Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
Drug Alcohol Depend. 2022 Jul 1;236:109468. doi: 10.1016/j.drugalcdep.2022.109468. Epub 2022 Apr 22.
Chronic abuse of synthetic cannabinoid receptor agonists (SCRAs), known as "K2″ or "Spice", threatens public health and safety. Recently, SCRAs of the indazole-carboxamide structural class have become more prevalent. Preclinical studies investigating the tolerance and dependence potentially involved in chronic SCRA abuse is limited. The present study determined the in vivo effects of chronic exposure to indazole-carboxamide SCRAs, AB-PINACA, 5F-AB-PINACA and 5F-ADB-PINACA compared to the first-generation SCRA, JWH-018.
Adult male C57Bl/6 mice were used for dose-effect determinations of hypothermic effects. Adult male NIH Swiss mice were used in biotelemetry studies to assess tolerance to hypothermic effects following repeated SCRA administration over 5 consecutive days, and to determine the role of Phase I drug metabolism via acute CYP450 inhibition in the presence of 1-ABT, a nonspecific CYP450 inhibitor. SCRA dependence was determined in adult male NIH Swiss mice via assessment of rimonabant-precipitated observable sign of withdrawal (i.e., front paw tremors).
All SCRAs elicited dose-dependent hypothermia mediated through cannabinoid CB1 receptors (CB1Rs). 1-ABT increased duration of hypothermia for all SCRAs tested, and increased the magnitude of hypothermia for all SCRAs except 5F-ADB-PINACA. Upon repeated administration, tolerance to hypothermic effects of AB-PINACA, 5F-AB-PINACA and 5F-ADB-PINACA was much less than that of JWH-018. Similarly, rimonabant-precipitated front paw tremors were much less frequent in mice treated with 5F-AB-PINACA and 5F-ADB-PINACA than in mice treated with JWH-018.
These findings suggest a decreased potential for tolerance and withdrawal among indazole-carboxamide SCRAs, and may imply structural class-dependent profiles of in vivo effects among SCRAs.
慢性滥用合成大麻素受体激动剂（SCRAs），俗称“K2”或“香料”，威胁着公共健康和安全。最近，吲唑羧酸酰胺结构类别的 SCRAs 变得更为流行。关于慢性滥用 SCRAs 可能涉及的耐受性和依赖性的临床前研究有限。本研究旨在确定慢性暴露于吲唑羧酸酰胺 SCRAs（AB-PINACA、5F-AB-PINACA 和 5F-ADB-PINACA）与第一代 SCRAs（JWH-018）相比，对体内的影响。
成年雄性 C57Bl/6 小鼠用于确定体温过低效应的剂量效应。成年雄性 NIH 瑞士小鼠用于生物遥测研究，以评估在连续 5 天重复 SCRAs 给药后对体温过低效应的耐受性，并通过急性 CYP450 抑制作用（在存在非特异性 CYP450 抑制剂 1-ABT 的情况下）确定Ⅰ相药物代谢的作用。通过评估安非他命引发的戒断可观察到的体征（即前爪震颤）来确定成年雄性 NIH 瑞士小鼠中的 SCRAs 依赖性。
所有 SCRAs 均通过大麻素 CB1 受体（CB1R）介导产生剂量依赖性的体温过低。1-ABT 增加了所有测试 SCRAs 的体温过低持续时间，并增加了除 5F-ADB-PINACA 以外的所有 SCRAs 的体温过低幅度。重复给药后，AB-PINACA、5F-AB-PINACA 和 5F-ADB-PINACA 的体温过低效应的耐受性明显低于 JWH-018。同样，与 JWH-018 相比，5F-AB-PINACA 和 5F-ADB-PINACA 处理的小鼠中，安非他命引发的前爪震颤发生频率要低得多。
这些发现表明吲唑羧酸酰胺 SCRAs 的耐受性和戒断的潜在可能性降低，并且可能暗示 SCRAs 中体内效应的结构类别依赖性特征。
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