Resistance exercise can acutely decrease pain sensitivity (hypoalgesia) both local and remote to the exercising muscle. This effect is maximised with higher intensity exercise (1) and is partly driven by endogenously produced opioid and endocannabinoid substances, which have antinociceptive effects. Resistance exercise is used to treat individuals with chronic pain, however many of these individuals are contraindicated to higher intensity exercise. It has been hypothesised that performing low intensity exercise with blood flow restriction (BFR) in the working limb could increase the analgesic effect of exercise to a similar level as high intensity exercise (2). However, the magnitude of this effect and possible mechanisms are not known. To investigate this, healthy active individuals (n=12) performed 4 trials of unilateral leg press exercise in a randomised, crossover design. The trials included: 1) low intensity exercise (30% 1RM, LIRE); 2) high intensity exercise (70% 1RM, HIRE); 3) BFR exercise (30% 1RM) with a low pressure (BFR-L) and 4) BFR exercise (30% 1RM) with a high pressure (BFR-H). Sensitivity to a pressure stimulus (pressure-pain threshold, [PPT]) measured in kilograms of force (kgf) was assessed before and 5min post-exercise using algometry, whereby an increase in PPT value represents hypoalgesia. This was performed in the exercising quadriceps muscle and three remote non-exercising muscles. Venous blood samples were taken before and 10min post-exercise. Plasma concentration of beta-endorphin and 2-arachidonoylglycerol (marker of opioid and endocannabinoid systems, respectively) were determined using enzyme linked-immunosorbence assays. Values are mean±SD and analysed with two-way repeated measures ANOVA for each outcome. Mediation analysis was performed to determine the impact of any change in plasma beta-endorphin and 2-arachidonoylglycerol concentrations on any change in PPT. There were no differences in baseline values between repeated trials for any outcome measured. In the exercising limb, at 5min post-exercise the PPT was 2.43±1.60 kgf higher, 3.72±2.24 kgf higher and 1.68±1.53 kgf higher following BFR-L, BFR-H and HIRE, respectively, compared to LIRE (all p<0.05). Following BFR-H, PPT was 1.29±1.18 kgf higher and 2.04±1.75 kgf higher compared to BFR-L and HIRE (both p<0.05). In the non-exercising remote muscles, a greater change in PPT occurred with BFR-L (11-17%), BFR-H (11-21%) and HIRE (10-18%) compared to LIRE (2-4%) (all p<0.05). At 5min post-exercise, plasma beta-endorphin concentration was greater following BFR-L (108.56±20.18 pg/ml), BFR-H (109.54±18.83 pg/ml) and HIRE (92.87±16.82 pg/ml) compared to LIRE (90.62±17.13 pg/ml) (all p<0.05). The increase in beta-endorphin was greater in BFR-L and BFR-H compared to HIRE (both p<0.05). There were no changes in plasma 2-arachidonoylglycerol concentration. The mediation model suggested that plasma beta-endorphin mediates 42% of the total effect of the exercise intervention on change in PPT. Thus, this data shows that addition of BFR to LIRE can increase the local and systemic analgesic effect of exercise (3). Importantly, the magnitude of this effect is either greater (local exercising muscle) or similar (remote non-exercising muscle) to HIRE. Moreover, analgesia with BFR exercise is partly driven by endogenous production of opioids. BFR exercise may be effective for treating individuals with chronic pain who cannot tolerate higher intensity exercise.