GPR55 and GPR119 Receptors Contribute to the Processing of Neuropathic Pain in Rats

Orphan G-protein-coupled receptors (GPCR) comprise a large number of receptors which are widely distributed in the nervous system and represent an opportunity to identify new molecular targets in pain medicine. GPR55 and GPR119 are two orphan GPCR receptors whose physiological function is unclear. The aim was to explore the participation of spinal GPR55 and GPR119 in the processing of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Protein localization and modulation were measured by immunohistochemistry and western blotting, respectively. Intrathecal administration of CID16020046 (selective GPR55 antagonist) or AS1269574 (selective GPR119 agonist) produced a dose-dependent antiallodynic effect, whereas O1062 (GPR55 agonist) and G-protein antagonist peptide dose-dependently prevented the antiallodynic effect of CID16020046 and AS1269574, respectively. Both GPR55 and GPR119 receptors were expressed in spinal cord, dorsal root ganglia and sciatic nerve, but only GPR119 was downregulated after 14 days of spinal nerve ligation. Data suggest that GPR55 and GPR119 participate in the processing of neuropathic pain and could be useful targets to manage neuropathic pain disorders.

Influence of novel GPR119 agonist in combination with metformin and sitagliptin on glycemia, body weight and food intake in rats fed a high-fat diet

BACKGROUND: Metabolic syndrome and obesity are often precursors of type 2 diabetes mellitus (DM), and current recommendations indicate the advisability of early initiation of drug therapy at the stage of prediabetes. Drugs with incretin activity are one of the priority groups for monotherapy of type 2 diabetes in the onset of the disease, and certain drugs are used to treat obesity. GPR119 agonists increase the secretion of endogenous incretins, and their effectiveness in the treatment of type 2 diabetes and obesity in mono- and combination therapy is currently being actively studied. AIM. To evaluate of the effect of administration of a GPR119 receptor agonist, its combination with metformin or sitagliptin on body weight, food intake and glycemia in rats under a high-calorie diet. MATERIALS AND METHODS: The study was conducted on 56 outbred female rats aged 78 months and an initial weight of 305320 g. Compound ZB-16 is a highly active GPR119 receptor agonist (EC50 = 7 nM). For 12 weeks, the animals were kept on a high-fat and carbohydrate diet and at the same time received the compound ZB-16, metformin and sitagliptin, or its combination (ZB-16 + metformin and ZB-16 + sitagliptin). During the experiment, the weight of the animals, the mass of feed eaten, as well as the level of glycemia after 6 hours of fasting and with an oral glucose load were assessed. RESULTS: In animals of the control group that were on a high-calorie and fatty diet for 12 weeks, an increase in body weight, glycemia and a decrease in the rate of glucose utilization were observed. The introduction of the GPR119 agonist (ZB-16) for 12 weeks led to a significant reduction in the amount of food consumed, limited weight gain and prevented the development of carbohydrate metabolism disorders. The addition of sitagliptin and especially metformin to therapy with the GPR119 agonist significantly increased the effectiveness of therapy compared to the control group, which was expressed in the normalization of animal body weight and glycemia (p 0.05). CONCLUSIONS: The introduction of a combination of the GPR119 agonist (compound ZB-16) with metformin and sitagliptin is more effective than monotherapy in terms of weight gain, food intake, and also prevents the development of carbohydrate metabolism disorders in animals when kept on a high-fat and carbohydrate diet.

WITHDRAWN AS DUPLICATE: Non-invasive evaluation of GPR119 agonist effects on β-cell mass in diabetic male mice using 111In-exendin-4 SPECT/CT

This article was originally published as https://doi.org/10.1210/en.2019-00556.