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Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved September 4, 2015 (received for review July 29, 2015)
Significance
A runner’s high is a subjective sense of well-being some humans experience after prolonged exercise. For decades, it was hypothesized that exercise-induced endorphin release is solely responsible for a runner’s high, but recent evidence has suggested that endocannabinoids also may play a role. Here, we demonstrate that wheel running increases endocannabinoids and reduces both anxiety and sensation of pain in mice. Ablation of cannabinoid receptor 1 receptors on GABAergic neurons inhibits running-induced anxiolysis, and pharmacological blockage of central and peripheral cannabinoid receptors inhibits analgesia. We thus show for the first time to our knowledge that cannabinoid receptors are crucial for main aspects of a runner’s high.
Abstract
Exercise is rewarding, and long-distance runners have described a runner’s high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner's high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models.
Footnotes
↵1J.F. and J.S. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: jo.fuss{at}uke.de.
Author contributions: J.F. and P.G. designed research; J.F., J.S., and L.B. performed research; L.B., M.K.A., H.K., and B.L. contributed new reagents/analytic tools; J.F. and J.S. analyzed data; and J.F., B.L., and P.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1514996112/-/DCSupplemental.
A runner's high depends on cannabinoid receptors
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