Synthetic cannabinoid receptor agonists exacerbate fentanyl-elicited respiratory depression and confer resistance to naloxone rescue in mice

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.