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 April 3, 2017; First published March 13, 2017
Citation Information: J Clin Invest. 2017;127(4):1370-1374. https://doi.org/10.1172/JCI90678.
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Categories: 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

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Figure 2

EP3 receptors on serotonergic cells are critical for the affective component of pain.

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EP3 receptors on serotonergic cells are critical for the affective compo...
(A and B) Aversion scores in mice lacking EP1 receptors (EP1R KO) (A) or EP3 receptors (EP3R KO) (B). (C and D) Confocal micrographs from the dorsal raphe nucleus of a Sert-Cre mouse. Labeling for TpH, a marker for serotonergic neurons, is shown in purple, and Cre labeling is shown in green. D is a higher magnification of parts of C. (E) Graph showing the aversive reaction to inflammatory pain in mice lacking EP3 receptors in serotonergic cells (EP3R-SERTCre) due to deletion driven by the Sert promoter. (F) Aversion scores in control mice and mice lacking the serotonin transporter (Sert KO). (G) Plot of the areas transfected with the viral vector encoding Cre in Ptger3fl/fl animals used in H. (H) Aversion scores in response to formalin-induced pain in mice with AAV-Cre–induced Ptger3 deletion in the area of the dorsal raphe nucleus (B6–B7). (I) Expression of hM3Dq-mCherry in serotonergic cells of the dorsal raphe. (J) Aversion scores from mice in which serotonergic cells were chemogenetically activated (AAV-hM3Dq Sert-Cre + CNO) during the pain session and controls (AAV-mCherry/Sert-Cre + CNO). (K) Expression of hM4Di-mCherry in serotonergic cells of the dorsal raphe. (L) Aversion scores from EP3R-SERTCre mice in which serotonergic cells were chemogenetically inactivated (AAV-hM4Di EP3R-SERTCre + CNO) during the pain sessions and controls (AAV-mCherry EP3R-SERTCre + CNO). Scale bars: 50 μm (C, I, and K); 30 μm (D). *P < 0.05; **P < 0.01, Student’s t test.