Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain

Abstract

Pain is fundamentally unpleasant and induces a negative affective state. The affective component of pain is mediated by circuits that are distinct from those mediating the sensory-discriminative component. Here, we have investigated the role of prostaglandins in the affective dimension of pain using a rodent pain assay based on conditioned place aversion to formalin injection, an inflammatory noxious stimulus. We found that place aversion induced by inflammatory pain depends on prostaglandin E-2 that is synthesized by cyclooxygenase 2 in neural cells. Further, mice lacking the prostaglandin E-2 receptor EP3 selectively on serotonergic cells or selectively in the area of the dorsal raphe nucleus failed to form an aversion to formalininduced pain, as did mice lacking the serotonin transporter. Chemogenetic manipulations revealed that EP3 receptor activation elicited conditioned place aversion to pain via inhibition of serotonergic neurons. In contrast to their role in inflammatory pain aversion, EP3 receptors on serotonergic cells were dispensable for acute nociceptive behaviors and for aversion induced by thermal pain or a kappa opioid receptor agonist. Collectively, our findings show that prostaglandin-mediated modulation of serotonergic transmission controls the affective component of inflammatory pain.<p>Funding Agencies|European Research Council; Swedish Medical Research Council; Knut and Alice Wallenberg Foundation; Swedish Brain Foundation; County Council of Ostergotland; National Institute of Neurological Disorders and Stroke (NINDS)</p

Genetic approaches to the investigation of serotonergic neuron functions in animals

“…Numerous studies using chemogenetic approaches were conducted to perceive the functions of serotonergic neurons and their projections. In such experiments mice of the Sert-Cre line are injected with adeno-associated viruses containing the sequence hM4Di or hM3Dq (AAV-hSyn-DIO-hM4Di/ hM3Dq) to obtain its expression in the serotonergic neurons (Urban et al, 2016;Fernandez et al, 2017;Singh et al, 2017). For example, it was found that serotonergic projections from the median raphe are essential for regulating the memory of objects and the synaptic plasticity of the hippocampus (Fernandez et al, 2017).…”

Molecular Mechanisms of Reward and Aversion

“…In particular the EP3Rs of the preoptic hypothalamus have been found to be responsible for signaling inflammatory fever (Lazarus et al, 2007). The EP3Rs also play a role in signaling PGE2 mediated hyperalgesia and in the affective component of pain (Minami et al, 2001;Singh et al, 2017). EP4Rs are Gs-coupled which are widely expressed throughout the brain of rodents.…”

Cyclooxygenase Inhibition: Pain, Inflammation, and the Cardiovascular System

“…PGE 2 formed in brain venules during systemic inflammation passes the blood–brain barrier and disinhibits neurons in the median preoptic nucleolus to generate fever . COX‐2‐derived prostanoids also play a role in other central responses to systemic inflammation, such as sleepiness and anorexia, and COX‐2 expressed in the brain may modulate the affective component of pain . Indeed, as a growing body of evidence suggests that inflammatory processes play a role in affective disorders, COX‐2 products have also been implicated in anxiety and major depression .…”