Distribution of the EP3 prostaglandin E2 receptor subtype in the rat brain: Relationship to sites of interleukin-1-induced cellular responsiveness

The activation of neurosecretory neurons that express corticotropin-releasing hormone (CRH) in response to increased circulating levels of interleukin-1beta (IL-1beta) depends on prostaglandin E(2) (PGE(2)) acting locally within the brain parenchyma. To identify potential central targets for PGE(2) relevant to pituitary-adrenal control, the distribution of mRNA encoding the PGE(2) receptor subtype EP3 (EP3R) was analyzed in rat brain. Hybridization histochemistry revealed prominent labeling of cells in discrete portions of the olfactory system, iso- and hippocampal cortices, and subcortical telencephalic structures in the septal region and amygdala. Labeling over the midline, intralaminar, and anterior thalamic groups was particularly prominent. EP3R expression was enriched in the median preoptic nucleus and adjoining aspects of the medial preoptic area (MPO) implicated in thermoregulatory/febrile responses and sleep induction. EP3R-expressing cells were also prominent in brainstem cell groups involved in nociceptive information processing/modulation (periaqueductal gray, locus coeruleus (LC), parabrachial nucleus (PB), caudal raphé nuclei), arousal and wakefulness (LC, midbrain raphé and tuberomammillary nuclei); and in conveying interoceptive input, including systemic IL-1 signals, to the endocrine hypothalamus (nucleus of the solitary tract (NTS) and rostral ventrolateral medulla VLM). Combined hybridization histochemical detection of EP3R mRNA with immunolocalization of IL-1beta-induced Fos protein expression identified cytokine-sensitive, EP3R-positive cells in the medial NTS, rostral VLM, and, to a lesser extent, aspects of the MPO. These findings are consistent with the view that increased circulating IL-1 may stimulate central neural mechanisms, including hypothalamic CRH neurons, through an EP3R-dependent mechanism involving PGE(2)-mediated activation of cells in the caudal medulla and/or preoptic region.