Prostaglandin (PG) D 2 is recognized as the most potent endogenous sleep-promoting substance whose mechanism of action is the best characterized among the various potential sleep substances thus far reported. Lipocalin-type PGD synthase is dominantly produced in the arachnoid membrane and choroid plexus of the brain, and is secreted into the cerebrospinal fluid to become β-trace, a major protein in human cerebrospinal fluid. PGD synthase and its resulting product, PGD 2, circulate in the ventricular system, subarachnoidal space and extracellular space of the brain system. PGD 2 then interacts with D type of prostanoid (DP) receptors on arachnoid trabecular cells in the chemosensory region of the ventromedial surface of the rostral basal forebrain to initiate the signal to promote sleep, probably via the activation of adenosine A 2A receptive neurons. The activation of the DP receptors results in activation of a cluster of neurons within the ventrolateral preoptic area, a recently identified sleep center, which may promote sleep by inhibiting the tuberomammillary nucleus, the source of the ascending histaminergic arousal system.
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