Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys.
Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys.
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发表时间：
1998-07
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通讯作者：
S. Negus;M. B. Gatch;Nancy K. Mello;Xiaoyan Zhang;Kenner C Rice
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作者：
S. Negus;M. B. Gatch;Nancy K. Mello;Xiaoyan Zhang;Kenner C Rice
在恒河猴中评估了非肽 δ 阿片受体激动剂 SNC80 和衍生自母体化合物 BW373U86 的一系列相关哌嗪基苯甲酰胺的行为效应。 SNC80 (0.1-10 mg/kg) 以剂量和时间依赖性方式降低食物强化维持的反应率，最大效果在肌内注射后 10 分钟内发生。 SNC80 和其他五种哌嗪基苯甲酰胺在这种时间表控制响应测定中的效力与它们对克隆人 delta 阿片受体的亲和力相关，但与它们对克隆人 mu 受体的亲和力无关。此外，SNC80的作用可被δ选择性拮抗剂纳曲吲哚（1.0 mg/kg）选择性拮抗，但不能被mu选择性拮抗剂卡达佐辛（0.1 mg/kg）或κ选择性拮抗剂降比那托菲明（3.2 mg/kg）选择性拮抗。这些发现表明，SNC80 作为一种系统活性的 δ 选择性激动剂，在恒河猴中起效迅速。在热伤害感受的温水尾部撤回试验中检查了 SNC80 的抗伤害作用。 SNC80 (0.1-10 mg/kg) 产生微弱但可复制的镇痛作用，可被纳曲吲哚 (1.0 mg/kg) 拮抗。 SNC80 的镇痛作用也被 BW373U86 (0.56-1.0 mg/kg) 剂量依赖性地拮抗，而 BW373U86 在此过程中没有活性。这些发现表明，SNC80 对 δ 阿片受体的功效可能比 BW373U86 更高。此外，SNC80剂量高达32 mg/kg时并未产生惊厥，这表明SNC80也可能比BW373U86更安全。 SNC80 的效果也在经过训练辨别可卡因（0.4 毫克/千克，肌肉注射）或自我注射可卡因（0.032 毫克/千克/注射，静脉注射）的猴子中进行了检查。在药物歧视研究中，SNC80（0.1-10 mg/kg）可产生剂量依赖性和纳曲吲哚可逆性的可卡因适当反应增加，并且在测试的七只猴子中有五只观察到完全替代可卡因。然而，SNC80（1.0-100微克/公斤/注射）在经过自我注射可卡因训练的猴子中并没有保持反应。因此，尽管 SNC80 能够产生类似可卡因的歧视性刺激效果，但其滥用潜力可能相对较低。
The behavioral effects of the nonpeptidic delta opioid agonist SNC80 and a series of related piperazinyl benzamides derived from the parent compound BW373U86 were evaluated in rhesus monkeys. SNC80 (0.1-10 mg/kg) decreased response rates maintained by food-reinforcement in a dose- and time-dependent manner, with maximal effects occurring within 10 min of intramuscular injection. The potency of SNC80 and five other piperazinyl benzamides in this assay of schedule-controlled responding correlated with their affinity at cloned human delta opioid receptors but not with their affinity for cloned human mu receptors. Moreover, the effects of SNC80 were selectively antagonized by the delta-selective antagonist naltrindole (1.0 mg/kg), but not by the mu selective antagonist quadazocine (0.1 mg/kg) or the kappa-selective antagonist norbinaltorphimine (3.2 mg/kg). These findings indicate that SNC80 functions as a systemically active, delta-selective agonist with a rapid onset of action in rhesus monkeys. The antinociceptive effects of SNC80 were examined in a warm-water tail-withdrawal assay of thermal nociception. SNC80 (0.1-10 mg/kg) produced weak but replicable antinociceptive effects that were antagonized by naltrindole (1.0 mg/kg). SNC80 antinociception was also dose-dependently antagonized by BW373U86 (0.56-1.0 mg/kg), which was inactive in this procedure. These findings suggest that SNC80 may have higher efficacy than BW373U86 at delta opioid receptors. Moreover, SNC80 at doses up to 32 mg/kg did not produce convulsions, which suggests that SNC80 may also be safer than BW373U86. The effects of SNC80 were also examined in monkeys trained to discriminate cocaine (0.4 mg/kg i.m.) or self-administer cocaine (0.032 mg/kg/injection,i.v.). In drug discrimination studies, SNC80 (0.1-10 mg/kg) produced a dose-dependent and naltrindole-reversible increase in cocaine-appropriate responding, and complete substitution for cocaine was observed in five of seven monkeys tested. However, SNC80 (1.0-100 micrograms/kg/injection) did not maintain responding in monkeys trained to self-administer cocaine. Thus, despite its ability to produce cocaine-like discriminative stimulus effects, SNC80 may have relatively low abuse potential.