Effect of cannabinoid-serotonin interactions in the regulation of neuropeptide Y1 receptors expression in rats: the role of CB1 and 5-HT2C receptor

Neuropeptide Y (NPY) is involved in a diversity of critical functions such as circadian rhythms, energy homeostasis, and appetite regulation in the hypothalamus. It has identified as a crucial participant in adjusting energy intake and energy storage as fat via central neuropeptide Y1 receptor (NPY1R), leading to obesity and metabolic disorders. The present study was expected to investigate the interaction between 2-AG (CB1R agonist), m-CPP (5HT2CR agonist), SB-242084 (5HT2CR antagonist), and SR-141716A (CB1R antagonist) by mediating through the NPY1R for treating or preventing obesity, metabolic disorders, and other abnormalities. The expression level of NPY1R mRNA has studied on the rat brain by real-time quantitative PCR assay. Based on our findings, intracerebroventricular (ICV) injection of combined 2-AG (1 μg) + m-CPP (2.5 μg) has antagonistic interaction in the expression of the NPY1R gene (P < 0.001). Moreover, the ICV co-injection of SB-242084 (3 μg) + SR-141716A (1 μg) has antagonistic interaction in the NPY1R gene expression (P < 0.001). Co-administration of 2-AG (1 μg) + SB-242084 (3 μg) amplified NPY1R gene expression (P < 0.001), while the ICV co-injection of m-CPP (2.5 μg) + SR-141716A (1 μg) decreased NPY1R gene expression in the hypothalamus (P < 0.001). These results revealed the interference in cannabinoid and serotonergic systems via CB1 and 5HT2C receptors in the expression of NPY1R mRNA in the hypothalamic area of rats.

Subchronic Central Administration of Cannabinoid Ligands Modulates Nociception in Bulbectomized Rats

Introduction: Endocannabinoid system is involved in neuropsychiatric disorders such as major depression. The bilaterally olfactory bulbectomized rat is widely used as an animal model of depression. The removal of the olfactory bulbs produces behavioural, physiological, and neurochemical alterations resembling clinical depression. There is increasing evidence that highlights the important role of cannabinoid signalling in depression and nociception. Aim: To investigate the effect of CB1 receptor agonist HU 210 and CB1 receptor antagonist SR 141716A administered icv subchronically (for 7 days) on nociception of rats with model of depression - bilateral olfactory bulbectomy (OBX). Material and methods: Experimental model of depression - bilateral olfactory bulbectomy (OBX). Bilaterally olfactory bulbectomized rats were used as an experimental model of depression. HU 210 (5 &micro;g) or SR 141716A (3 &micro;g) were infused icv for 7 consecutive days, starting 15 days after the olfactory bulbectomy. Nociception was examined by applying paw pressure test (analgesy-meter) evaluating the rat pain threshold. On day 7, five minutes after the last microinjection, the rats were tested in an analgesy-meter and their mechanically evoked pain responses were measured in arbitrary units (AU). Results: Microinjections of HU 210 (5 &micro;g) significantly decreased the pain threshold in olfactory bulbectomized rats, while SR 141716A (3 &micro;g) exerted antinociceptive effect by increasing the pain threshold. Conclusions: Data point to an involvement of CB1 receptors in depression-like behaviour and nociception in olfactory bulbectomized rats and support the data for the association between depressive disorder and pain pathways.

Effect of CB1 Ligands on Neurogenic and Myogenic Contractile Responses in the Guinea-Pig Ileum

This study aimed at investigating whether the synthetic cannabinoid receptor agonist (+)-WIN 55212-2 has neurogenic and myogenic relaxant effects on the longitudinal muscle-myenteric plexus (LMMP) strip of the guinea-pig ileum. (+)-WIN 55212-2, 1–1,000 nmol/L, concentration-dependently inhibited both the electrical stimulation-induced cholinergic twitch responses as well as the myogenic smooth muscle contractions in the LMMP preparation. SR-141716A (rimonabant) 1–1,000 nmol/L, the cannabinoid CB1 receptor antagonist, being without effect on its own, antagonized the (+)-WIN 55212-2-induced effects. The allyl isothiocyanate (mustard oil, 100 µmol/L) induced a relaxant effect in the guinea-pig ileum, which can be regarded as neurogenic and myogenic, was augmented by (+)-WIN 55212-2, and inhibited by SR-141716A. (+)-WIN 55212-2 only moderately modified the 60 mmol/L KCl-evoked contractions. These results provide functional evidence that the CB1 agonist (+)-WIN 55212-2-induced inhibitory effects in the guinea-pig ileum are exerted both at the neuronal as well as at the intestinal smooth muscle cell level.