New Whole-Body Imaging Study Reveals Sex-Based Differences in Opioid Receptor Blocking

A groundbreaking first-in-human imaging study has revealed that naloxone, the widely used antidote for opioid overdose, binds more effectively to opioid receptors in women’s brains than in men’s—suggesting sex-specific differences in treatment efficacy for opioid use disorder.

Published in the July 2025 issue of The Journal of Nuclear Medicine, the study used advanced whole-body PET imaging to assess the distribution of μ-opioid receptors (MORs) in healthy male and female participants before and after administration of naloxone. The findings may pave the way for more personalized approaches to treating opioid addiction and overdose.

“Naloxone reduced receptor availability by 40–50% in multiple brain regions with high MOR density, but the effect was more pronounced in women,” said senior author Jacob Dubroff, MD, PhD, associate professor of radiology at the University of Pennsylvania’s Perelman School of Medicine. “Our findings indicate that biological sex may influence how individuals respond to opioid reversal agents”.

The study involved 13 healthy participants (six women and seven men) who each underwent two PET scans with the radiotracer [11C]carfentanil—once at baseline and again following naloxone administration. The PET scans were performed using the PennPET Explorer, a long axial field-of-view (LAFOV) imaging system that allows dynamic, high-resolution, whole-body imaging with short-lived tracers.

Researchers quantified MOR availability using brain and peripheral reference regions. The descending aorta and upper arm muscles served as non-brain references, helping to extend the analysis beyond the central nervous system. These reference strategies are particularly important for future neuroreceptor imaging agents that lack dedicated brain-based comparison regions.

In the brain, women exhibited higher MOR receptor occupancy in areas such as the thalamus, amygdala, and hippocampus following naloxone injection. Peripheral measurements also showed reliable naloxone-induced blocking effects. The findings suggest that not only do women respond differently at a molecular level, but that whole-body imaging could be used to track these effects more comprehensively.

“This research is significant because it suggests that there may be sex-based differences in how men and women respond to opioid overdose treatments,” Dubroff added. “Additionally, we showed how regions outside the brain can be used to help measure radiotracer binding in the brain. This strategy could be applied to other radiotracers used for PET brain imaging and boost the development of new ones”.

The study represents the first application of [11C]carfentanil PET for whole-body imaging in humans. The methodology may expand how researchers study other neuroreceptors and improve the design of precision-medicine approaches for addiction, pain management, and mental health disorders.

As the opioid epidemic continues to claim lives globally, this work adds a new layer of insight into how treatment responses may vary by sex—and why future therapies must account for those differences.

The research was supported by the National Institute on Drug Abuse and the Crescenz VA Medical Center. Additional authors include Chia-Ju Hsieh, Corinde E. Wiers, and Henry R. Kranzler.