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Renal, Cardiovascular, and Pulmonary Functions of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
In addition to DA biosynthesis, expression and functions of the DA receptors are also affected by diabetes. Obese Zucker rats, serving as a model of obesity-related diabetes, are hyper-insulinemic, hyperglycemic, and hypertensive compared with lean rats [36]. DA produced a concentration-dependent inhibition of Na/K‐ATPase activity in the proximal tubules of lean rats, but its inhibitory effect was reduced in obese rats. The D1-like receptors in the basolateral membranes of obese rats showed a 45% decrease in B(max) without a change in K(d) compared with lean rats. DA and SKF 38393 (a D1/D5 agonist) failed to stimulate G proteins in obese rats, suggesting a receptor–G protein coupling defect. It was concluded that a decrease in D1-like receptor binding sites and diminished activation of G proteins, resulting from defective coupling to the receptor, led to the reduced inhibition by DA of Na/K‐ATPase activity in the proximal tubules of obese Zucker rats. Such a defect in renal DAR function may contribute to sodium retention and development of hypertension in obese rats.
Istradefylline, an adenosine A2a receptor antagonist, inhibits the CD4+ T-cell hypersecretion of IL-17A and IL-8 in humans
Published in Immunological Medicine, 2022
Mieko Tokano, Masaaki Kawano, Rie Takagi, Sho Matsushita
Neutrophilic inflammation is associated with many diseases [16], including autoimmune diseases [17–26], neutrophilic airway inflammation [27,28], psoriasis [29,30], and severe atopic dermatitis [31]. There are currently no specific therapies using low-molecular-weight chemicals for neutrophilic inflammation; nevertheless, corticosteroids have proven effective for eosinophilic inflammation. However, recent studies by ourselves and others have suggested that dopamine D1-like receptor antagonists and dopamine D2-like receptor agonists suppress neutrophilic inflammation by suppressing Th17 differentiation and activation [32–34].
Dopaminergic and glutamatergic biomarkers disruption in addiction and regulation by exercise: a mini review
Published in Biomarkers, 2022
Muhammad Abdullah, Li-Chung Huang, Shih-Hsien Lin, Yen Kuang Yang
Addictive substances change the expression level or density of dopamine receptors. Dopamine receptors are G-protein coupled receptors containing stimulatory D1-like (D1, D5) and inhibitory D2-like (D2, D3, D4) receptors (Hou et al.2012). As the D1-like receptor and its family and the D2-like family behave differently, discussion in this review paper focuses mainly on D1 and D2 receptors. However, due to the particular interest of addiction scientists and the current surge in research into medicinal agents targeting D3 receptors for the treatment of drug addiction (Maramai et al.2016, de Guglielmo et al. 2020), the role of D3 receptors is also discussed. D1 and D2 receptors exhibit segregation in terms of their effects via so called ‘Direct and Indirect Pathways’. The D2 receptor is considered a negative modulator of drug addiction, that acts via the indirect pathway, the ‘no-go pathway’ (Volkow and Morales 2015, Yager et al.2015). D2 receptor downregulation has been reported in imaging studies of a wide variety of addictions including, substance addiction (Baik 2013), behavioural addiction (Kim et al.2011) and food addiction (obesity) (Wang et al.2001). Via imaging of brain D2 receptors, Volkow et al. were the first to report downregulation (Volkow et al.1990), with consistent outcomes in cocaine addicts in later studies (Volkow et al.1990, 1997, Martinez et al.2011). Other drugs, such as opioids, alcohol, methamphetamine (Trifilieff and Martinez 2014) and nicotine (Trifilieff and Martinez 2014, Okita et al.2016) follow a similar pattern. Contrarily, the association of the D1 receptor expression with addiction has not been explored as thoroughly. One imaging study of cocaine abusers showed a negative association (r = −0.47) of D1 receptor density with cocaine choices, but the density was not different from the health control group (Martinez et al.2009). Similarly, a recent study by Okita et al. also did not find any difference in the D1 receptor density between methamphetamine addicts and health control group, but the receptor density was negatively associated with cortical gray-matter thickness in methamphetamine addicts (Okita et al.2018). However, animal studies of binge and chronic cocaine administration have demonstrated increased expressions of D1 receptors at the mRNA and protein levels in the reward circuit and other brain regions (Kuzhikandathil 2017).
Genetic and epigenetic mechanisms influencing acute to chronic postsurgical pain transitions in pediatrics: Preclinical to clinical evidence
Published in Canadian Journal of Pain, 2022
Adam J. Dourson, Adam Willits, Namrata G.R. Raut, Leena Kader, Erin Young, Michael P. Jankowski, Vidya Chidambaran
Given difficulties in developing large genetic data banks with well-characterized CPSP phenotypes in children, leveraging systems biology may offer an alternative strategy to overcome sample size limitations.174 Integrating genetic-level data with biologic processes can generate prioritized candidate gene lists. Chidambaran et al. demonstrated the utility of functional annotation–based prioritization and enrichment approaches to identify novel genes and unique/shared biological processes in acute and chronic postoperative pain.175 Certain molecular mechanisms were elucidated to be common to acute and CPSP (e.g., CREB phosphorylation, ion channels, N-methyl-d-aspartate). Certain other genetic processes played a role in CPSP but not acute pain. These included immune/inflammatory (Toll-like receptor signaling, interferon gamma signaling, cytokines, mitogen-activated protein kinase/extracellular signal–regulated protein kinase signaling) and neurotransmitter-involved processes (purinergic, oxytocin, GABA, glutaminergic, catecholaminergic, dopaminergic). Despite the findings mostly being in adult studies, some of the pathways may be pertinent to pediatric populations, based on clinical and preclinical evidence. Several genes are common to immune, dopaminergic, serotoninergic, and catecholamine pathways (described in Table 1). The latter three are also known to be involved in psychological disorders176 implicated in the chronification of pain in children. For example, genes involved in dopaminergic neurotransmission (catechol-O-methyl transferase [COMT], GTP cyclohydrolase 1 [GCH1], and dopamine receptor [DRD2]) have different mechanisms.177GCH1 is involved in the production of BH4, a key molecule in the synthesis of dopamine, and variants (rs841) decrease GCH1 expression and are generally protective in chronic pain.178COMT is involved in degradation of dopamine and other catecholamines with key roles in chronic pain.179 Its variants rs4680 and rs165774 decrease its enzymatic activity, increase catecholamine availability, and alter the signaling cascade. The dopaminergic receptors (D1-like receptor [D1LR] family [includes D1 and D5 receptors, which are stimulatory] and D2-like receptor [D2LR] family [consisting of D2, D3, and D4 receptors, which are inhibitory]) have opposite effects on nociceptive transmission. Variant rs6277 located in DRD2 decreases the stability of mRNA, thereby decreasing the expression of the D2 receptor, and increases CPSP risk.180,181 This pathway in modulation of nociception after surgery thus presents excellent targets for prevention and treatment of CPSP.182–184