| In the cutaneous response to ultraviolet radiation (UV) exposure, p53 stimulates keratinocytes to produce proopiomelanocortin (POMC), a pro-protein that is posttranslationally cleaved into biologically functional peptides. In the local cutaneous UV response, alpha-MSH is an important POMC peptide that acts on melanocytes to stimulate production of the dark pigment eumelanin. In producing alpha-MSH, other POMC peptides are also produced, including the opioid beta-endorphin. B-endorphin is structurally and functionally similar to small-molecule exogenous opiates (ie. morphine), which act to relieve pain, but may also cause side-effects such as euphoria and fatigue. These opiate-induced side effects are similar to certain systemic effects observed following radiation exposure. UV-seeking behavior, defined as indoor or outdoor tanning two or more times per week, stems from a UV-induced rewarding sensation that can render UV reinforcing, and is believed to contribute to the increasing incidence of skin cancers. Radiation-induced fatigue is the most commonly-reported side-effect among cancer patients receiving X-irradiation therapy. Its incidence and severity correlate more with radiation field size than with depth, thus cutaneous factors may play causative roles. This study explores the role of beta-endorphin in these radiation-mediated systemic effects, and how it may affect physiologic parameters often affected by exogenous opiates and that are highly variable between individuals, such as pain tolerance.;In rodents, I modeled UV exposure patterns of UV-seekers and developed a regimen of gamma radiation to the tail, modeling radiation therapy targeting mostly skin. Plasma beta-endorphin increased over these regimens and was paralleled by opioid-mediated behavioral phenotypes, including analgesic threshold changes and radiation-induced fatigue that were reversed by the opioid antagonist naloxone. UV exposure regimens induced evidence of opiate addiction including naloxone-induced somatic symptoms of opiate withdrawal, naloxone-conditioned place aversion and morphine cross-tolerance. Thus beta-endorphin may function as a link between radiation exposure and human behavior that could provide physiologically-based credence for the often-made but controversial claim that UV, for UV-seekers, is an addictive substance and offer guidance for policies to regulate the indoor tanning industry. These findings may offer a physiologic mechanism for fatigue during cancer radiation therapy, and suggest therapeutic strategies for ameliorating this debilitating condition. |
