Distance running or other forms of endurance exercise can produce a feeling called “runner’s high,” which is associated with a feeling of euphoria, a reduction in anxiety (anxiolysis) and pain (analgesia), and an increased sense of relaxation (sedation). Increased abundance of β-endorphin, an endogenous opioid, and anandamide, an endocannabinoid, are observed in the plasma of humans and mice after long distance running. However, β-endorphin cannot cross the blood-brain barrier. Fuss et al. used mice to investigate the molecular mechanisms that could result in runner’s high. After habituating the mice to the presence of running wheels and then blocking the wheels to establish a baseline, the wheels for one group were unblocked for 5 hours immediately before testing both groups (run group and control group) for anxiety-associated and pain-associated behaviors. Compared with the control group, the mice in the run group spent more time in the light-aversive bright area, an indication of reduced anxiety. Mice in the run group also displayed increased latency to either jump or lick their paws when placed on a hot plate, an indication of analgesia. After returning to the cage with the running wheel, the mice in the run group ran less than the control mice, which could reflect a sedation effect. The mice in the run group, but not in the control group, had increased abundance of endocannabinoids in the plasma but not in the brain or in the cerebrospinal fluid. Mice injected intraperitoneally with antagonists to cannabinoid receptor 1 (CB1) and then given access to the running wheel prior to behavioral testing did not exhibit the anxiolytic phenotype, spending the same amount of time in the light as mice that did not have access to a functional wheel. Injection of the run group with antagonists of the cannabinoid receptors CB1 or CB2 blocked the running-induced analgesic effect. Mice in the run group that were injected with naloxone, which blocks endorphin activity, displayed running-induced reduction of thermal pain sensitivity. Thus, the pharmacological data suggested that endocannabinoids rather than endorphins played a role in analgesia associated with running. To confirm that the effects were mediated by receptors in the brain, the authors examined mice lacking CB1 receptors in γ-aminobutyric acid (GABA) neurons (GABA-CB1–/–), which displayed more anxiety than wild-type mice both in the control nonrunning group and in the run group. The enhanced anxiolytic and analgesic effects of running were also absent in these CB1-deficient mice. Thus, this study suggests that endocannabinoids mediate some of the positive effects associated with endurance exercise and the runner’s high.
J. Fuss, J. Steinle, L. Bindila, M. K. Auer, H. Kirchherr, B. Lutz, P. Gass, A runner’s high depends on cannabinoid receptors in mice. Proc. Natl. Acad. Sci. U.S.A. 112, 13105–13108 (2015). [PubMed]