Nasal spray formulations of naloxone, a mu-opioid receptor (MOR)
antagonist, are currently used for the treatment of opioid overdose.
They may have additional therapeutic utility also in the absence of
opioid agonist drugs, but the onset and duration of action at brain MORs
have been inadequately characterized to allow such projections. This
study provides initial characterization of brain MOR availability at
high temporal resolution following intranasal (IN) naloxone
administration to healthy volunteers in the absence of a competing
opioid agonist. Fourteen participants were scanned twice using positron
emission tomography (PET) and [¹¹C]carfentanil, a selective
MOR agonist radioligand. Concentrations of naloxone in plasma and MOR
availability (relative to placebo) were monitored from 0 to 60 min and
at 300–360 min post naloxone. Naloxone plasma concentrations peaked at
~20 min post naloxone, associated with slightly delayed development of
brain MOR occupancy (half of peak occupancy reached at ~10 min).
Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN
doses, respectively. The estimated half-life of occupancy disappearance
was ~100 min. The rapid onset of brain MOR occupancy by IN naloxone,
evidenced by the rapid onset of its action in opioid overdose victims,
was directly documented in humans for the first time. The employed high
temporal-resolution PET method establishes a model that can be used to
predict brain MOR occupancy from plasma naloxone concentrations. IN
naloxone may have therapeutic utility in various addictions where brain
opioid receptors are implicated, such as gambling disorder and alcohol
use disorder.