Antisense mapping of MOR-1 in rats: distinguishing between morphine and morphine-6beta-glucuronide antinociception.
Antisense mapping of MOR-1 in rats: distinguishing between morphine and morphine-6beta-glucuronide antinociception.
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发表时间：
1997-04
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通讯作者：
G. Rossi;L. Leventhal;Ying Pan;J. L. Cole;W. Su;R. J. Bodnar;G. Pasternak
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作者：
G. Rossi;L. Leventhal;Ying Pan;J. L. Cole;W. Su;R. J. Bodnar;G. Pasternak
为了将最近克隆的MOR-1受体与吗啡和吗啡-6β-葡萄糖醛酸苷(M6G)的药理作用联系起来，我们使用了反义范式。大鼠侧脑室注射(i.c.v.)分别于给药后第1、3、5天注射反义寡核苷酸，于注射吗啡或M6G后第6天进行镇痛试验。或直接向中脑导水管周围灰质或蓝斑微量注射吗啡。静脉注射吗啡时，针对外显子1 5‘非翻译区的反义寡核苷酸显著降低吗啡的镇痛作用。或直接显微注射入中脑导水管周围灰质或蓝斑，最严重的抑制发生在中脑导水管周围灰质。因此，侧脑室注射反义寡核苷酸可以扩散到脑干，干扰吗啡的作用。其中四个碱基的序列改变的具有相同碱基组成的错配反义寡核苷酸是无效的。同样的外显子1反义寡核苷酸对吗啡镇痛有抑制作用，但不能阻断M6G的镇痛作用。相反，来自外显子2和3的反义序列减少了M6G的镇痛作用，而不是吗啡。针对外显子4的反义寡核苷酸略微降低了吗啡和M6G的抗伤害性。这些结果证实了小鼠MOR-1外显子1、2和3的反义定位研究，这表明存在一种新的负责M6G镇痛的Mu受体亚型，该亚型可能代表MOR-1的剪接变体。与小鼠不同，针对外显子4的探针对M6G的止痛作用影响很小。
In an effort to correlate the recently cloned MOR-1 receptor with the pharmacological actions of morphine and morphine-6beta-glucuronide (M6G), we have used an antisense paradigm. Rats were injected intracerebroventricularly (i.c.v.) with antisense oligodeoxynucleotides on days 1, 3 and 5 and tested for analgesia on day 6 after administration of morphine or M6G i.c.v. or after microinjection of morphine directly into either the periaqueductal gray or the locus coeruleus. When given i.c.v., the antisense oligodeoxynucleotide targeting the 5'-untranslated region of exon 1 significantly decreased the analgesic actions of morphine administered i.c.v. or microinjected directly into the periaqueductal gray or locus coeruleus, with the most profound inhibition occurring in the periaqueductal gray. Thus, antisense oligodeoxynucleotides administered into the lateral ventricle can diffuse into the brainstem and interfere with morphine actions. A mismatch antisense oligodeoxynucleotide with the same base composition in which the sequence of four bases was changed was inactive. This same exon 1 antisense oligodeoxynucleotide, which was active against morphine analgesia, failed to block M6G analgesia. In contrast, antisense sequences from exons 2 and 3 decreased M6G, and not morphine, analgesia. The antisense oligodeoxynucleotide against exon 4 slightly decreased both morphine and M6G antinociception. These results confirm the antisense mapping studies on exons 1, 2 and 3 of MOR-1 in mice, which implied the presence of a novel mu receptor subtype responsible for M6G analgesia that may represent a splice variant of MOR-1. Unlike in mice, the probe against exon 4 had a small effect on M6G analgesia.