TY - JOUR

T1 - Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain

AU - Singh, Anand Kumar

AU - Zajdel, Joanna

AU - Mirrasekhian, Elahe

AU - Almoosawi, Nader

AU - Frisch, Isabell

AU - Klawonn, Anna M

AU - Jaarola, Maarit

AU - Fritz, Michael

AU - Engblom, David

PY - 2017/4/3

Y1 - 2017/4/3

N2 - 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.

AB - 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.

KW - Affect

KW - Animals

KW - Cyclooxygenase 2/metabolism

KW - Cyclooxygenase Inhibitors/pharmacology

KW - Dinoprostone/physiology

KW - Drug Evaluation, Preclinical

KW - Inflammation/pathology

KW - Mice, Knockout

KW - Pain/psychology

KW - Pain Perception

KW - Pyrazoles/pharmacology

KW - Receptors, Prostaglandin E, EP3 Subtype/metabolism

KW - Serotonergic Neurons/drug effects

KW - Serotonin/physiology

KW - Signal Transduction

U2 - 10.1172/JCI90678

DO - 10.1172/JCI90678

M3 - Journal article

C2 - 28287401

VL - 127

SP - 1370

EP - 1374

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -