James Jared C, Thrush Jessica R, Yusufali Taher M, Shaw Hannah E, Avram Marina, Moran Jeffery H, Fantegrossi William E
College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Drug Alcohol Depend. 2025 Jul 1;272:112672. doi: 10.1016/j.drugalcdep.2025.112672. Epub 2025 Apr 15.
Concurrent use of fentanyl with other drugs may contribute to the growing phenomenon of naloxone-resistant overdose. Synthetic cannabinoid receptor agonists (SCRAs) bind to CB1 receptors with high affinity and efficacy, eliciting psychoactive and abuse-related effects. Fentanyl is a common adulterant in SCRA products, and SCRAs are frequently detected as adulterants in street opioids, suggesting that these drugs are coadministered. Here we compared respiratory depressant effects of fentanyl to those of two structurally-distinct SCRAs: the naphthyl indole JWH-018 and the indazole carboxamide 5F-ADB-PINACA, following acute and chronic administration, using whole body plethysmography in mice. Fentanyl and the SCRAs were also co-administered, and antagonist rescue studies were conducted using large doses of naloxone, rimonabant, or a combination of both antagonists. In separate groups of mice, fentanyl and the SCRAs were administered alone or in binary combiations, and a single blood sample was drawn at a time of maximal respiratory depression to provide a pharmacokinetic snapshot of blood concentrations of drugs at this overdose-relevant timepoint. Fentanyl decreased respiratory rate, no tolerance to this effect was observed, and naloxone (but not rimonabant) attenuated respiratory depression. Both of the SCRAs similarly decreased respiratory rate, tolerance to this effect was observed with JWH-018 but not with 5F-ADB-PINACA, and rimonabant (but not naloxone) attenuated respiratory depression. Co-administration of fentanyl and the SCRAs exacerbated respiratory depression and confered resistance to naloxone rescue, most likely via pharmacodynamic interactions between μ-opioid and CB1 cannabinoid receptors, but we also suggest that some SCRAs will also instigate pharmacokinetic drug-drug interactions with fentanyl.
芬太尼与其他药物同时使用可能会导致耐纳洛酮过量这一现象日益增多。合成大麻素受体激动剂（SCRAs）以高亲和力和效力与CB1受体结合，引发精神活性和与滥用相关的效应。芬太尼是SCRAs产品中常见的掺杂物，并且在街头阿片类药物中也经常检测到SCRAs作为掺杂物，这表明这些药物会共同给药。在此，我们使用小鼠全身体积描记法，比较了急性和慢性给药后，芬太尼与两种结构不同的SCRAs（萘基吲哚JWH - 018和吲唑甲酰胺5F - ADB - PINACA）的呼吸抑制作用。芬太尼和SCRAs也进行了共同给药，并使用大剂量的纳洛酮、利莫那班或两种拮抗剂的组合进行了拮抗剂解救研究。在单独的小鼠组中，芬太尼和SCRAs单独给药或二元组合给药，并在最大呼吸抑制时采集单个血样，以提供在这个与过量相关的时间点药物血药浓度的药代动力学快照。芬太尼降低了呼吸频率，未观察到对这种效应的耐受性，并且纳洛酮（而非利莫那班）减轻了呼吸抑制。两种SCRAs同样降低了呼吸频率，观察到JWH - 018产生了对这种效应的耐受性，而5F - ADB - PINACA未产生，并且利莫那班（而非纳洛酮）减轻了呼吸抑制。芬太尼和SCRAs共同给药加剧了呼吸抑制，并导致对纳洛酮解救产生抗性，最有可能是通过μ - 阿片受体和CB1大麻素受体之间的药效学相互作用，但我们也认为一些SCRAs也会与芬太尼引发药代动力学药物 - 药物相互作用。
