Inhibitory effects of endotoxin on LH secretion in the ovariectomized monkey are prevented by naloxone but not by an interleukin-1 receptor antagonist

Citation
E. Xiao et al., Inhibitory effects of endotoxin on LH secretion in the ovariectomized monkey are prevented by naloxone but not by an interleukin-1 receptor antagonist, NEUROIMMUNO, 7(1), 2000, pp. 6-15
Citations number
42
Categorie Soggetti
Neurosciences & Behavoir
Journal title
NEUROIMMUNOMODULATION
ISSN journal
10217401 → ACNP
Volume
7
Issue
1
Year of publication
2000
Pages
6 - 15
Database
ISI
SICI code
1021-7401(2000)7:1<6:IEOEOL>2.0.ZU;2-O
Abstract
Endotoxin (lipopolysaccharides, LPS), the pathogenic moiety of gram-negativ e bacteria, is a well-known trigger for the central release of cytokines. T he objective of this study is to evaluate the effects of systemic endotoxin administration on LH and cortisol secretion in a nonhuman primate model an d 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 pept ides mediate these endocrine effects of LPS, using the opiate antagonist na loxone. The experiments were performed in long-term-ovariectomized rhesus m onkeys. Blood samples for hormone determination were obtained at 15-min int ervals 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 firs t experiment we tested the potency of several doses of this antagonist in p reventing the effects of centrally administered IL-1 alpha, a cytokine whic h is known to inhibit LH and stimulate cortisol release. Rhesus monkeys rec eived a 30-min intracerebroventricular infusion of IL-1 alpha (4.2 mu g/30 min) alone or together with various doses of IL-1ra (30-180 mu g/h i.c.v.). IL-1ra infusion was initiated 1 h before IL-1 and extended over the experi mental period. As previously reported, IL-1 alpha induced a significant inh ibition of LH, to 36.5 +/- 3.3% (mean +/- SE) by 5 h as a percentage from t he 3-hour baseline. This inhibitory effect was reversed by cotreatment with the 180 mu g/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 mu g) was administe red 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 admini stration of IL-1ra (52.5 +/- 9.6%). Cortisol secretion increased in respons e 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 experi ment 3, we investigated whether the opiate antagonist naloxone reverses the endocrine effects of endotoxin. Both LPS (50 mu g) and naloxone (5-mg bolu s + 5 mg/h) were infused intravenously. Naloxone was effective in preventin g the inhibitory effect of LPS on LH (to 124.6 +/- 22.1%, NS vs, saline) bu t 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 secre tion. These data demonstrate that, in the ovariectomized monkey, a systemic inflammatory/immune-like stress challenge acutely inhibits tonic LH secret ion while concomitantly stimulating cortisol release. Although endotoxin is known to affect central cytokine release, these endocrine effects do not r equire a mediatory role of central IL-1 in the primate. In contrast, endoge nous opioid pathways appear to be involved in this process. Copyright (C)19 99 S. Karger AG, Basel.