Intraperitoneal injection of antisense peptide nucleic acids targeted to the mu receptor decreases response to morphine and receptor protein levels in rat brain.
Intraperitoneal injection of antisense peptide nucleic acids targeted to the mu receptor decreases response to morphine and receptor protein levels in rat brain.
复制标题
腹腔注射针对 mu 受体的反义肽核酸可降低大鼠脑中对吗啡和受体蛋白水平的反应。
DOI：
10.1016/s0006-8993(01)02511-2
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发表时间：
2001
期刊：
影响因子：
2.9
通讯作者：
Richelson,E
中科院分区：
文献类型：
--
作者：
McMahon,BM;Stewart,JA;Jackson,J;Fauq,A;McCormick,DJ;Richelson,E
为了确定肽核酸（PNAs）在体内的有效性，我们设计并合成了μ受体（吗啡诱导抗伤害感受的分子靶点）的反义PNAs。观察大鼠对吗啡的反应性及吗啡处理后μ受体表达水平。我们将靶向μ受体的反义PNA（AS-MOR）、错配PNA（AS-MOR MM）、靶向神经降压素受体亚型1的反义PNA（AS-NTR 1）或盐水腹膜内注射，然后用5 mg/kg吗啡（腹膜内）或神经降压素直接攻击大鼠脑的导水管周围灰质区。为了避免耐受性，在PNA处理后24、48和72小时测试单独的动物组。只有用AS-MOR治疗的动物显示出它们对吗啡的抗伤害性反应的降低。吗啡对AS-MOR大鼠的作用在24和48 h时明显缺乏，但在72 h时测试的动物与对照组相似。在24小时，AS-MOR大鼠中脑导水管周围灰质区的μ受体水平显著降低55%，而AS-MOR MM大鼠没有显示出显著变化。最后，AS-MOR大鼠继续表现出正常的抗伤害性反应的神经降压素。因此，本研究为使用PNA通过全身施用PNA靶向脑内蛋白质提供了额外的支持。
To determine the effectiveness of peptide nucleic acids (PNAs) in vivo, we designed and synthesized PNAs antisense to the mu receptor, the molecular target of morphine for inducing antinociception. Responsiveness of rats to morphine and the levels of mu receptor expression after treatment was measured. We delivered intraperitoneal injections of antisense PNAs targeted to the mu receptor (AS-MOR), mismatch PNAs (AS-MOR MM), antisense PNAs targeted to the neurotensin receptor subtype 1 (AS-NTR1), or saline and then challenged the rats with 5 mg/kg morphine (intraperitonally) or neurotensin directly into the periaqueductal gray region of the brain. To avoid tolerance, separate groups of animals were tested at 24, 48, and 72 h post-PNA treatment. Only animals treated with the AS-MOR showed a reduction in their antinociceptive response to morphine. The lack of effect of morphine on the AS-MOR rats was profound at 24 and 48 h, but animals tested at 72 h were similar to control groups. At 24 h the AS-MOR rats had a significant 55% decrease in the levels of mu receptor in their periaqueductal gray region, while AS-MOR MM rats showed no significant change. Lastly, the AS-MOR rats continued to show a normal antinociceptive response to neurotensin. This study, therefore, provides additional support for the use of PNAs to target proteins within brain by systemically administered PNAs.