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

Abstract

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.

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

“…This reduction significantly inhibited the opioid-induced reward [32]. Later, we reported the non-painful carrageenan induced inflammation had protective effects to morphine-induced conditioned place preference [13]. Additionally, we found this effect was reversed by administering a cyclooxygenase inhibitor.…”

“…However, we recently found that carrageenan-induced painless inflammation is responsible for blocking morphine reward behavior. Moreover, the administration of ibuprofen significantly increases reward behavior and at the same time blocks the inflammation processes [13]. We speculate that the cause for this is related to the increase of pro-inflammatory molecules which is induced by carrageenan administration and modulated by administering ibuprofen.…”

“…Clinical studies have shown that there is a lower opioid addiction incidence in patients with chronic pain (0.19%), compared to the general population (10%) [11]. In addition to this, some animal models have shown that peripheral inflammation can affect DA release in the central nervous system (CNS) [12], and that carrageenan-induced painful inflammation decreases morphine reward in the conditioning place preference model and the morphine withdrawal syndrome [13] [14] [15]. This evidence suggests that a low susceptibility to developing an opioid dependence could be attributed to a pain process.…”