Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment
Tolerance develops in spinal cord, but not in brain with chronic [Dmt1]DALDA treatment
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DOI：
10.1038/sj.bjp.0706007
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发表时间：
2004-12-01
影响因子：
7.3
通讯作者：
Lee, NM
中科院分区：
文献类型：
--
作者：
Ben, Y;Smith, AP;Lee, NM
1此前，我们报道了H-2‘，6’-二甲基酪氨酸[DMT(1)]-D-Arg-Phe-Lys-NH2(DALDA)，是一种天然阿片肽的类似物，是一种对吗啡的交叉耐受性低的高效、选择性的Mu受体激动剂。在本研究中，我们研究了[DMT(1)]Dalda治疗小鼠慢性疾病的效果。[DMT(1)]Dalda(S.C.)的AD(50)长期服用这种药物的动物的AD(50)增加了八倍；相比之下，长期服用吗啡的小鼠的AD(50)增加了两倍。吗啡(S.C.)的AD(50)在这些[DMT(1)]处理的动物中，DALDA处理的动物增加了120多倍，而鞘内注射更具选择性的MU激动剂[D-ALA(2)-MePhe(4)-Gly-ol(5)]脑啡肽(DAMGO)则增加了240多倍。然而，脑室注射DAMGO的AD(50)在长期使用[DMT(1)]DALDA的动物中与在幼稚动物中基本相同。[DMT(1)]Dalda处理的动物催促戒断所需的纳洛酮剂量比吗啡耐受动物低20倍。2利用实时定量聚合酶链式反应，我们发现[DMT(1)]Dalda处理后，大脑中m阿片受体、增量阿片受体、前脑啡肽原和前强啡肽基因的表达上调。[DMT(1)]DALDA处理组小鼠脊髓中阿片受体或阿片肽基因的表达未见明显变化，吗啡处理组小鼠的脑或脊髓中也未见明显变化。我们的结论是，对[DMT(1)]DALDA的高度耐受发生在脊髓而不是脑中，并且不能通过这些组织中阿片受体或阿片肽表达的变化来解释。
1 Previously, we reported that H-2',6'-dimethyltyrosine [Dmt(1)]-D-Arg-Phe-Lys-NH2 (DALDA), an analogue of the naturally occurring opioid peptide dermorphin, is a highly potent and selective mu receptor agonist with low cross-tolerance to morphine. In the present study, we investigated the effect of treating mice chronically with [Dmt(1)]DALDA. The AD(50) of [Dmt(1)]DALDA (s.c.) increased eight-fold in animals given this drug chronically; in contrast, the AD(50) increased two-fold in mice chronically treated with morphine. The AD(50) of morphine (s.c.) in these [Dmt(1)]DALDA-treated animals was increased more than 120 times, while that of the more selective mu agonist [D-Ala(2)-MePhe(4)-Gly-ol(5)]enkephalin (DAMGO) given intrathecally was increased more than 240 times. However, the AD(50) of DAMGO given intracerebroventricularly was essentially the same in animals treated chronically with [Dmt(1)]DALDA as in naive animals. The dose of naloxone required to precipitate withdrawal in [Dmt(1)]DALDA-treated animals was 20 times lower than that in morphine-tolerant animals.2 Using real-time quantitative PCR, we found that expression of the m opioid receptor, delta opioid receptor, preproenkephalin and preprodynorphin genes was upregulated in the brain by [Dmt(1)] DALDA treatment. No significant changes in expression of opioid receptor or opioid peptide genes were detected in the spinal cord of [Dmt(1)]DALDA-treated mice, nor in the brain or spinal cord of morphine-treated mice. We conclude that a high degree of tolerance to [Dmt(1)]DALDA develops in the spinal cord but not brain, and cannot be accounted for by changes in expression of opioid receptors or opioid peptides in these tissues.