicio
中科院分区：
文献类型：
--
作者：
Castaneda-Corral, Gabriela;Rocha-Gonzalez, Hector I.;Granados-Soto, Vinicio
Na+/H+交换器（NHE）通过介导H+的电中性转运来调节细胞内的pH和体积。由于NHE 1调节神经元和星形胶质细胞中的pH，并且其在伤害性神经纤维中表达，因此NHE可能调节神经元兴奋性和疼痛传递。本研究的目的是评估外周和脊髓NHE在福尔马林诱导的继发性异常性疼痛/痛觉过敏中的参与。此外，我们确定了福尔马林注射是否改变了NHE 1在腰椎背根神经节（DRG）和脊髓背侧的表达。将0.5%福尔马林皮下注射到后爪的背侧表面中产生急性伤害性行为（退缩和舔/提升），随后产生持久的双侧继发性机械异常性疼痛/痛觉过敏。用选择性NHE抑制剂进行外周和鞘内预处理（~ 10分钟）5-（N，N-二甲基）阿米洛利盐酸盐（DMA，0.3-30 μ M），5-（N-乙基-N-异丙基）阿米洛利（EIPA，0.3-30 μ M）和[1-（喹啉-5-基）-5-环丙基-1H-吡唑-4-羰基]胍盐酸盐（zoniporide，0.03-3 μ M）显著增加0.5%福尔马林诱导的双侧持久继发性异常性疼痛/痛觉过敏。此外，局部外周或鞘内后处理（注射后第6天）与这些NHE抑制剂不影响福尔马林诱导的伤害性行为。从第1天到第12天，福尔马林注射降低了同侧和对侧脊髓背角的NHE 1表达。此外，福尔马林在第12天减少DRG中的NHE 1蛋白表达。这些结果表明，NHE 1在福尔马林诱导的持久伤害性行为中在外周和脊髓水平的疼痛处理中起作用。此外，这些结果表明，参与pH调节的蛋白质可能是开发新镇痛药物的目标。(c)2012爱思唯尔有限公司版权所有。
The Na+/H+ exchanger (NHE) is involved in the regulation of intracellular pH and volume by mediating the electroneutral transport of H+ against an influx of Na+ ions. Since NHE1 regulates pH in neurons and astrocytes and it is expressed in nociceptive nerve fibers, it is likely that NHE may modulate neuronal excitability and pain transmission. The purpose of this study was to assess the participation of peripheral and spinal NHE in the secondary allodynia/hyperalgesia induced by formalin. In addition, we determined whether formalin injection modifies the expression of NHE1 in lumbar dorsal root ganglia (DRG) and dorsal spinal cord. Subcutaneous injection of 0.5% formalin into the dorsal surface of the hind paw produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-lasting bilateral secondary mechanical allodynia/hyperalgesia. Peripheral and intrathecal pre-treatment (-10 min) with selective NHE inhibitors 5-(N,N-dimethyl)amiloride hydrochloride (DMA, 0.3-30 mu M), 5-(N-ethyl-N-isopropyl)amiloride (EIPA, 0.3-30 mu M) and [1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine dihydrochloride (zoniporide, 0.03-3 mu M) significantly increased 0.5% formalin-induced bilateral long-lasting secondary allodynia/hyperalgesia. Contrariwise, local peripheral or intrathecal post-treatment (day 6 postinjection) with these NHE inhibitors did not affect formalin-induced nociceptive behaviors. Formalin injection reduced NHE1 expression in ipsilateral and contralateral spinal dorsal horns from day 1 to 12. In addition, formalin diminished NHE1 protein expression in DRG at day 12. These results suggest that NHE1 plays a role in pain processing at peripheral and spinal levels in formalin-induced long-lasting nociceptive behaviors. Additionally, these results suggest that proteins involved in pH regulation could be targets for the development of new analgesic drugs. (c) 2012 Elsevier B.V. All rights reserved.