Convulsant activity of a non-peptidic δ-opioid receptor agonist is not required for its antidepressant-like effects in Sprague-Dawley rats
Convulsant activity of a non-peptidic δ-opioid receptor agonist is not required for its antidepressant-like effects in Sprague-Dawley rats
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DOI：
10.1007/s00213-002-1179-y
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发表时间：
2002-10-01
影响因子：
3.4
通讯作者：
Woods, JH
中科院分区：
文献类型：
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作者：
Broom, DC;Jutkiewicz, EM;Woods, JH
原理：非肽类δ阿片受体激动剂在大鼠强迫游泳试验中具有抗抑郁样活性。这些化合物以前也被证明在小鼠中具有惊厥特性。目的：本研究的目的是检查大鼠是否发生此类惊厥，并研究δ-阿片类激动剂诱导的抗抑郁样活性的介导是否需要δ-介导的惊厥活性。研究方法：对雄性Sprague-Dawley大鼠外周给予δ-阿片受体激动剂后，观察一段时间的惊厥活性。在这段时间后和δ-阿片样物质激动剂给药后60分钟，在强迫游泳测定中测试大鼠。结果如下：非肽类δ-阿片受体激动剂（+）-4-[（R）-[（2S，5 R）-2，5-二甲基-4-（2-丙烯基）-1-哌嗪基]-（3-甲氧基苯基）甲基]-N，N-二乙基苯甲酰胺（SNC 80）和（+）-4- [（R）-[（2S，5 R）-2，5-二甲基-4-（2-丙烯基）-1-哌嗪基]-（3-羟基苯基）甲基]-N，N-二乙基苯甲酰胺二盐酸盐[（+）BW 373 U86]均在大鼠中产生剂量依赖性惊厥活性，并在强迫游泳试验中降低不动性。δ-阿片受体拮抗剂纳曲吲哚阻止（+）BW 373 U86的惊厥活性及其在强迫游泳试验中的作用。这表明这两种作用都存在δ阿片类药物机制。咪达唑仑可防止惊厥，但不能防止强迫游泳试验中的活动。耐受（+）BW 373 U86惊厥作用的大鼠仍表现出抗抑郁样作用。结论：大鼠中确实发生δ介导的惊厥，并且可以在不影响强迫游泳试验中δ介导的效应的情况下进行预防。因此，（+）BW 373 U86和可能的其他非肽δ-激动剂的惊厥活性对于强迫游泳测定中的活性不是必需的。
Rationale: Non-peptidic delta-opioid receptor agonists possess antidepressant-like activity in the forced swim assay in the rat. These compounds have also previously been shown to possess convulsant properties in mice. Objective: The aim of the present study was to examine whether such convulsions occurred in rats and to investigate if delta-mediated convulsant activity was necessary for the mediation of delta-opioid agonist-induced antidepressant-like activity. Methods: The peripheral administration of delta-opioid receptor agonists to male Sprague-Dawley rats was followed by a period of observation for convulsant activity. Following this period and 60 min after delta-opioid agonist administration, rats were tested in the forced swim assay. Results: The non-peptidic delta-opioid receptor agonists (+)-4-[(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methox- yphenyl)methyl]-N,N-diethylbenzamide (SNC80) and (+)-4- [(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide dihydrochloride [(+)BW373U86] both produced dose-dependent convulsant activity in rats and decreased immobility in the forced swim assay. The delta-opioid receptor antagonist naltrindole prevented the convulsant activity of (+)BW373U86 and its effects in the forced swim assay. This suggested a delta-opioid mechanism for both effects. Midazolam prevented convulsions but did not prevent activity in the forced swim assay. Rats tolerant to the convulsive effects of (+)BW373U86 still displayed antidepressant-like effects. Conclusion: delta-Mediated convulsions do occur in rats and can be prevented without affecting the delta-mediated effects in the forced swim assay. Therefore the convulsant activity of (+)BW373U86 and possibly other non-peptidic delta-agonists is not required for activity in the forced swim assay.