Interleukin-1 induces slow-wave sleep at the prostaglandin D2-sensitive sleep-promoting zone in the rat brain

Abstract

To determine the site of action of the sleep-promoting effect of interleukin-1 (IL-1), we continuously infused (between 11 P.M. and 5 A.M.) murine recombinant IL-1beta into seven different locations in the ventricular and subarachnoid systems of the brain in freely moving rats. When IL-1 was infused at 10 ng/6 hr into the subarachnoid space underlying the ventral surface of the rostral basal forebrain, which previously was defined as the "prostaglandin (PG) D2-sensitive sleep-promoting zone" (PGD2-SZ), the total amount of slow-wave sleep (SWS) increased by 110.7 min (IL-1 was 208.1 +/- 14.3 min vs control at 97.4 +/- 9.3 min; n = 8; p < 0.01 by paired Student's t test) from the baseline control level obtained under continuous infusion of saline vehicle. The hourly SWS during the infusion period reached the level of daytime SWS, the physiological maximum, whereas paradoxical sleep (PS) was decreased transiently. This site of action for the SWS promotion was dissociated from the site in the third ventricle sensitive to the IL-1-mediated PS suppression, fever, and anorexia. The SWS increase caused by IL-1 infusion into the PGD2-SZ was blocked completely by coadministered diclofenac, a nonselective cyclooxygenase (COX) inhibitor. Pretreatment of rats with NS-398 or piroxicam (3 mg/kg of body weight, i.p.), which are said, respectively, to possess high and relative specificity for the COX-2 enzyme, also blocked the SWS-promoting effect of IL-1. We present a hypothesis that IL-1 induces SWS, at least in part, via COX-2-mediated PG production in the PGD2-SZ.

Fig. 1.

Schematic sagittal and coronal drawings indicating the seven locations (L1 throughL7) for infusing IL-1 into the ventricle and subarachnoid space in the rat brain. Numerals indicate the distance from bregma, the reference point, in the stereotaxic coordinates. L1, In the subarachnoid space of the PGD₂-SZ; L2, in the 3V, apposed to the medial preoptic area; L3, in the lateral ventricle;L4, in the subarachnoid space underlying the posterior hypothalamus; L5, in the 3V, near the aqueduct of Sylvius; L6, between the aqueduct of Sylvius and the fourth ventricle, apposed to the locus coeruleus; L7, in the cisterna magna.

Fig. 2.

Changes in SWS, PS, brain temperature, and food intake from respective baseline levels caused by the 6 hr (from 11 P.M. to 5 A.M.) infusion of IL-1. The difference between the experimental level by the IL-1 infusion and the baseline level (control) under the infusion of saline vehicle was calculated for each rat; eachcolumn indicates the mean ± SEM of the differences obtained in this manner in a group of rats (n = 8 each) ascribed to the experiment for one of the seven locations. *p < 0.05, **p < 0.01 by paired Student’s t test, compared between the IL-1 experiment and vehicle baseline. ^§p < 0.05, ^§§p < 0.01 compared among the changes for the seven locations by Student–Newman–Keuls test following one-way ANOVA, wherein the mark above L1 in the panel for ΔSWS and that above L2 in the panel for Δbrain temperature (ΔBrain temp.) indicate the significant differences over the changes for the other six locations.

Fig. 3.

Changes in SWS, PS, brain temperature, and food intake caused by the 6 hr infusion of IL-1 at different doses from respective baseline (control) levels. See Figure 2 for the method of calculation. Each datum point represents the mean ± SEM of eight rats. ○, Results by IL-1 infused into L2; •, results by IL-1 infused into L1. *p < 0.05, **p < 0.01 by paired Student’s ttest, compared between the IL-1 experiment and the baseline under saline infusion. ^§§p < 0.01 by repeated two-way ANOVA between L1 and L2.

Fig. 4.

The 24 hr profiles of SWS, PS, brain temperature, and food intake in rats that received IL-1 into L1 andL2. ○, Baseline; •, experimental day; eachdatum point represents the mean ± SEM of eight values. IL-1 was infused into each rat between 11 P.M. and 5 A.M. (indicated by the shaded area) on the experimental day at 10 ng/6 hr. *p < 0.05, **p< 0.01 by paired Student’s t test, compared between the experimental datum point and the corresponding baseline point.

Fig. 5.

Changes in the hourly mean of SWS episode duration caused by the IL-1 infusion. L1-A, The 24 hr profiles of the hourly mean of the SWS episode duration on the baseline day (○) and on the experimental day (•), which were obtained for rats that received IL-1 infusion into L1; L1-B, Histogram indicating the changes in the number of SWS episodes of various length ranges, which was for the SWS episodes that appeared between 12 and 1 A.M. on the baseline day (open column) and on the experimental day (open + closed column) in L1-A. L2-A, The 24 hr profiles of the hourly mean of the SWS episode duration in rats that received the IL-1 infusion into L2; L2-B, Histogram for the SWS episodes that appeared between 2 and 3 A.M. in L2-A. SWS episode duration is expressed as the mean ± SEM of eight rats. IL-1 was infused between 11 P.M. and 5 A.M. (indicated by the shaded area) at 10 ng/6 hr through implanted cannulae. *p < 0.05, **p < 0.01 by paired Student’s t test.

Fig. 6.

Effect of COX inhibitors on the SWS-promoting effect of IL-1 in L1. Shown are the 24 hr profiles of the hourly amount of SWS (A) and those of the hourly mean of the SWS episode duration (B) in rats that received the coinfusion into L1 of IL-1 (10 ng/6 hr) and diclofenac sodium (46 μg/6 hr) between 11 P.M. and 5 A.M. (indicated by the shaded area). ○, Baseline day; •, experimental day.C, Piroxicam (3 mg/kg), NS-398 (3 mg/kg), or vehicle (for the column marked IL-1) was injected intraperitoneally at 500 μl, 3.2 hr before the commencement of the continuous infusion of IL-1 (or saline vehicle) into L1 between 11 P.M. and 5 A.M. at 10 ng/6 hr. Each datum column represents the mean ± SEM of eight rats. **p < 0.01 by paired Student’s t test between the experimental result (filled column) and the corresponding control result (open column).