Interaction With the Lipid Membrane Influences Fentanyl Pharmacology

Journal article

2026The escalating crisis of opioid overdose, driven largely by fentanyl and increasingly complicated by polysubstance use, presents challenges to public health and clinical practice. This dissertation provides a transdisciplinary investigation into the impact of fentanyl and its co-administration with other substances on sleep–wake architecture, respiratory function, neurobiology, molecular pathways, and the effectiveness of post-overdose outreach interventions. Using piezoelectric monitoring and polysomnography in mouse models, I demonstrated that both acute and chronic fentanyl exposure markedly reduced non-rapid eye movement sleep, with subtler but persistent rapid eye movement sleep disruptions following opioid cessation. The complexity of opioid-induced sleep disruption is further magnified by the widespread adulteration of fentanyl with xylazine. Fentanyl–xylazine co-exposure produced sex-dependent alterations in sleep, including reduced non-rapid eye movement sleep recovery, shortened bout duration, altered rapid eye movement sleep dynamics, and exacerbated respiratory depression, particularly in males. Pharmacological antagonism with yohimbine partially reversed these effects, implicating α2-adrenergic receptor mechanisms. At the circuit level, the locus coeruleus, a key addiction and sleep hub containing both α2-adrenergic receptors and μ-opioid receptors, displayed upregulated μ-opioid receptor expression only after fentanyl or xylazine exposure, which normalized under co-administration, suggesting complex α2-adrenergic driven μ-opioid receptor adaptations. In parallel, serum proteomic analyses highlighted fibroblast growth factor 21 as a potential regulator at the intersection of sleep, metabolism, and substance use. Polysubstance use also poses challenges and critical gaps in knowledge at the public health level. Evaluation of Massachusetts post-overdose outreach programs revealed that a subset of programs had begun conducting stimulant outreach, in addition to opioids, reflecting the changing overdose landscape. Programs that adapted to these shifts in use were those engaging Black, Latine, Native, and youth populations while maintaining strong harm reduction practices—highlighting the importance of flexibility and cultural responsiveness in community-based interventions. Thus, this dissertation provides foundational knowledge on the neurobiological and public health consequences of fentanyl and polysubstance misuse, offering actionable pathways for future research that may improve clinical care and community interventions in the ongoing effort to mitigate overdose and enhance recovery

Authors: Sutcliffe, KJ; Corey, RA; Alhosan, N; Cavallo, D; Groom, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Frontiers Media
• Journal: Advances in Drug and Alcohol Research
• Volume: 2
• Pages: 10280
• Article number: 10280
• Publication date: 2022-03-21
• DOI: 10.3389/adar.2022.10280
• EISSN: 2674-0001
• ISSN: 2674-0001
• Language: English
• Keywords: Chemistry; Receptor; Opioid; Pharmacology; Morphine; Biology; (+)-Naloxone; Biochemistry; Fentanyl; Medicine; Biophysics