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It is world knowledge that regular physical exercise increases physical fitness and reduces general health risk factors like overweight or hypertension. There is emerging evidence that regular physical exercise does also have profound effects on the brain: It affects many aspects of the brain like increasing perfusion or inducing hippocampal growth. Neurogenesis is stimulated as well as angiogenesis and increased synaptic plasticity is observed. Up to date, most data are mainly supported by animal models but human data become more and more available. There is also emerging evidence that exercise has an positive effect on pain processing: One can find anecdotal reports that runners continue to run despite stress fractures, angina and or sever blisters. But there is also experimental evidence, that athletes have increased pain thresholds and show reduced responses to noxious stimuli. Indirect measures such as raised endorphin levels in peripheral blood and cerebrospinal fluid as well as the reversibility of exercise-induced mood changes and pain perception effects by naloxone (unspecific opioid receptor antagonist) presented strong arguments for an opioidergic involvement in exercise („endorphin hypothesis”). This was also supported lately by showing opioidergic activation effects in fronto-limbic brain regions after sustained physical exercise. Based on this work and assuming central opioidergic mechanisms, we examined in an fMRI-study the effect of a two hours outdoor RUN, as compared to a control condition (two hours outdoor WALK) on pain processing in 20 right-handed male athletes (age 39.0±9.2 years, average training distance: 59.3±29.2km/week). Physical exercise was expected to affect pain processing on the behavioural and the systemic (activation) level. On the behavioural level we found a significant time x treatment interaction of the euphoria ratings, and a post-hoc significant reduction of the McGill affective subscale in the post-run condition. All other measures (including pain and sensory thresholds) were not affected. The peripheral blood endorphin levels were drastically elevated after the RUN-condition and the fMRI-analysis revealed a reduced time x treatment interaction in the antinociceptive pathway (rACC, PAG) and reduced functional connectivity of the PAG (trend). These findings suggest, that the brain seems to be in a less pain sensitive state after exercise and, therefore, the necessity to recruit the descending pain network is reduced. In conclusion, the demonstration of elevated beta-endorphin levels in plasma (RIA), the specific effect on the affective dimension of pain, and the loco-regional convergence with previous ligand PET and naloxone pharma-fMRI studies suggest an underlying opioidergic effect promoted by exercise.