Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opiold receptor antagonist pharmacophores
Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opiold receptor antagonist pharmacophores
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DOI：
10.1016/j.ejphar.2007.02.040
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发表时间：
2007-07-02
影响因子：
5
通讯作者：
Roerig, Sandra C.
中科院分区：
文献类型：
--
作者：
Lenard, Natalie R.;Daniels, David J.;Roerig, Sandra C.
用阿片类药物治疗疼痛受到其潜在滥用风险的限制。为了开发无这种副作用的镇痛药，我们合成了一系列二价配体，其中含有一个μ -阿片受体激动剂药效团，通过变长间隔（16-21个原子）与一个δ -阿片受体拮抗剂药效团相连。该系列的成员[mu-阿片受体(M)-delta-阿片受体(D)-激动剂(A)-拮抗剂(N): MDANs]在尾弹试验中具有抗伤害性，但抗伤害性耐受性和身体依赖性不会对具有19-21原子间隔的配体产生。目前的研究比较了三种二价配体（MDAN-16， -19和-21）和一种mu-阿片受体激动剂（MA-19）在小鼠静脉注射后的条件位置偏好实验中与吗啡的奖励特性。对吗啡和MA-19有位置偏好，但对MDANs没有。对MDAN-16的反应是高度可变的，尽管出现了边界显著性的位置偏好。吗啡条件下的位置偏好消失后的恢复情况也进行了评估；吗啡和MA-19，而不是MDANs，恢复了吗啡条件下的位置偏好。综上所述，这些结果表明，与吗啡相比，二价药物在阿片类药物初始小鼠中的回报更低，并且不会诱导先前偏好吗啡的小鼠恢复。与MDAN-16的模糊结果相比，MDAN-19和-21缺乏条件位置偏好反应，表明mu-阿片受体和delta-阿片受体识别位点之间存在最小距离要求。这一要求可能反映了MDAN-19和-21与阻断奖励而非抗感觉的μ -阿片受体- δ -阿片受体异二聚体受体的结合。Elsevier B.V.出版
Treatment of pain with opioids is limited by their potential abuse liability. In an effort to develop analgesics without this side effect, a series of bivalent ligands containing a mu-opioid receptor agonist pharmacophore connected to a delta-opioid receptor antagonist pharmacophore through variable-length spacers (16-21 atoms) was synthesized. Members of this series [mu-opioid receptor (M)-delta-opioid receptor (D)-agonist (A)-antagonists (N): MDANs] are antinociceptive in the tail flick assay, but antinociceptive tolerance and physical dependence do not develop to ligands having spacers with 19-21 atoms. The current studies compared the rewarding properties of three bivalent ligands (MDAN-16, -19 and -21) and a mu-opioid receptor agonist (MA-19) to those of morphine in the conditioned place preference assay in mice after i.v. administration. Place preference developed to morphine and to MA-19, but not to the MDANs. The responses to MDAN-16 were highly variable, although place preference of borderline significance appeared to develop. Reinstatement was also evaluated after extinguishing morphine conditioned place preference; morphine and MA-19, but not the MDANs, reinstated morphine conditioned place preference. Taken together, these results suggest that the bivalents are less rewarding compared to morphine in opioid-naive mice and do not induce reinstatement in previously morphine-preferring mice. The lack of a conditioned place preference response for MDAN-19 and -21, compared to the equivocal results with MDAN-16, suggests a minimum distance requirement between mu-opioid receptor and delta-opioid receptor recognition sites. This requirement may reflect the binding of MDAN-19 and -21 to mu-opioid receptor-delta-opioid receptor heterodimeric receptors that block reward but not antinociception. Published by Elsevier B.V.