prostaglandin-d2 and Sleep-Initiation-and-Maintenance-Disorders

Prostaglandin (PG) D2 and adenosine are potent endogenous somnogens and their sleep-inducing mechanisms are well characterized. We examined the contribution of these somnogens to physiological sleep by the combination of pharmacological tools and gene-knockout (KO) mice. Complete insomnia was observed in wild-type mice after an intraperitoneal injection of SeCl4, an inhibitor of PGD synthase (PGDS), or caffeine, an antagonist of adenosine A2A receptors. The SeCl4-induced insomnia was not observed in PGDS- or DP1 receptor-KO mice and the caffeine-induced insomnia, in A(2A) receptor-KO mice. A DP1 antagonist, ONO-4127Na, reduced sleep of rats by 30% during infusion into the subarachnoid space of the basal forebrain. These results indicate that the PGD2/ adenosine system plays a critical role in the regulation of physiological sleep.

Topics: Adenosine; Animals; Gene Knockout Techniques; Mice; Prostaglandin D2; Sleep; Sleep Initiation and Maintenance Disorders

The correlation between the somnogenic effect of prostaglandin (PG) D2 and the serotoninergic system was examined in freely-moving rats (n = 64) by use of a continuous infusion method. Rats pretreated with para-chlorophenylalanine (PCPA: 450 mg/kg body weight, i.p.) or non-PCPA-pretreated rats received infusion of PGD2, serotonin, or its direct precursor, 5-hydroxytryptophan (5HTP), into their third cerebral ventricle at a rate of 100 pmol/0.2 microliter/min between 11:00 and 17:00 h. In the PCPA-pretreated insomniac rats, PGD2 infusion resulted in an immediate increase in slow-wave sleep (SWS) and an increase with a 2-h latency in paradoxical sleep (PS). The total amounts of SWS and PS during the PGD2-infusion period were 151% and 154% of the respective control values. These results indicate that inhibition of the biosynthesis of serotonin and 5HTP by PCPA marginally affects the sleep-promoting effect of PGD2. The transient sleep restoration produced by 5HTP infusion into PCPA-pretreated rats was hardly affected by the simultaneous infusion (200 pmol/0.2 microliter/min; 07:00-17:00 h) of diclofenac sodium, an inhibitor of cyclo-oxygenase, suggesting that PGD2 production is not critically involved in the sleep restoration by 5HTP. The sleep-promoting property of PGD2 is thus probably independent of the serotoninergic modulation of sleep-wake activity.

Topics: 5-Hydroxytryptophan; Animals; Cerebral Ventricles; Diclofenac; Fenclonine; Male; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Serotonin; Sleep; Sleep Initiation and Maintenance Disorders; Temperature