Evidence of substance P autocrine circuitry that involves TNF-α, IL-6, and PGE2 in endogenous pyrogen-induced fever

Substance P (SP) is involved in fever that is induced by lipopolysaccharide (LPS) but not by interleukin-1 beta or macrophage inflammatory protein-1 alpha. Intracerebroventricular (i.c.v.) administration of the neurokinin-1 (NK1) receptor antagonist SR140333B in rats reduced fever that was induced by an i.c.v. injection of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), prostaglandin E-2 (PGE(2)), corticotropin-releasing factor (CRF), endothelin-1 (ET-1), and morphine (MOR). Furthermore, an i.c.v. injection of SP induced a febrile response that was inhibited by indomethacin concomitant with an increase in PGE(2) levels in cerebrospinal fluid. Lipopolysaccharide and PGE(2) caused higher expression and internalization of NK1 receptors in the hypothalamus which were prevented by SR140333B. These data suggest that SP is an important mediator of fever, in which it induces a prostaglandin-dependent response and is released after TNF-alpha, IL-6, PGE(2), CRF, endogenous opioids, and ET-1. (C) 2016 Elsevier B.V. All rights reserved.