Broom Daniel C, Jutkiewicz Emily M, Folk John E, Traynor John R, Rice Kenner C, Woods James H
Department of Pharmacology, University of Michigan Medical School, 1301 Medical Science Research Building III, Ann Arbor, MI 48109-0632, USA.
Psychopharmacology (Berl). 2002 Oct;164(1):42-8. doi: 10.1007/s00213-002-1179-y. Epub 2002 Jul 30.
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.
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.
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.
The non-peptidic delta-opioid receptor agonists (+)-4-[(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)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.
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.
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。这些化合物此前还被证明在小鼠中具有惊厥特性。
本研究旨在检测此类惊厥是否在大鼠中发生，并探究δ介导的惊厥活性对于δ-阿片受体激动剂诱导的抗抑郁样活性的介导是否必要。
对雄性斯普拉格-道利大鼠外周给予δ-阿片受体激动剂，随后观察惊厥活性一段时间。在此时间段之后以及给予δ-阿片受体激动剂60分钟后，对大鼠进行强迫游泳试验。
非肽类δ-阿片受体激动剂(+)-4-[(R)-[(2S,5R)-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(SNC80)和(+)-4-[(R)-[(2S,5R)-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[(+)BW3⁷³U86]在大鼠中均产生剂量依赖性惊厥活性，并减少了强迫游泳试验中的不动时间。δ-阿片受体拮抗剂纳曲吲哚可预防(+)BW3⁷³U86的惊厥活性及其在强迫游泳试验中的作用。这表明两种效应均通过δ-阿片受体机制介导。咪达唑仑可预防惊厥，但不能预防强迫游泳试验中的活性表现。对(+)BW3⁷³U86惊厥效应产生耐受的大鼠仍表现出抗抑郁样效应。
δ介导的惊厥在大鼠中确实会发生，并且可以在不影响强迫游泳试验中δ介导效应的情况下得到预防。因此，(+)BW3⁷³U86以及可能其他非肽类δ激动剂的惊厥活性对于强迫游泳试验中的活性并非必需。
