The role of linagliptin, a selective dipeptidyl peptidase-4 inhibitor, in the morphine rewarding effects in rats
Introduction
Drug dependence is classified as a chronic recurrent disease of the central nervous system (CNS) that leads to personality disorders, co-morbidities and premature death. One of the strongest drugs of abuse is morphine, which is also used in clinical practice for acute and chronic pain alleviation. The rewarding effect of various drugs of abuse is associated with the induced stimulations of structures within the mesolimbic system, such as the ventral tegmental area (VTA) and the nucleus accumbens. A stimulation of the mesolimbic areas leads to an increased dopamine release in the nucleus accumbens (Di Chiara, 2000), which determines the feeling of pleasure. Despite numerous investigations, the number of addicted patients is steadily increasing, while still no effective methods can be found for the therapy of morphine dependence and this raises a need to seek for new therapeutic strategies. In this context, the endogenous pathways that control appetite and food intake, such as incretin hormones, seem to be important targets.
The glucagon-like peptide-1 (GLP-1) belongs to gastrointestinal hormones, commonly deemed as ‘incretins’. GLP-1 is synthesized in the L-type enteroendocrine cells in response to food intake. The major effect of GLP-1 is the normalization of blood glucose levels by a stimulation of postprandial insulin production and reduction of glucagon synthesis (Donnelly, 2012; Drucker et al., 1987; Karaca et al., 2009). GLP-1 exerts its effects by binding to its receptors, which are expressed in the pancreatic beta cells (Körner et al., 2007). These receptors are coupled with G protein and their stimulation raises intracellular cyclic adenosine monophosphate (cAMP) levels [Drucker et al., 1987; Takhar et al., 1996]. As the pharmacological effect of GLP-1 is of extremely short duration (1–2 min), because of its rapid degradation by the enzyme, dipeptidyl peptidase-4 (DPP-4) (Karaca et al., 2009; Kieffer et al., 1995), two subgroups of synthetic and long-lasting incretin drugs (GLP-1 analogs and DPP-4 inhibitors) were introduced for the therapy of diabetes mellitus type II. GLP-1 analogs act directly on GLP-1 receptors but their absorption from the gastrointestinal tract is rather poor, while DPP-4 inhibitors stimulate GLP-1 receptors indirectly, but they are well absorbed from the gastrointestinal tract. The major advantage of these drugs is their ability to reduce hyperglycemia without inducing hypoglycemia.
Recent data have shown that GLP-1 receptors are also expressed in the heart (Baggio et al., 2018), the kidneys (Körner et al., 2007) and the brain (Cork et al., 2015; Körner et al., 2007). In the brain, GLP-1 is expressed in preproglucagon neurons and synthesized within the nucleus of the solitary tract (NTS) in the brain stem (Grill and Hayes, 2012), acting as a regulatory neuropeptide. From the NTS, GLP-1 neurons transmit their outputs to other brain areas, such as the VTA, the nucleus accumbens, the dorsomedial hypothalamus, the rostral ventrolateral medulla and the arcuate nucleus (Dossat et al., 2011; Llewellyn-Smith et al., 2011; Merchenthaler et al., 1999). GLP-1 takes part in the food intake mechanisms, influences the regulation of satiety and controls food rewarding effects. It was indeed confirmed that the activation of GLP-1 receptors in the VTA suppressed feeding behaviors (Alhadeff et al., 2012; Dickson et al., 2012) and the increased levels of incretin hormones in the VTA and in the nucleus accumbens inhibited the activity of dopaminergic neurons in the mesolimbic system (Wang et al., 2015), reducing the rewarding effects of food. Recent data have also demonstrated some involvement of GLP receptors in the activity of abused drugs. For example, exendin-4, a GLP-1 analogue, was found to attenuate the rewarding effect of amphetamine, cocaine and nicotine in mice (Egecioglu et al., 2013a, 2013b; Graham et al., 2013) and decreased the cocaine uptake in mice in the self-administration test (Sørensen et al., 2015). Moreover, liraglutide, another GLP-1 analogue, reduced the rewarding effect of ethanol in the conditioned place preference (CPP) test in rats (Vallöf et al., 2016) and also prevented the development of ethanol tolerance to the anxiolytic effect in rats (Sharma et al., 2015). Furthermore, the activation of GLP-1 receptors attenuated the cocaine seeking behaviors in rats (Hernandez et al., 2018).
Since the relationship between GLP-1 receptors and morphine dependence was not fully explored, the major purpose of the reported study was to investigate the significance of linagliptin, a selective DPP-4 inhibitor, in the rewarding effect of morphine in rats. The morphine rewarding effect was studied via the CPP test in several paradigms: the expression, acquisition, extinction and reinstatement of morphine rewarding effect. The experiments significantly improved our knowledge on the role of GLP-1 receptors in the morphine rewarding effect in particular and in morphine dependence in general.
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Animals
The experiments were performed on male Wistar rats (160–200 g). The animals were fed a standard pelleted diet of Murigran (Agropol, Poland) and provided with water ad libitum. During the experiments, six to eight animals were kept per cage at room temperature of 22 ± 1 °C and exposed to a normal day/night cycle. All the experiments were carried out between 8:00 a.m. and 5:00 p.m. The study was performed, according to the National Institute of Health Guidelines for the Care and Use of Laboratory
Effects of linagliptin (10 and 20 mg/kg, i.p.) on the expression of morphine-induced CPP in the experimental rats
Two-way ANOVA revealed a significant effect of the drug (F1,49 = 5.164, P = 0.0275) and interaction (F2,49 = 5.153, P = 0.0093). The post-hoc analysis (Tukey's test) showed that the animals had spent significantly more time at the morphine-paired compartment on the post-test day, as compared to the 0.9% NaCl control group (P < 0.01). A single injection of linagliptin in both doses statistically significantly inhibited the expression of morphine-induced CPP (both doses P < 0.05). Both doses of
Discussion
The major result of the reported experiments was that linagliptin, the selective DPP-4 inhibitor, reduced the morphine rewarding effect in rats. That effect was observed in several paradigms of the CPP test. In the first step of our study, we demonstrated that linagliptin significantly suppressed both the expression and the acquisition of morphine-induced CPP in the rats. Regarding the acquisition of morphine-induced place preference, the attenuating effect of linagliptin was, however, observed
Funding
The reported study was supported by the Statutory Activity Fund of Medical University of Lublin in Poland (MNsd 6).
Author statement
Małgorzata Łupina: Data curation, Investigation, Methodology, Funding acquisition, Resources, Wiriting – original draft, Sylwia Talarek Software, Writing - original draft, Jolanta Kotlińska Supervision, Writing – review & editing, Ewa Gibuła-Tarłowska Validation, Writing - original draft, Piotr Listos Project administration, Visualisation, Joanna Listos: Conceptualization, Formal analysis, Writing - original draft, Writing – review & editing.
Declaration of competing interest
The authors declare no conflict of interest.
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