ROLE OF HYPOTHALAMIC HISTAMINERGIC NEURONS IN MEDIATION OF ACTH AND BETA-ENDORPHIN RESPONSES TO LPS ENDOTOXIN IN-VIVO

The involvement of hypothalamic histaminergic neurons in the mediation of the ACTH and beta-endorphin (beta-END) response to lipopolysaccharide (LPS) endotoxin was investigated in conscious male rats. LPS stimulated the release of ACTH and beta-END dose-dependently and increased the hypothalamic concentration of the histamine (HA) metabolite tele-methylhistamine significantly and that of HA slightly, indicating an increased turnover of neuronal HA. Pretreatment with the HA synthesis inhibitor alpha-fluoromethyl-histidine administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) inhibited the ACTH and beta-END response to LPS about 60%, whereas i.p. administration of the H-3 receptor agonist R(alpha)methylHA, which inhibits HA synthesis and release, decreased the response about 50%. Pretreatment with the H-1 receptor antagonist mepyramine (67 mu g x 2 i.c.v.) inhibited the hormone response to LPS about 50%, while pretreatment with equimolar doses of the H-2 receptor antagonists cimetidine (67 mu g x 2 i.c.v.) or ranitidine (83 mu g x 2 i.c.v.) had no effect on the LPS-induced release of ACTH and beta-END. When the H-1 receptor antagonists mepyramine and cetirizine were administered i.p. in doses (10 mg/kg) which penetrate the blood-brain barrier the hormone response to LPS was inhibited 50% and 30%, respectively. Administered i.p. the H-2 receptor antagonists had no effect on the hormone response to LPS. We conclude that hypothalamic histaminergic neurons in rats are involved in the mediation of the ACTH and beta-END response to LPS stimulation via activation of central postsynaptic H-1 receptors.