Dopamine receptors in emesis: Molecular mechanisms and potential therapeutic function

• Published in: Pharmacological research Vol. 161; p. 105124
• Main Authors: Belkacemi, Louiza, Darmani, Nissar A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-11-2020
• Subjects: Benzamides; Biased GPCRs signaling; Dopamine subtypes; Intracellular emetic signals; Parkinson’s disease; Phenothiazines; AADC; CNTF; Ras; Dopamine subtypes; Akt/PKB; 6-OHDA; COMT; GRKs; PI3K; mTOR; NK1R; PMNT; PKA; PKC; MAPK; SERCA; ER; 5-HT3R; MEK; NE; ROS; GABA; PIP3; MAO; Biased GPCRs signaling; PIP2; PP1, PP2A, or PP2B; TKRs; TRVP1; Arr; HIAA; SER; IP3R; CNS; DARPP-32; GSK-3; RyR; LTCC; cAMP; Th34; GPCRs; PDK; L-DOPA; ERK1/2 or p44ERK and p42ERK; DOPAC; Phenothiazines; DAG; IP3; PLCβ; ALDH; HVA; CaMKII; Ca2; Intracellular emetic signals; PDGF; Raf; Benzamides; PL; Parkinson’s disease
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2020.105124

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•Dopamine has diverse physiological functions.•Dopamine deficits or surfeits result in severe pathological conditions.•Dopamine D2/3 receptor agonist therapy can lead to side-effects including emesis.•Potential dopamine receptor-mediated intracellular emetic signals are discussed.•Antiemetic use of current dopamine antagonists and potential signal biased therapies are reviewed.
Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely linked to neurological disorders such as schizophrenia, Parkinson’s disease, depression, attention deficit–hyperactivity, and restless leg syndrome. Unfortunately, several dopamine receptor-based agonists used to treat some of these diseases cause nausea and vomiting as impending side-effects. The high degree of cross interactions of dopamine receptor ligands with many other targets including G-protein coupled receptors, transporters, enzymes, and ion-channels, add to the complexity of discovering new targets for the treatment of nausea and vomiting. Using activation status of signaling cascades as mechanism-based biomarkers to foresee drug sensitivity combined with the development of dopamine receptor-based biased agonists may hold great promise and seems as the next step in drug development for the treatment of such multifactorial diseases. In this review, we update the present knowledge on dopamine and dopamine receptors and their potential roles in nausea and vomiting. The pre- and clinical evidence provided in this review supports the implication of both dopamine and dopamine receptor agonists in the incidence of emesis. Besides the conventional dopaminergic antiemetic drugs, potential novel antiemetic targeting emetic protein signaling cascades may offer superior selectivity profile and potency.