Prostaglandin E₂Activates the Histaminergic System via the EP₄Receptor to Induce Wakefulness in Rats

Abstract

Prostaglandin (PG)E2 promotes the wakeful state when administered into the posterior hypothalamus, in which the histaminergic tuberomammillary nucleus (TMN) is located. To explore the neurotransmitter mechanisms responsible for PGE2-induced wakefulness in rats, we examined the effect of PGE2 on the activity of the histaminergic system and the involvement of PGE2 receptor subtypes in the response. PGE2 perfusion in the TMN at doses of 100, 200, and 400 pmol/min for 2 hr significantly increased histamine release from the medial preoptic area and frontal cortex in a dose-dependent manner, as measured by in vivo microdialysis. Among the agonists of the four distinct subtypes of PGE2 receptors (EP1-4) tested, only the EP4 receptor agonist (ONO-AE1-329) mimicked the excitatory effect of PGE2 on histamine release from both the medial preoptic area and frontal cortex. Perfusion of either PGE2 or the EP4 agonist into the TMN at a dose of 200 pmol/min for 1 hr increased histidine decarboxylase activity, histidine decarboxylase mRNA level, and histamine content in the hypothalamus. In situ hybridization revealed that EP4 receptor mRNA was expressed in histidine decarboxylase-immunoreactive neurons of the TMN region. Furthermore, EP4 agonist perfusion into the TMN induced wakefulness. These findings indicate that PGE2 induces wakefulness through activation of the histaminergic system via EP4 receptors.

Central PGE2exhibits anxiolytic-like activity via EP1and EP4receptors in a manner dependent on serotonin 5-HT1A, dopamine D1and GABAAreceptors

“…Bicuculline (5 mg/kg, i.p.) and flumazenil, antagonists for the binding site of GABA and benzodiazepine, respectively, of the GABA A receptor, also inhibited the anxiolytic-like activity induced by the central administration of PGE 2 (Fig. 6).…”

“…Although the EP selective drugs used in this study have been shown to be selective across EP receptor subtypes, we sought to confirm the involvement of EP 1 /EP 4 receptors in the anxiolytic-like activity by using knockout mice deficient in each EP subtype [9,14]. Genetic deletion of the EP 4 receptor abolished the anxiolytic-like activity of PGE 2 (Fig. 5A).…”

“…Prostaglandin (PG) E 2 is produced in the mammalian central nervous system (CNS), and has a variety of central actions such as in fever, pain generation, wakefulness and anorexia under both physiological and pathophysiological conditions [1][2][3][4][5]. PGE 2 exerts its actions through four different types of G-protein-coupled seven-transmembrane receptors, known as EP 1 , EP 2 , EP 3 and EP 4 [6,7].…”

“…Interestingly, psychological stress not related sickness also enhances PG production in the CNS [10,11]; however, the mechanism underlying the emotional regulation of central PGs is largely unknown. We have recently reported that PGD 2 , a structural isomer of PGE 2 , has anxiolytic-like activity via DP 1 receptor among two receptor subtypes for PGD 2 [12]. In this study, we focused on the role of PGE 2 in the emotional regulation, behavioral pharmacologically using highly selective ligands for receptor subtypes for PGE 2 [13] as well as knockout mice.…”

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

“…mPGES-1 is induced in the delayed phase of inflammation, with activation time occurring in the course of approximately 1 hour. It is involved in wakefulness, inflammation, hyperalgesia, pain, fever, and cancer [16,19]. Its expression, together with that of COX-2, is induced by proinflammatory stimuli such as IL-1β and has been suggested to be down-regulated by antiinflammatory glucocorticoids, docosahexaenoic acid, and eicosapentaenoic acid [16,20].…”