An antisense oligonucleotide to the N-methyl-D-aspartate (NMDA) subunit NMDAR1 attenuates NMDA-induced nociception, hyperalgesia, and morphine tolerance
An antisense oligonucleotide to the N-methyl-D-aspartate (NMDA) subunit NMDAR1 attenuates NMDA-induced nociception, hyperalgesia, and morphine tolerance
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DOI：
10.1124/jpet.104.074856
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Inturrisi, CE
中科院分区：
文献类型：
--
作者：
Shimoyama, N;Shimoyama, M;Inturrisi, CE
我们确定了i.t.施用降低N-甲基-D-天冬氨酸（NMDA）受体的大鼠NMDAR 1亚单位表达的18-mer磷酸二酯反义寡脱氧核苷酸（ODN）将影响伤害感受行为并阻止吗啡耐受性的发展。大鼠接受5穆尔i.t.生理盐水、30 nM反义或错配ODN，每天两次，持续5天（NMDA诱导的伤害感受、NMDA诱导的热痛觉过敏、NR 1 mRNA和配体结合研究）或3天（福尔马林研究）。对于耐受性研究，ODN或盐水5天之后是ODN或盐水（每天两次）和i.t.吗啡（一天三次）。反义而非错配导致福尔马林2期退缩减少50%，脊髓背角NMDAR 1 mRNA水平减少30%，配体结合减少50%。信息科技NMDA诱导的伤害性行为的ED 50加倍，并且热痛觉过敏被反义治疗阻断。反义对NMDA诱导的伤害性感受和热痛觉过敏的影响可被反义的终止完全逆转。反义核酸与增加剂量的i.t.吗啡3天减弱吗啡耐受性的发展。这些结果表明，在体内反义靶向的NMDAR 1亚基的结果在抗痛觉过敏的效果和脊髓吗啡耐受的部分封锁。它们为NMDA受体在这些形式的脊髓伤害感受和吗啡耐受性的发展中的关键作用提供了额外的支持，并表明这种方法的潜在治疗效用。
We determined whether the i.t. administration of an 18-mer phosphodiester antisense oligodeoxynucleotide (ODN) that reduces the expression of the rat NMDAR1 subunit of the N-methyl-D- aspartate ( NMDA) receptor would affect nociceptive behaviors and prevent the development of morphine tolerance. Rats received 5 mul of i.t. saline, 30 nM antisense, or mismatch ODN twice a day for 5 days (NMDA-induced nociception, NMDA-induced thermal hyperalgesia, NR1 mRNA, and ligand binding studies) or for 3 days ( formalin study). For the tolerance study, 5 days of ODNs or saline were followed by 3 days of concurrent administration of ODNs or saline ( twice a day) and i.t. morphine ( three times a day). Antisense, but not mismatch, results in the reduction of formalin phase 2 flinching by 50%, the spinal cord dorsal horn levels of NMDAR1 mRNA by 30%, and ligand binding by 50%. The i.t. ED50 for NMDA-induced nociceptive behaviors is doubled, and thermal hyperalgesia is blocked by antisense treatment. The effects of antisense on NMDA-induced nociception and thermal hyperalgesia are completely reversed by discontinuing antisense. The coadministration of antisense with increasing doses of i.t. morphine for 3 days attenuates the development of morphine tolerance. These results demonstrate that an in vivo antisense targeting of the NMDAR1 subunit results in antihyperalgesic effects and a partial blockade of spinal morphine tolerance. They provide additional support for the critical role of the NMDA receptor in these forms of spinal nociception and in the development of morphine tolerance and suggest the potential therapeutic utility of this approach.