Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats

Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB1, CB2, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoyle

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors

Background: Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow. Methods: Pithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure. Results: DHE inhibited the vasodepressor responses to electrical stimulation (0.56–5.6 Hz), without affecting those to i.v. α-CGRP (0.1–1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-like; 310 μg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses. Conclusion: DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE’s vasoconstrictor properties resulting in an increased vascular resistance

The oncogenic lysophosphatidylinositol (LPI)/GPR55 signaling

GPR55 is a class A orphan G protein-coupled receptor that has drawn important therapeutic attention in the last decade because of its role in pathophysiological processes including vascular functions, metabolic dysfunction, neurodegenerative disorders, or bone turnover among others. Several cannabinoids of phytogenic, endogenous, and synthetic nature have shown to modulate this receptor leading to propose it as a member of the endocannabinoid system. The putative endogenous GPR55 ligand is L-α-lysophosphatidylinositol (LPI) and it has been associated with several processes that control cell survival and tumor progression. The relevance of GPR55 in cancer is currently being extensively studied in vitro and in vivo using diverse cancer models. The LPI/GPR55 axis has been reported to participate in pro-oncogenic processes including cellular proliferation, differentiation, migration, invasion, and metastasis being altered in several cancer cells via G and G signaling. Moreover, GRP55 and its bioactive lipid have been proposed as potential biomarkers for cancer diagnosis. Indeed, GPR55 overexpression or high expression has been shown to correlate with cancer aggressiveness in specific tumors including acute myeloid leukemia, uveal melanoma, low grade glioma and renal cancer. This review aims to analyze and summarize current evidence on the cancerogenic role of the LPI/GPR55 axis providing a critical view of the therapeutic prospects of this promising target.BAM-C were supported by the Direcci ́on General de Investigaci ́on y Posgrado from the Autonomous University of Aguascalientes (grant PIFF21-1

Potential metabolic and behavioural roles of the putative endocannabinoid receptors gpr18, gpr55 and gpr119 in feeding

Endocannabinoids are ancient biomolecules involved in several cellular (e.g., metabo-lism) and physiological (e.g., eating behaviour) functions. Indeed, eating behaviour alterations in marijuana users have led to investigate the orexigenic/anorexigenic effects of cannabinoids in ani-mal/human models. This increasing body of research suggests that the endocannabinoid system plays an important role in feeding control. Accordingly, within the endocannabinoid system, cannabinoid receptors, enzymes and genes represent potential therapeutic targets for dealing with multiple metabolic and behavioural dysfunctions (e.g., obesity, anorexia, etc.). Paradoxically, our understanding on the endocannabinoid system as a cellular mediator is yet limited. For example: (i) only two cannabinoid receptors have been classified, but they are not enough to explain the pharmacological profile of several experimental effects induced by cannabinoids; and (ii) several orphan G protein-coupled receptors (GPCRs) interact with cannabinoids and we do not know how to classify them (e.g., GPR18, GPR55 and GPR119; amongst others). On this basis, the present review attempts to summarize the lines of evidence supporting the potential role of GPR18, GPR55 and GPR119 in metabolism and feeding control that may explain some of the divergent effects and puzzling data related to cannabinoid research. Moreover, their therapeutic potential in feeding behaviour alterations will be considered