PGE2 as a Morphine-Seeking Behavior Modulator in the Place Preference Model

The opioid epidemic has become one of the most concerning public health issues in the world, and currently does not have an adequate treatment available. It has been observed that, despite opioids being highly addictive, patients with chronic inflammation are less likely to develop an opioid dependence. This protective effect may be caused by Prostaglandin E2 (PGE2) as it has been found that non-painful carrageenan inflammation reduces morphine induced reward. Taking this into account, the aim of this study was to determine if the direct administration of PGE2 into the central nervous system could modulate the morphine-induced reward. We used the morphine-conditioned place preference (CPP) model with and without PGE2 or PGE2R antagonist in order to test the reward response. We found a significant reduction of morphine-induced reward after administering PGE2. Moreover, we found that this effect could be reversed by PGE2 receptor antagonism. Our data suggest that PGE2 may reduce morphine-induced reward making it an important drug-target research alternative to explore the possibility of modifying or even preventing opioid addiction.

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

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 place-aversion 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 × 107 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.

Carrageenan-Induced Non-Painful Inflammation Reduces Voluntary Sucrose Consumption in a Two-Bottle Choice Paradigm: A New Model of Inflammation Induced Anhedonia

Anhedonia, the presence of diminished pleasure or decreased motivation for rewards is considered one of the core symptoms of depression. Studies have shown that anhedonia and reduced reward learning predict a poor prognosis with a higher prevalence of treatment failure among patients. Several mechanisms have been implicated in the onset and progression of depression;furthermore, an important amount of evidence supports not only the importance of the reward circuitry in the development of depressive anhedonia but also, that it is closely related with the presence of inflammation. In the current paper we show that 500 ul carrageenan administration in the right hind paw after deafferentation surgery leads to anhedonia, which is evident by a decrease in saccharine consumption in a two-bottle choice test;these findings suggest that carrageenan mediated inflammation is a reliable model of anhedonia that could lead to a better understanding of the immune-neural axis in motivation.