Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

Fritz, Michael E.; Klawonn, Anna M.; Nilsson, Anna; Singh, Anand Kumar; Zajdel, Joanna; Wilhelms, Daniel Bjӧrk; Lazarus, Michael; Löfberg, Andreas; Jaarola, Maarit; Kugelberg, Unn; Billiar, Timothy R.; Hackam, David J.; Sodhi, Chhinder P.; Breyer, Matthew D.; Jakobsson, Johan; Schwaninger, Markus; Schütz, Günther; Parkitna, Jan Rodriguez; Saper, Clifford B.; Blomqvist, Anders; Engblom, David

doi:10.1172/jci83844

Cited by 57 publications

(71 citation statements)

References 71 publications

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“…are quite different from those of the stimulus used in this study. Thus, the systemic inflammation was presumably nonpainful and the signaling mechanisms involved the brain endothelium, COX1, and EP 1 receptors on dopamine D1 receptor-expressing neurons in the striatum (30). In contrast, the aversion seen in this study was dependent on nociceptive input and could consequently be blocked by deletion of Trpa1 (Supplemental Figure 2E), the receptor activated by formalin on the primary afferents (31).…”

Section: Acknowledgmentsmentioning

confidence: 61%

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

Singh¹,

Zajdel²,

Mirrasekhian³

et al. 2017

Journal of Clinical Investigation

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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.

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)

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Section: Acknowledgmentsmentioning

confidence: 61%

“…Thus, other types of pain may access the serotonergic cells by pathways not involving prostaglandins and EP 3 receptors. We recently found that the aversion induced by systemic inflammation is mediated by prostaglandins (30). The characteristics of the aversive stimulus used in that study (LPS injected i.p.)…”

Section: Acknowledgmentsmentioning

confidence: 98%

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

Singh¹,

Zajdel²,

Mirrasekhian³

et al. 2017

Journal of Clinical Investigation

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“…Tanaka K. showed that PGE 2 activity is essential for depressive behavior induced by a chronic social defeat model, as the administration of a prostaglandin antagonist, or a conditional knock-out of prostaglandin receptors, increased the activity of mesocortical dopaminergic pathways in this model and prevented the depressive behavior [21]. Prostaglandin synthesis in the CNS can even induce conditioned place-aversion in other models [22].…”

Section: Discussionmentioning

confidence: 97%

“…For example, the intraperitoneal CGB administration causes a dose dependent depression as increased immobility in a forced swim and tail suspension tests and a decrease in sucrose consumption [22] [32] [33].…”

Section: Discussionmentioning

confidence: 99%

Non-Painful Peripheral Inflammation Blocks Conditioned Place-Preference to Morphine and Nicotine through an Ibuprofen-Sensitive and an Ibuprofen Insensitive Pathway

Sotomayor-Sobrino¹,

Ochoa-Aguilar²,

Tenorio³

et al. 2018

JBBS

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The field of neuroimmunology has expanded in recent years providing new insights and therapies into pathologies like stroke, autism, and depression. However, few works explore the relationship between inflammatory stimuli and motivation. Thus, the aim of this study was to determine how non-painful inflammatory stimuli affect reward. To test reward-response, we used the morphine and the nicotine induced conditioned place-preference and placeaversion model in rats with non-painful inflammation. The following inflammatory models were used: non-painful infectious inflammation: 24 hrs prior to conditioning sessions, an injection with Calmette-Guerin bacillus (CGB) 1 × 10 7 cfu, ip, was administered. Non-painful non-infectious inflammation: 24 hrs prior to conditioning sessions, rats' sciatic nerve was blocked and cut, followed by the injection of carrageenan (750 μl) in the paw. We then measured the cytokine concentration to determine the inflammatory profile of each of our models. Finally, we administered ibuprofen to determine if it could prevent the effect of inflammation over conditioned place-preference. We show that carrageenan significantly reduced the morphine-induced reward. Non-painful inflammatory stimulus, CGB and denervation + carrageenan, inhibit the conditioned place-preference to morphine and nicotine, CGB also block conditioned place-aversion to nicotine; carrageenan has no effect on CPA. The administration of ibuprofen reinstates conditioned place-preference to morphine and nicotine in the carrageenan model, but has no effect in the CGB model; finally ibuprofen has no effect on CPA. Our data suggest that non-painful-inflammatory stimuli inhibit the reward system, independent of cytokine concentration. Furthermore, the administration of a PGE 2 inhibitor can importantly modulate this phenomenon.

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“…Upon inflammation, mPGES-1 has been shown to be co-expressed with COX-2 [95,97]. The importance of mPGES-1 during inflammatory conditions is profound and includes involvement in fever [69] anorexia [101,102] and malaise [103]. Anorexia can be defined as loss of appetite with an accompanying reduction of food intake, and can be seen during infection in a wide range of species [104].…”

Section: Terminal Isomerasesmentioning

confidence: 99%

Mechanisms Behind Illness-Induced Anorexia

Nilsson¹

2016

Linköping University Medical Dissertations

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Loss of appetite is together with fever and malaise hallmarks of infection. Loosing appetite during an acute infection such as influenza does not result in any long-lasting effects, but loosing appetite during chronic diseases such as cancer or AIDS constitutes a risk factor for mortality. Food intake regulation during inflammation is orchestrated by the brain in response to peripheral inflammatory signals. It is known that expression of the prostaglandin synthesizing enzyme cyclooxygenase 2 (COX-2) is crucial for the mechanisms underlying inflammation-induced anorexia, and that prostaglandin E2 (PGE2) is involved in anorexia induced by interleukin-1 beta (IL-1β). In this thesis I examined the prostaglandin pathways proposed to be involved in anorexia. We show that acute anorexia is dependent on COX-2 expression, while cancer-induced anorexia is mediated by cyclooxygenase 1 (COX-1), at least in the initial stages, suggesting that the signaling pathways for chronic-and acute anorexia are distinct. We were able to demonstrate that the pathway underlying acute anorexia is distinct from that of fever, and that taste aversion is prostaglandin independent. We could also show that both acute and chronic anorexia-cachexia is dependent on expression of myeloid differentiation primary response gene (MyD88) in hematopoietic/myeloid cells. De generella slutsatser vi kan dra av studierna som ligger till grund för denna avhandling är att symptomen som vi upplever när vi blir sjuka, och som länge har ansetts ha samma bakomliggande signalvägar, till stor del signaleras till hjärnan på olika sätt. Aptitförlusten som uppkommer vid en infektion är inte alls lika beroende av ett specifikt prostaglandin, prostaglandin E2, som man tidigare trott, men en viktig faktor för att utveckla aptitförlust både vid akut-och kronisk sjukdom verkar vara MyD88-signallering i kroppens immunceller.Att kartlägga hur dessa signalvägar fungerar och vad som skiljer olika sjukdomssymptom åt är av stor vikt för utvecklingen av nya läkemedel. Dagens receptfria anti-inflammatoriska läkemedel är visserligen effektiva, men påverkar många av kroppens homeostatiska processer. Det är därför vanligt med allvarliga biverkningar såsom nedsatt hjärtfunktion och ökad risk för stroke och hjärtinfarkt, påverkan på njurfunktionen och magsår vid kronisk användning av dessa preparat. Önskvärt vore om det fanns läkemedel som endast påverkade de processer som missgynnar välmående.

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Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

Cited by 57 publications

References 71 publications

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

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

Non-Painful Peripheral Inflammation Blocks Conditioned Place-Preference to Morphine and Nicotine through an Ibuprofen-Sensitive and an Ibuprofen Insensitive Pathway

Mechanisms Behind Illness-Induced Anorexia

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