title: Inhibitory effects of endotoxin on LH secretion in the ovariectomized monkey are prevented by naloxone but not by an interleukin-1 receptor antagonist.
abstract: Endotoxin (lipopolysaccharides, LPS), the pathogenic moiety of gram-negative bacteria, is a well-known trigger for the central release of cytokines. The objective of this study is to evaluate the effects of systemic endotoxin administration on LH and cortisol secretion in a non-human primate model and to investigate whether these endocrine effects are mediated by centrally released interleukin-1 (IL-1) using the receptor antagonist to IL-1 (IL-1ra). An additional objective is to investigate whether endogenous opioid peptides mediate these endocrine effects of LPS, using the opiate antagonist naloxone. The experiments were performed in long-term-ovariectomized rhesus monkeys. Blood samples for hormone determination were obtained at 15-min intervals for a period of 8 h, which included a 3-hour baseline period. Since the effective central dose of IL-1ra in the monkey was unknown, in the first experiment we tested the potency of several doses of this antagonist in preventing the effects of centrally administered IL-1alpha, a cytokine which is known to inhibit LH and stimulate cortisol release. Rhesus monkeys received a 30-min intracerebroventricular infusion of IL-1alpha (4.2 microg/30 min) alone or together with various doses of IL-1ra (30-180 microg/h i.c.v.). IL-1ra infusion was initiated 1 h before IL-1 and extended over the experimental period. As previously reported, IL-1alpha induced a significant inhibition of LH, to 36.5 +/- 3.3% (mean +/- SE) by 5 h as a percentage from the 3-hour baseline. This inhibitory effect was reversed by cotreatment with the 180 microg/h dose of IL-1ra (to 82.5 +/- 3.8% by 5 h; NS vs. saline) but not with the lower doses. IL-1 stimulated cortisol release to 165.9 +/- 7.7%, but this increase was prevented by IL-1ra (66.6 +/- 8.9%; p < 0.05 vs. IL-1, NS vs. saline). In the second experiment, LPS (50 microg) was administered intravenously, alone or in combination with intracerebroventricular IL-1ra infusion. LPS induced a significant decrease in LH secretion (to 57.1 +/- 5.2%). These effects were not reversed by intracerebroventricular administration of IL-1ra (52.5 +/- 9.6%). Cortisol secretion increased in response to LPS, but this stimulatory effect was not affected by IL-1ra (178.3 +/- 13.4 vs. 166.9 +/- 5.7%). There were no effects of IL-1ra alone. In experiment 3, we investigated whether the opiate antagonist naloxone reverses the endocrine effects of endotoxin. Both LPS (50 microg) and naloxone (5-mg bolus + 5 mg/h) were infused intravenously. Naloxone was effective in preventing the inhibitory effect of LPS on LH (to 124.6 +/- 22.1%, NS vs. saline) but not the increase in cortisol (to 166.7 +/- 16.7%; p < 0.05 vs. saline, NS vs. LPS). Naloxone alone has no significant effect on LH or cortisol secretion. These data demonstrate that, in the ovariectomized monkey, a systemic inflammatory/immune- like stress challenge acutely inhibits tonic LH secretion while concomitantly stimulating cortisol release. Although endotoxin is known to affect central cytokine release, these endocrine effects do not require a mediatory role of central IL-1 in the primate. In contrast, endogenous opioid pathways appear to be involved in this process.
authors.affiliation: Department of Obstetrics and Gynecology, and Center for Reproductive Sciences, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: E
authors.initials: E
authors.lastname: Xiao
authors.forename: L
authors.initials: L
authors.lastname: Xia-Zhang
authors.forename: M
authors.initials: M
authors.lastname: Ferin
mesh_terms: D000818:Animals; D005260:Female; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000276:immunology; D007276:Injections, Intraventricular; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000378:metabolism*; D008253:Macaca mulatta; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D015213:Neuroimmunomodulation / Q000187:drug effects*; D018847:Opioid Peptides / Q000502:physiology; D010052:Ovariectomy; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012795:Sialoglycoproteins / Q000494:pharmacology*; D013312:Stress, Physiological / Q000276:immunology
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D009270:Naloxone; D007986:Luteinizing Hormone; D006854:Hydrocortisone