Nitric oxide and interleukin-1β mediate noradrenergic induced corticotrophin-releasing hormone release in organotypic cultures of rat paraventricular nucleus

Abstract

Noradrenergic inputs from the brainstem are critical for the central stress response. It has been suggested that endogenous interleukin-1β (IL-1β) is involved in norepinephrine (NE)-induced release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus (PVN). However, no IL-1 receptor on PVN CRH neurons has been identified. Therefore we hypothesized that the action of IL-1β in the PVN requires downstream modulators that eventually lead to CRH release by PVN neurons. In the current study, we used organotypic cultures from neonatal rat PVN which display neuroendocrine characteristics suitable for in vitro studies. Pharmacological treatments with NE or IL-1β elicited nitric oxide (NO) release from the PVN cultures, implying that local NO might be a candidate for modulating the action of IL-1β. In addition, NE treatments significantly increased IL-1β and CRH release. Treatment with IL-1β or sodium nitroprusside also induced CRH release. Next, we also showed that either an IL-1 receptor antagonist or NOS inhibitor Nω-nitro-l-arginine (l-NNA) attenuated the NE-induced CRH release. These results suggest that IL-1β and NO are involved in NE-induced CRH release. Moreover, we found that application of l-NNA attenuated IL-1β-induced CRH release, indicating that NO likely mediates this process. In summary, the current study demonstrates that IL-1β plays a significant role in NE-induced CRH release, and that neuroendocrine response in the PVN may depend on local NO action.