Introduction: Central μ-opioid receptors (MORs) modulate affective responses to physical exercise. Individuals with higher aerobic fitness report greater exercise-induced mood improvements than those with lower fitness, but the link between cardiorespiratory fitness and the MOR system remains unresolved. Here we tested whether maximal oxygen uptake (VO2peak) and physical activity level are associated with cerebral MOR availability and whether these phenotypes predict endogenous opioid release following a session of exercise.

Methods: We studied 64 healthy lean men who performed a maximal incremental cycling test for VO2peak determination, completed a questionnaire assessing moderate-to-vigorous physical activity (MVPA, min/week), and underwent positron emission tomography (PET) with [11C]carfentanil, a specific radioligand for MOR. A subset of 24 subjects underwent additional PET scan also after a one-hour session of moderate-intensity exercise and 12 of them also after a bout of high-intensity interval training (HIIT).

Results: Higher self-reported MVPA level predicted greater opioid release after HIIT, and both VO2peak and MVPA level were associated with a larger decrease in cerebral MOR binding after aerobic exercise in the ventral striatum, orbitofrontal cortex, and insula. That is, more trained individuals showed greater opioid release acutely following exercise in brain regions especially relevant for reward and cognitive processing. Fitness was not associated with MOR availability.

Conclusions: We conclude that regular exercise training and higher aerobic fitness may induce neuroadaptation within the MOR system, which might contribute to improved emotional and behavioural responses associated with long-term exercise.