Direct inhibition by cannabinoids of human 5-HT(3A) receptors: probable involvement of an allosteric modulatory site

1. Excised outside-out patches from HEK293 cells stably transfected with the human (h) 5-HT(3A) receptor cDNA were used to determine the effects of cannabinoid receptor ligands on the 5-HT-induced current using the patch clamp technique. In addition, binding studies with radioligands for 5-HT(3) as well as for cannabinoid CB(1) and CB(2) receptors were carried out. 2. The 5-HT-induced current was inhibited by the following cannabinoid receptor agonists (at decreasing order of potency): Δ(9)-THC, WIN55,212-2, anandamide, JWH-015 and CP55940. The WIN55,212-2-induced inhibition was not altered by SR141716A, a CB(1) receptor antagonist. WIN55,212-3, an enantiomer of WIN55,212-2, did not affect the 5-HT-induced current. 3. WIN55,212-2 did not change the EC(50) value of 5-HT in stimulating current, but reduced the maximum effect. 4. The CB(1) receptor ligand [(3)H]-SR141716A and the CB(1)/CB(2) receptor ligand [(3)H]-CP55940 did not specifically bind to parental HEK293 cells. In competition experiments on membranes of HEK293 cells transfected with the h5-HT(3A) receptor cDNA, WIN55,212-2, CP55940, anandamide and SR141716A did not affect [(3)H]-GR65630 binding, but 5-HT caused a concentration dependent-inhibition. 5. In conclusion, cannabinoids stereoselectively inhibit currents through recombinant h5-HT(3A) receptors independently of cannabinoid receptors. Probably the cannabinoids act allosterically at a modulatory site of the h5-HT(3A) receptor. Thus the functional state of the receptor can be controlled by the endogenous ligand anandamide. This site is a potential target for new analgesic and antiemetic drugs

Does Pharmacogenomics Account for Variability in Control of Acute Chemotherapy-Induced Nausea and Vomiting with 5-Hydroxytryptamine Type 3 Receptor Antagonists?

Chemotherapy-induced nausea and vomiting is one of the most concerning adverse drug effects from cytotoxic chemotherapy. Despite appropriate use of antiemetic guidelines, 20–30% of patients experience breakthrough nausea and vomiting secondary to chemotherapy. To assess the variability of 5-hydroxytryptamine type 3 receptor antagonist efficacy caused by genetic variation, a review of the available literature was conducted. From the literature, three sources of pharmacogenomic variability were identified: polymorphisms associated with 5-hydroxytryptamine type 3 receptor subunits, drug metabolism via cytochromes P450, and drug transport in the body. Testing for receptor subunit polymorphisms is not applicable to a clinical setting at this time; however, cytochrome P450 2D6 testing is FDA-approved and widely accessible. Cytochrome P450 2D6 ultrarapid metabolizers and poor metabolizers displayed altered antiemetic efficacy when compared with intermediate metabolizers and extensive metabolizers. We postulate that testing for cytochrome P450 2D6 phenotypes may be the most accessible way to provide individualized antiemetic therapy in the future

Clinical and Experimental Human Sleep-Wake Pharmacogenetics

Sleep and wakefulness are highly complex processes that are elegantly orchestrated by fine-tuned neurochemical changes among neuronal and non-neuronal ensembles, nuclei, and networks of the brain. Important neurotransmitters and neuromodulators regulating the circadian and homeostatic facets of sleep-wake physiology include melatonin, γ-aminobutyric acid, hypocretin, histamine, norepinephrine, serotonin, dopamine, and adenosine. Dysregulation of these neurochemical systems may cause sleep-wake disorders, which are commonly classified into insomnia disorder, parasomnias, circadian rhythm sleep-wake disorders, central disorders of hypersomnolence, sleep-related movement disorders, and sleep-related breathing disorders. Sleep-wake disorders can have far-reaching consequences on physical, mental, and social well-being and health and, thus, need be treated with effective and rational therapies. Apart from behavioral (e.g., cognitive behavioral therapy for insomnia), physiological (e.g., chronotherapy with bright light), and mechanical (e.g., continuous positive airway pressure treatment of obstructive sleep apnea) interventions, pharmacological treatments often are the first-line clinical option to improve disturbed sleep and wake states. Nevertheless, not all patients respond to pharmacotherapy in uniform and beneficial fashion, partly due to genetic differences. The improved understanding of the neurochemical mechanisms regulating sleep and wakefulness and the mode of action of sleep-wake therapeutics has provided a conceptual framework, to search for functional genetic variants modifying individual drug response phenotypes. This article will summarize the currently known genetic polymorphisms that modulate drug sensitivity and exposure, to partly determine individual responses to sleep-wake pharmacotherapy. In addition, a pharmacogenetic strategy will be outlined how based upon classical and opto-/chemogenetic strategies in animals, as well as human genetic associations, circuit mechanisms regulating sleep-wake functions in humans can be identified. As such, experimental human sleep-wake pharmacogenetics forms a bridge spanning basic research and clinical medicine and constitutes an essential step for the search and development of novel sleep-wake targets and therapeutics