Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain
Anand Kumar Singh, … , Michael Fritz, David Engblom
Anand Kumar Singh, … , Michael Fritz, David Engblom
Published March 13, 2017
Citation Information: J Clin Invest. 2017;127(4):1370-1374. https://doi.org/10.1172/JCI90678.
View: Text | PDF
Brief Report Inflammation Neuroscience

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 E2 that is synthesized by cyclooxygenase 2 in neural cells. Further, mice lacking the prostaglandin E2 receptor EP3 selectively on serotonergic cells or selectively in the area of the dorsal raphe nucleus failed to form an aversion to formalin-induced 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 κ opioid receptor agonist. Collectively, our findings show that prostaglandin-mediated modulation of serotonergic transmission controls the affective component of inflammatory pain.

Authors

Anand Kumar Singh, Joanna Zajdel, Elahe Mirrasekhian, Nader Almoosawi, Isabell Frisch, Anna M. Klawonn, Maarit Jaarola, Michael Fritz, David Engblom

×

Figure 1

The affective component of inflammatory pain is dependent on prostaglandin E2 generated by COX2 in neural cells.

Options: View larger image (or click on image) Download as PowerPoint
The affective component of inflammatory pain is dependent on prostagland...
(A–D) Conditioned place aversion induced by injection of diluted formalin in the dorsal part of the hind paws in mice lacking COX1 (Cox1 KO) (A), mice treated with a COX1 inhibitor (COX1 inhib) (sc560, 5 mg/kg, i.p.; B), mice lacking COX2 (Cox2 KO) (C), mice treated with a COX2 inhibitor (parecoxib, 10 mg/kg, i.p.; D), and corresponding control mice. (E) Aversion scores in mice lacking COX2 in myeloid cells (Cox2fl/fl LysM-Cre). See Supplemental Methods for calculation of aversion scores. (F and G) Aversion scores in mice lacking COX2 in brain endothelial cells (Cox2fl/fl Slco1c1-Cre) or mice lacking COX2 in neural cells (Cox2fl/fl Nes-Cre). (H) Aversion is also blocked in mice lacking the inducible microsomal prostaglandin E synthase (mPGES-1 KO). *P < 0.05; **P < 0.01, Student’s t test.