Pharmacological characterization of prostaglandin E2 EP receptors in the rodent brain: functional studies in locus coeruleus neurons and the preBötzinger complex

Abstract

This work focuses on the study of the neuropharmacological mechanisms underlying prostaglandin E2 (PGE2) receptor (EP) activation in locus coeruleus (LC) neurons and the preBötzinger complex (preBötC). PGE2 is an inflammatory mediator synthesized by the brain constitutive cyclooxygenase (COX) enzyme, whose activity is blocked by the nonsteroidal anti-inflammatory drugs (NSAIDs). PGE2 binds to G protein-coupled EP1-4 receptors (EP1 to Gq, EP2 and EP4 to Gs, and EP3 to Gi/o). Activation of EP receptors by PGE2 has been shown to modulate synaptic transmission and neuronal activity in various brain regions. The noradrenergic nucleus LC, which is involved in the regulation of the sleep-wake cycle, arousal, cognition, pain, and reward behavior, expresses EP2, EP3, and EP4 receptors, but their functional role remains unexplored. Therefore, we aimed to characterize the EP2, EP3, and EP4 receptors pharmacologically in the rat LC by extracellular electrophysiological recordings in acute slices. On the other hand, the inspiratory pattern is generated by the preBötC, whose inspiratory neurons express ¿-opioid receptors (MOR) and respond to PGE2. Thus, administration of opioids produces respiratory depression while PGE2 increases the frequency of sighs and induces gasps under hypoxic circumstances. However, the possible interaction between both systems to cause major respiratory disturbances remains to be elucidated. For this purpose, we also examined the interaction between opioids and PGE2 in the mice preBötC by live time-lapse calcium imaging in organotypic slice cultures.