Abstract
In view of the fact that GPR55 receptors are localized in brain areas implicated in the pathophysiology of depression, GPR55 gene expression is reduced in the dorsolateral prefrontal cortex of suicide victims, and GPR55 receptor agonism exerts an anxiolytic-like effect, GPR55 receptors have drawn our attention as a potential target in the treatment of mood disorders. Therefore, in the present study, we wanted to check whether a 7-day intravenous administration of O-1602 (0.25 mg/kg/day) – a phytocannabinoid-like analogue of cannabidiol that belongs to the agonists of GPR55 receptors, was able to reverse the corticosterone-induced depressive-like behavior accompanied by detrusor overactivity in female Wistar rats. Additionally, we tried to determine the influence of GPR55 stimulation on the bladder, hippocampal and urine levels of several biomarkers that play a role in the functioning of the urinary bladder and/or the pathophysiology of depression. Our experiments showed that O-1602 therapy improved signs of depression (measured by the forced swim test) and detrusor contractility (measured by conscious cystometry) in animals exposed to the corticosterone treatment. Moreover, the treatment reduced the oxidative damage in the urinary bladder and neuroinflammation (observed as the reduction of elevated levels of 3-NIT, MAL, and IL-1β, TNF-α, CRF, respectively). The O-1602 treatment also reversed the abnormal changes in the bladder, hippocampal or urine values of CGRP, OCT3, VAChT, BDNF, and NGF. The above-mentioned findings allow to suggest that in the future the modulation of atypical cannabinoid receptors GPR55 could have a potential role in the treatment of depression and overactive bladder.
Highlights
The endocannabinoid system as well as both exogenous and endogenous ligands of the cannabinoid receptors have attracted scientists’ attention for decades
It has been revealed that GPR55 receptors activate Gq and Ga12/13 proteins and affect different signaling pathways like calcium release from the intracellular stores and the signaling dependent on Rho kinase, small GTPases (RhoA, cdc42, rac1), nuclear factor kappa-lightchain-enhancer of activated B cells (NF-kB), nuclear factor of activated T-cells (NFAT), and cAMP response element binding (CREB) (Baker et al, 2006)
Bearing in mind the following facts: (1) localization of GPR55 receptors in the brain areas implicated in the pathophysiology of depression (Wu et al, 2013), (2) reduced GPR55 gene expression in the dorsolateral prefrontal cortex of suicide victims (GarciaGutierrez et al, 2018), and (3) anxiolytic-like effect of GPR55 receptor agonism (Rahimi et al, 2015; Shi et al, 2017), GPR55 receptors have drawn our attention as a potential target in the treatment of mood disorders
Summary
The endocannabinoid system as well as both exogenous and endogenous ligands of the cannabinoid receptors have attracted scientists’ attention for decades Apart from their noxious psychoactive properties, cannabinoids exert a variety of positive biological effects. They could be promising analgesic, antiinflammatory, anti-allergic, anti-emetic, antineoplastic, muscle relaxant, immunosuppressive, bronchodilator, sedative, and neuroprotective agents. GPR55 receptors are found in numerous cells and organs, such as the osteoclasts, cancer cells, liver, adrenal glands, spleen, small intestine, pancreas, lungs, and kidneys Their activity is associated with mechanisms of bone formation, glucose homeostasis, inflammatory response, neuropathic pain, angiogenesis, fetoplacental development, oncogenesis, and others (Alavi et al, 2018). Existence of GPR55 receptors has been detected in different parts of the brain, including the striatum, hippocampus, forebrain, cortex, and Abbreviations: 3-NIT, 3-nitrotyrosine; ANVC; amplitude of nonvoiding contractions; AUC, area under the pressure curve; BP, basal pressure; BC, bladder compliance; BDNF, brain-derived neurotrophic factor; CGRP, calcitonin gene related peptide; CREB, cAMP response element binding; CB receptor, cannabinoid receptor; CRF, corticotropin-releasing factor; DO, detrusor overactivity; DOI, detrusor overactive index; FST, forced swim test; FNVC, frequency of nonvoiding contractions; ICI, intercontraction interval; IL-1b, interleukin 1b; MAL, malondialdehyde; MVP, micturition voiding pressure; NGF, nerve growth factor; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NFAT, nuclear factor of activated T-cells; OCT3, organic cation transporter 3; PVR, postvoid residual; SEM, standard error of the mean; TP, threshold pressure; TNF-a, tumor necrosis factor a; VAChT, vesicular acetylcholine transporter; VV, voided volume; VTNVC, volume threshold to elicit nonvoiding contractions
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