Endotoxin-induced inflammation promotes, via the adrenomedullary system, a hyperglycemic and anti-inflammatory reflex.

Immune challenges elicit significant physiological responses which are coordinated by the central nervous system. Among these is the sympathetic system-mediated anti-inflammatory reflex, which suppresses the TNF response. The sympathetic system has two main effector pathways: direct organ-targeted noradrenergic innervation and hormonal secretion from the adrenal gland. Experiments supporting the sympathetic nature of the anti-inflammatory reflex are based on observations that both β-blockers and splanchnic nerve transection increase the TNF response, yet these not only interfere with direct noradrenergic signaling but also negatively impact adrenal gland function. Meanwhile, endotoxin administration causes hyperglycemia; however, the role of the sympathetic nervous system in this process remains unclear. Additionally, most experimental approaches exploring sympathetic responses are conducted in anesthetized animals, where the sympathetic response is changed. Therefore, we examined the effect of i.v. LPS administration in stress-free intact animals. Inhibiting prostaglandin synthesis with indomethacin and blocking β-adrenergic receptors with propranolol caused increased TNF levels and prevented LPS-induced hyperglycemia, without affecting the Corticosterone response. Adrenal de-medullated animals (AdMX) receiving LPS lacked a hyperglycemic response and had higher circulating TNF levels. Intravenous adrenaline, but not noradrenaline administration in AdMX, recovered hyperglycemia and reduced TNF responses after LPS. Prostaglandin administration induced hyperglycemia in Sham but not in AdMX animals, showing that prostaglandins require the adrenal to promote acute biological effects