β-Endorphin mediates radiation therapy fatigue

Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin irradiation has been suggested. beta-Endorphin, an endogenous opioid, is synthesized in skin following genotoxic ultraviolet irradiation and acts systemically, producing addiction. Exogenous opiates with the same receptor activity as beta-endorphin can cause fatigue. Using rodent models of radiation therapy, exposing tails and sparing vital organs, we tested whether skin-derived beta-endorphin contributes to radiation-induced fatigue. Over a 6-week radiation regimen, plasma beta-endorphin increased in rats, paralleled by opiate phenotypes (elevated pain thresholds, Straub tail) and fatigue-like behavior, which was reversed in animals treated by the opiate antagonist naloxone. Mechanistically, all these phenotypes were blocked by opiate antagonist treatment and were undetected in either beta-endorphin knockout mice or mice lacking keratinocyte p53 expression. These findings implicate skin-derived beta-endorphin in systemic effects of radiation therapy. Opioid antagonism may warrant testing in humans as treatment or prevention of radiationinduced fatigue.

Automated summary

Fatigue is a common adverse effect of radiation therapy in cancer patients. This study suggests that skin-derived beta-endorphin plays a role in radiation-induced fatigue, and opioid antagonism may be a potential treatment for this condition.