Retention of supraspinal delta-like analgesia and loss of morphine tolerance in δ opioid receptor knockout mice
Retention of supraspinal delta-like analgesia and loss of morphine tolerance in δ opioid receptor knockout mice
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DOI：
10.1016/s0896-6273(00)80836-3
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发表时间：
1999-09-01
期刊：
影响因子：
16.2
通讯作者：
Pintar, JE
中科院分区：
文献类型：
--
作者：
Zhu, YX;King, MA;Pintar, JE
利用基因打靶技术缺失编码阿片受体的小鼠DOR-1外显子2。突变小鼠基本上不与~3H-[D-Pen(2)，D-Pen(5)]脑啡肽(H-3-DPDPE)和~3H-[D-Ala(2)，D-Glu(4)]Deltorphin(H-3-Deltorphin-2)结合，表明DOR-1编码Delta(1)和Delta(2)受体亚型。纯合子突变小鼠的脊髓6号镇痛作用显著降低，但6肽激动剂保留了脊髓上止痛剂的效力，而纳曲哚只能部分拮抗这一效应。福尔马林试验也证明了DPDPE的残留镇痛作用，而非肽6激动剂BW373U69在DOR-L突变小鼠中表现出增强的活性。总而言之，这些发现表明存在第二个类似于三角洲的止痛系统。最后，DOR-1突变小鼠不会对吗啡产生止痛耐受，从基因上证明了DOR-1在这一过程中的核心作用。
Gene targeting was used to delete exon 2 of mouse DOR-1, which encodes the delta opioid receptor. Essentially all 3H-[D-Pen(2),D-Pen(5)]enkephalin (H-3-DPDPE) and 3H-[D-Ala(2),D-Glu(4)]deltorphin (H-3-deltorphin-2) binding is absent from mutant mice, demonstrating that DOR-1 encodes both delta(1) and delta(2) receptor subtypes. Homozygous mutant mice display markedly reduced spinal 6 analgesia, but peptide 6 agonists retain supraspinal analgesic potency that is only partially antagonized by naltrindole. Retained DPDPE analgesia is also demonstrated upon formalin testing, while the nonpeptide 6 agonist BW373U69 exhibits enhanced activity in DOR-l mutant mice. Together, these findings suggest the existence of a second delta-like analgesic system. Finally, DOR-1 mutant mice do not develop analgesic tolerance to morphine, genetically demonstrating a central role for DOR-1 in this process.