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.
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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 3

The involvement of EP3 receptors on serotonergic cells is specific for the affective component of pain.

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The involvement of EP3 receptors on serotonergic cells is specific for t...
(A and B) Nociceptive scores in mice given a COX2 inhibitor or mPGES-1 KO mice (parecoxib, 10 mg/kg, i.p.; n = 9 + 7 + 6). B shows means of the scores during the peak of the second phase of the formalin-induced pain (defined as 30–40 minutes after injection). See Supplemental Methods for calculation of nociceptive scores. (C and D) Corresponding data for mice lacking EP3 receptors in serotonergic cells (EP3R-SERTCre; n = 5 + 5). Note that the blunted response seen after COX2 inhibition cannot be seen in EP3R-SERTCre mice. (E) Febrile responses in WT and EP3R-SERTCre mice. Mean body temperatures 5 to 9 hours after an injection of lipopolysaccharide (100 μg/kg) are plotted. (F) Aversion scores in response to the κ receptor agonist U50488 (2.5 mg/kg, i.p.). Note that EP3R-SERTCre mice display normal acute nociceptive responses and a normal U-50488–induced aversion. (G and H) Conditioned place aversion induced by thermal pain in Cox2fl/fl Nes-Cre mice (G) and EP3R-SERTCre mice (H) and their WT littermates. **P < 0.01; ***P < 0.001, Student’s t test (B, D, and F–H); ANOVA (E).