Abstract
The suppression of anti-tumor immune responses was considered as the prime factor in the tumor growth. Additionally, cancer inactivates the mechanism of host immune surveillance. On the other hand, β-endorphin, a cleavage product of pro-opiomelanocortin (POMC), is an endogenous µ-opioid polypeptide primarily produced by the hypothalamus. POMC neuronal cell bodies are primarily localized in the arcuate nucleus (ARC) of the hypothalamus. The terminals of these POMC neurons are distributed throughout the CNS, including the paraventricular nucleus (PVN) of the hypothalamus, which is an important area of the brain to the stress response of the hypothalamic-pituitary-adrenal (HPA) axis. Therefore, β-endorphin released by the activation of the hypothalamic POMC neuron is believed to change innate immune function. In this study, we investigated the role of hypothalamic µ-opioidergic systems in anti-tumor immune responses using the designer receptors exclusively activated by designer drugs (DREADD) system. To perform the activation of hypothalamic POMC neurons, we generated the transgenic mice expressing Gq-coupled human muscarinic M3 DREADD (hM3Dq) protein under the control of the POMC promoter in the hypothalamus. The hM3Dq was activated by a designer drug, clozapine N-oxide (CNO). Under these conditions, CNO-induced activation of hypothalamic POMC neurons significantly suppressed tumor growth in tumor-bearing mice. This suppression of tumor growth induced by the activation of hypothalamic POMC neurons by the administration of CNO was reversed by the pre-microinjection of naloxone into the PVN. Furthermore, CNO-induced activation of hypothalamic POMC neurons significantly decreased the plasma level of corticosterone and increased the number of NK cells in the spleen. These findings suggest that β-endorphin released by the activation of hypothalamic POMC neurons may suppress tumor growth via the PVN µ-opioid receptor-mediated suppression of the stress response of the HPA axis and the activation of cell-mediated immunity associated with NK cell activation.