Our previous studies have shown that norepinephrine (NE) upregulates proinflammatory cytokines by activating ₂-adrenoceptor. Therefore, modulation of the sympathetic nervous system represents a novel treatment for sepsis. We have also shown that a novel stomach-derived peptide, ghrelin, is downregulated in sepsis and that its intravenous (IV) administration decreases proinflammatory cytokines and mitigates organ injury. However, it remains unknown whether ghrelin inhibits sympathetic activity through central ghrelin receptors (i.e., GHSR-la) in sepsis. To study this, sepsis was induced in male rats by cecal ligation and puncture (CLP). Ghrelin was administered through IV or intracerebroventricular (ICV) injection 30min before CLP. Our results showed that IV administration of ghrelin significantly reduced the elevated NE and TNF- levels at 2h after CLP. NE administration partially blocked the inhibitory effect of ghrelin on TNF- in sepsis. GHSR-la inhibition by the administration of a GHSR-la antagonist, [D-Arg¹ D-Phe⁵ D-Trp^{7, 9} Leu¹¹]-substance P, significantly increased both NE and TNF- levels even in normal animals. Markedly elevated circulating levels of NE 2h after CLP were also significantly decreased by ICV administration of ghrelin. Ghrelin's inhibitory effect on NE release was completed blocked by ICV injection of the GHSR-1a antagonist or a neuropeptide Y (NPY)/Y1 receptor antagonist. However, ghrelin's downregulatory effect on TNF- release was only partially diminished by these agents. Thus, ghrelin has sympathoinhibitory properties which are mediated by central ghrelin receptors involving a NPY/Y1 receptor dependent pathway. Ghrelin's inhibitory effect on TNF- production in sepsis is partially due to its modulation of the over-stimulated sympathetic nerve activation.