Navigating the duality of opioids' potent analgesia and side effects, including tolerance and hyperalgesia, is a significant challenge in chronic pain management, often prompting hazardous dose escalation to maintain analgesic effects. The peripheral mu-opioid receptor (MOR) is known to mediate these contradictory effects. Here, we show that the fms-like tyrosine kinase receptor 3 (FLT3) in peripheral somatosensory neurons drives morphine tolerance and hyperalgesia in a male rodent model.
View Article and Find Full Text PDFBefore 1990, the multiplicity of dopamine receptors beyond D1 and D2 had remained a controversial concept, despite its substantial clinical implications, at a time when it was widely accepted that dopamine interacted with only two receptor subtypes, termed D1 and D2, differing one from the other by their pharmacological specificity and opposite effects on adenylyl cyclase. It was also generally admitted that the therapeutic efficacy of antipsychotics resulted from blockade of D2 receptors. Thanks to molecular biology techniques, the D3 receptor could be characterized as a distinct molecular entity having a restricted anatomical gene expression and different signaling, which could imply peculiar functions in controlling cognitive and emotional behaviors.
View Article and Find Full Text PDFInhibiting receptor tyrosine kinases is commonly achieved by two main strategies targeting either the intracellular kinase domain by low molecular weight compounds or the extracellular ligand-binding domain by monoclonal antibodies. Identifying small molecules able to inhibit RTKs at the extracellular level would be highly desirable to gain exquisite selectivity but is believed to be challenging owing to the size of RTK endogenous ligands (cytokines, growth factors) and the topology of RTK extracellular domains. We here report the high-throughput screening of the French Chemical Library (48K compounds) for extracellular inhibitors of the Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase, by a homogeneous time-resolved fluorescence competition assay.
View Article and Find Full Text PDFF17464 (N-(3-{4-[4-(8-Oxo-8H-[1,3]-dioxolo-[4,5-g]-chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide, hydrochloride) is a new potential antipsychotic with a unique profile. The compound exhibits high affinity for the human dopamine receptor subtype 3 (hD) (K = 0.17 nM) and the serotonin receptor subtype 1a (5-HT) (K = 0.
View Article and Find Full Text PDFRationale: F17464, a dopamine D3 receptor antagonist with relatively high D3 selectivity (70 fold vs D2 in vitro), exhibits an antipsychotic profile in preclinical studies, and therapeutic efficacy was demonstrated in a randomized placebo-controlled clinical trial in patients with schizophrenia (Bitter et al. Neuropsychopharmacology 44(11):1917-1924, 2019).
Objective: This open-label study in healthy male subjects aimed at characterizing F17464 binding to D3/D2 receptors and the time course of receptor occupancy using positron emission tomography (PET) imaging with a D3-preferring tracer, [C]-(+)-PHNO.
F17464, a highly potent preferential D3 antagonist, is a novel compound in development for schizophrenia treatment. This phase II, double-blind, randomized, placebo-controlled, parallel-group study in five European countries evaluated the efficacy and safety of F17464, 20 mg twice daily, versus placebo over 6 weeks in patients with acute exacerbation of schizophrenia. Change from baseline to Day 43 of the Positive and Negative Syndrome Scale (PANSS) total score was the primary outcome.
View Article and Find Full Text PDFPeripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve injury site express the cytokine FL, the ligand of fms-like tyrosine kinase 3 receptor (FLT3). FLT3 activation by intra-sciatic nerve injection of FL is sufficient to produce pain hypersensitivity, activate PNP-associated gene expression and generate short-term and long-term sensitization of sensory neurons.
View Article and Find Full Text PDFThis review updates the existing knowledge suggesting a role for the D3 receptor in schizophrenia and drug addiction. The D3 receptor is expressed in brain regions controlling reward, emotions, and motivation. Antipsychotics bind in vitro to the D3 receptor with similar affinity as to the D2 receptor, and occupancy of D3 receptors in vivo by these compounds given acutely at clinical dosage have been demonstrated in Positron Emission Tomography (PET) studies.
View Article and Find Full Text PDFGPR88 is a neuronal cerebral orphan G-protein-coupled receptor (GPCR) that has been linked to various psychiatric disorders. However, no extensive description of its localization has been provided so far. Here, we investigate the spatiotemporal expression of the GPR88 in prenatal and postnatal rat tissues by using in situ hybridization and immunohistochemistry.
View Article and Find Full Text PDFPalmitoylation is involved in several neuropsychiatric and movement disorders for which a dysfunctional signaling of the dopamine D3 receptor (Drd3) is hypothesized. Computational modeling of Drd3's homologue, Drd2, has shed some light on the putative role of palmitoylation as a reversible switch for dopaminergic receptor signaling. Drd3 is presumed to be palmitoylated, based on sequence homology with Drd2, but the functional attributes afforded by Drd3 palmitoylation have not been studied.
View Article and Find Full Text PDFThe dopamine D3 receptor is located in the limbic area and apparently mediates selective effects on motivation to take drugs and drug-seeking behaviors, so that there has been considerable interest on the possible use of D3 receptor ligands to treat drug addiction. However, only recently selective tools allowing studying this receptor have been developed. This chapter presents an overview of findings that were presented at a symposium on the conference Dopamine 2013 in Sardinia in May 2013.
View Article and Find Full Text PDFBackground: GABAA receptor (GABAAR) function is maintained by an endogenous phosphorylation mechanism for which the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is the kinase. This phosphorylation is specific to the long intracellular loop I2 of the α1 subunit at two identified serine and threonine residues. The phosphorylation state is opposed by an unknown membrane-bound phosphatase, which inhibition favors the phosphorylated state of the receptor and contributes to the maintenance of its function.
View Article and Find Full Text PDFNaunyn Schmiedebergs Arch Pharmacol
February 2013
This article, based on original data as well as on previously reported preclinical and clinical data that are reviewed, describes direct and indirect interactions of the D(3) receptor with N-methyl-D-aspartate receptor (NMDA) signaling and their functional consequences and therapeutic implications for schizophrenia. D(3) receptor immunoreactivity at ultrastructural level with electron microscopy was identified at presumably glutamatergic, asymmetric synapses of the medium-sized spiny neurons of the nucleus accumbens. This finding supports the existence of a direct interaction of the D(3) receptor with glutamate, in line with previously described interactions with NMDA signaling involving Ca(2+)/calmodulin-dependent protein kinase II at post-synaptic densities (Liu et al.
View Article and Find Full Text PDFWe have shown that the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is the kinase involved in the endogenous phosphorylation of the alpha1 subunit of the gamma-aminobutyric acid (GABA)(A) receptor (GABA(A)R), maintaining GABA(A)-R function. GABA(A)R endogenous phosphorylation is opposed by one or several atypical phosphatases. We have shown in addition, using cerebral tissue obtained during epilepsy surgery and control tissue from patients undergoing brain tumor surgery, that both endogenous phosphorylation and GABA(A)R function are significantly reduced in the "epileptogenic" cerebral cortex when compared to control.
View Article and Find Full Text PDFStudy Objective: Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine.
View Article and Find Full Text PDFWe developed a cellular Bioluminescent Resonance Energy Transfer (BRET) assay based on the interaction of TrkB fused to Renilla luciferase with the intracellular adaptor protein Shc fused to Enhanced Yellow Fluorescent Protein (EYFP). The TrkB agonist Brain Derived Neurotrophic Factor (BDNF) induced a maximum BRET signal as of 10 min with an EC(50) value of 1.4 nM, similar to the other endogenous agonists NT-3 and NT-4/5, 1.
View Article and Find Full Text PDFRationale: Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man).
Objectives: The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit.
Materials And Methods: In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine.
GPR88, an orphan G protein-coupled receptor, was designated Strg/GPR88 for striatum-specific G protein-coupled receptor (K. Mizushima et al. (2000)Genomics, 69, 314-321).
View Article and Find Full Text PDFMouse models of MPTP intoxication have been used extensively to explore the molecular mechanisms of Parkinson's disease. However, these models present some limitations since; (i) Dopaminergic (DA) cell death occurs rapidly in contrast to the presumably slow evolution of the disease process. (ii) Some of the key histological features of the disease such as Lewy body like inclusions and long-term inflammatory changes are lacking.
View Article and Find Full Text PDFEpidemiological evidence suggests that caffeine or its metabolites reduce the risk of developing Parkinson's disease, possibly by protecting dopaminergic neurons, but the underlying mechanism is not clearly understood. Here, we show that the primary metabolite of caffeine, paraxanthine (PX; 1, 7-dimethylxanthine), was strongly protective against neurodegeneration and loss of synaptic function in a culture system of selective dopaminergic cell death. In contrast, caffeine itself afforded only marginal protection.
View Article and Find Full Text PDFGrowing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus.
View Article and Find Full Text PDFA series of eight substituted N-(4-(4-(2-halogenophenyl)piperazin-1-yl)butyl)-3-phenylacryl amide derivatives have been synthesized and screened for binding affinities at dopamine hD(2) and hD(3) receptors. All compounds have shown high to remarkable receptor affinities and some have led to distinct selectivity for D(3) receptors. Highest D(3)-receptor affinity has been observed for 3-(4-aminophenyl)-N-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)acryl amide (hD(3) K(i) 0.
View Article and Find Full Text PDFExpert Opin Investig Drugs
January 2007
This review considers the potential use of the dopamine D(3) receptor (DRD3) as a novel therapeutic target for the treatment of tobacco dependence. Among the 5 dopamine receptors identified, the DRD3 is located in the nucleus accumbens, ventral tegmental area and amygdala: 3 brain structures that are implicated in the motivational control of drug-seeking behaviour and drug-conditioning processes. Although it has been proposed that modulating dopamine transmission would be effective in the treatment of drug dependence, no validation has been provided in humans so far.
View Article and Find Full Text PDFFamilial essential tremor (ET), the most common inherited movement disorder, is generally transmitted as an autosomal dominant trait. A genome-wide scan for ET revealed one major locus on chromosome 3q13. Here, we report that the Ser9Gly variant in the dopamine D(3) receptor gene (DRD3), localized on 3q13.
View Article and Find Full Text PDFNeuropharmacology
September 2005
Abused drugs (alcohol, heroin, cocaine, tetrahydrocannabinol and nicotine) elicit a variety of chronically relapsing disorders by interacting with brain reward systems. All of these drugs increase dopamine levels in the shell of nucleus accumbens, a structure that has been involved in their hedonic and reinforcing properties. Dopamine D(3) receptors (DRD3) are predominantly expressed in the nucleus accumbens, but also in the ventral tegmental area and in the amygdala, brain structures implicated in drug dependence.
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