Agonist RS Research Articles

Sigma-1 receptor targeting inhibits connexin 43 based intercellular communication in chronic neuropathic pain.

Neuropathic pain is a chronic condition characterized by aberrant signaling within the somatosensory system, affecting millions of people worldwide with limited treatment options. Herein, we aim at investigating the potential of asigma-1 receptor (σ1R) antagonist in managing neuropathic pain. A Chronic Constriction Injury (CCI) model was used to induce neuropathic pain. The potential of (+)-MR200 was evaluated following daily subcutaneous injections of the compound. Its mechanism of action was confirmed by administration of a well-known σ1R agonist, PRE084. (+)-MR200 demonstrated efficacy in protecting neurons from damage and alleviating pain hypersensitivity in CCI model. Our results suggest that (+)-MR200 reduced the activation of astrocytes and microglia, cells known to contribute to the neuroinflammatory process, suggesting that (+)-MR200 may not only address pain symptoms but also tackle the underlying cellular mechanism involved. Furthermore, (+)-MR200 treatment normalized levels of the gap junction(GJ)-forming protein connexin 43 (Cx43), suggesting a reduction in harmful intercellular communication that could fuel the chronicity of pain. This approach could offer a neuroprotective strategy for managing neuropathic pain, addressing both pain symptoms and cellular processes driving the condition. Understanding the dynamics of σ1R expression and function in neuropathic pain is crucial for clinical intervention.

WLB-87848, a Selective σ1 Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity.

The synthesis and pharmacological activity of a new series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as sigma-1 receptor (σ1R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1R agonist (14qR) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1R association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.

Synthesis of Fentanyl Triazole Derivatives and their Affinity for Mu-Opioid and Sigma-1 Receptors

The search for compounds with affinity for both mu-opioid receptor (MOR) and sigma-1 receptor (σ1R) is one of the innovative directions to develop painkillers with reduced side effects. Additionally, triazole scaffolds have been extensively explored in the last two decades in medicinal chemistry. In this context, we synthesized a series of new triazole fentanyl derivatives and evaluated their affinity for both MOR and σ1R. The binding affinity of the compounds for human MOR was determined in competitive radioligand binding assays, using fentanyl as standard. For the assays with σ1R, a σ1R agonist (SKF10047) was employed. The most active analogue was 6d which moderately binds to MOR with half-maximal inhibitory concentrations (IC50) = 1.9 μM and to σ1R with IC50 = 6.9 μM. Molecular docking calculations were carried out, providing a structural elucidation for the observed values of affinity. Absorption, distribution, metabolism, and excretion toxicity (ADMET) parameters for the new compounds were simulated with the SwissADME tool

Anti-Anxiety Effects of Prelimbic 5-HT4 Receptors in the Rat Model of Parkinson’s Disease: Evidence from Behavioral and Electrophysiological Study

Objective: Clinical and laboratory studies have demonstrated that prelimbic (PrL) and serotonin-4 (5-HT4) receptors may have the key role in regulating anxiety. However, the pathophysiology of anxiety in Parkinson’s disease (PD) remains obscure. In this research, the effects of PrL 5-HT4 receptors on anti-anxiety behaviors in hemiparkinsonian rats were investigated. Methods: PD model rats were used as the research subjects, starting with behavioral changes, from the point of view of electrophysiology, the regulatory effect of PrL 5-HT4 receptors on PD-related anxiety and the possible mechanism were explored. Results: Anxiety-like behaviors were induced via MFB lesion in rats. Intra-PrL injection of 5-HT4 receptors agonist RS67333 induced anti-anxiety effects in both sham and PD group. In the sham group, PrL administration of 5-HT4 receptors antagonist SB204070 produce anti-anxiety effects, but in the PD group, the expression of anxiety-like behavior was increased. Compared to the sham group, the effective dose of the behavioral effects of the two drugs in the PD group was obviously higher. Electrophysiological data suggested that PrL administration of RS67333 (SB204070) increased (decreased) the ?ring activities of ?-aminobutyric acid (GABA) neurons in both groups. Compared with rats in sham group, lesioned rats had a shorter duration of the excitation (inhibition) effects on firing activities of GABA neurons. Conclusion: PrL 5-HT4 receptors regulate anxiety behaviors in PD rats, and its mechanism may be related to the down-regulation of expression or function of PrL 5-HT4 receptors in PD.

Activation of uroepithelial 5-HT4R inhibits mechanosensory activity of murine bladder afferent nerves.

Serotonin (5-HT) is known to act via multiple 5-HT receptors at spinal and supraspinal levels to regulate micturition. However, the contribution of peripheral 5-HT and its receptors in bladder physiology and pathology is not very well understood, despite evidence showing expression of multiple 5-HT receptors in the bladder wall and 5-HT may activate bladder afferent nerves. The current study was designed to investigate the possible role of 5-HT4R in modulation of the sensitivity of bladder afferents to bladder filling. Immunofluorescent staining showed abundant 5-HT4R immunoreactivity largely confined to the uroepithelium in wild type (WT) but not 5-HT4R−/− mice. In the ex vivo bladder-pelvic nerve preparation, intravesical application of the 5-HT4R agonist RS67333 (1–30 μm) caused concentration-dependent decreases of the pelvic nerve response to bladder filling. Such effect was not observed in the presence of 5-HT4R antagonist GR125487 or in 5-HT4R−/− preparations. A cohort of 5-HT4R−/− and WT control mice were treated with intraperitoneal injections of cyclophosphamide (CYP) (75 mg/kg, three times at 2 days interval) to induce chronic cystitis. Void spot analysis showed that CYP-treated 5-HT4R−/− mice urinated more frequently than their CYP-treated WT counterparts. Concomitantly, bladder afferents of CYP-treated 5-HT4R−/− mice displayed exaggerated sensitivity to bladder filling in comparison with the CYP-treated WT controls. These data suggest that 5-HT4R expressed on uroepithelial cells plays an inhibitory role in mechanosensory transduction in the bladder. Loss of 5-HT4R-mediated inhibition may enhance bladder afferent sensitivity and exacerbate bladder overactivity in pathological conditions. We propose that 5-HT4R agonists might be exploited for the treatment of overactive and painful bladder symptoms.

Benzylaminofentanyl derivates: Discovery of bifunctional μ opioid and σ1 receptor ligands as novel analgesics with reduced adverse effects

To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ1 receptor (σ1R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (Ki = 6.5 nΜ; EC50 = 48.5 nΜ, Emax = 66.3%) and σ1R antagonism (Ki = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED50 = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED50 = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED50 = 0.30 mg/kg, in mice). The contributions of MOR and σ1R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ1R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects—including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion—than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ1R ligands as a promising avenue for the development of potent and safe analgesics.

Lupeol protects against cardiac hypertrophy via TLR4-PI3K-Akt-NF-κB pathways.

Inflammation and apoptosis are main pathological processes that lead to the development of cardiac hypertrophy. Lupeol, a natural triterpenoid, has shown anti-inflammatory and anti-apoptotic activities as well as potential protective effects on cardiovascular diseases. In this study we investigated whether lupeol attenuated cardiac hypertrophy and fibrosis induced by pressure overload in vivo and in vitro, and explored the underlying mechanisms. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery, and in neonatal rat cardiomyocytes (NRCMs) by stimulation with phenylephrine (PE) in vitro. We showed that administration of lupeol (50 mg ·kg-1· d-1, i.g., for 4 weeks) prevented the morphological changes and cardiac dysfunction and remodeling in TAC mice, and treatment with lupeol (50 μg/mL) significantly attenuated the hypertrophy of PE-stimulated NRCMs, and blunted the upregulated hypertrophic markers ANP, BNP, and β-MHC. Furthermore, lupeol treatment attenuated the apoptotic and inflammatory responses in the heart tissue. We revealed that lupeol attenuated the inflammatory responses including the reduction of inflammatory cytokines and inhibition of NF-κB p65 nuclear translocation, which was mediated by the TLR4-PI3K-Akt signaling. Administration of a PI3K/Akt agonist 740 Y-P reversed the protective effects of lupeol in TAC mice as well as in PE-stimulated NRCMs. Moreover, pre-treatment with a TLR4 agonist RS 09 abolished the protective effects of lupeol and restored the inhibition of PI3K-Akt-NF-κB signaling by lupeolin PE-stimulated NRCMs. Collectively, our results demonstrate that the lupeol protects against cardiac hypertrophy via anti-inflammatory mechanisms, which results from inhibiting the TLR4-PI3K-Akt-NF-κB signaling.

Negative Impact of Sigma-1 Receptor Agonist Treatment on Tissue Integrity and Motor Function Following Spinal Cord Injury.

In traumatic spinal cord injury, the initial trauma is followed by a cascade of impairments, including excitotoxicity and calcium overload, which ultimately induces secondary damages. The sigma-1 receptor is widely expressed in the central nervous system and is acknowledged to play a key role in calcium homeostasis. Treatments with agonists of the sigma-1 receptor induce beneficial effects in several animal models of neurological diseases. In traumatic injury the use of an antagonist of the sigma-1 receptor reversed several symptoms of central neuropathic pain. Here, we investigated whether sigma-1 receptor activation with PRE-084 is beneficial or detrimental following SCI in mice. First, we report that PRE-084 treatment after injury does not improve motor function recovery. Second, using ex vivo diffusion weighted magnetic resonance imaging completed by histological analysis, we highlight that σ1R agonist treatment after SCI does not limit lesion size. Finally, PRE-084 treatment following SCI decreases NeuN expression and increases astrocytic reactivity. Our findings suggest that activation of sigma-1 receptor after traumatic spinal cord injury is detrimental on tissue preservation and motor function recovery in mice.

Wildtype σ1 receptor and the receptor agonist improve ALS-associated mutation-induced insolubility and toxicity

Genetic mutations related to ALS, a progressive neurological disease, have been discovered in the gene encoding σ-1 receptor (σ1R). We previously reported that σ1RE102Q elicits toxicity in cells. The σ1R forms oligomeric states that are regulated by ligands. Nevertheless, little is known about the effect of ALS-related mutations on oligomer formation. Here, we transfected NSC-34 cells, a motor neuronal cell line, and HEK293T cells with σ1R-mCherry (mCh), σ1RE102Q-mCh, or nontagged forms to investigate detergent solubility and subcellular distribution using immunocytochemistry and fluorescence recovery after photobleaching. The oligomeric state was determined using crosslinking procedure. σ1Rs were soluble to detergents, whereas the mutants accumulated in the insoluble fraction. Within the soluble fraction, peak distribution of mutants appeared in higher sucrose density fractions. Mutants formed intracellular aggregates that were co-stained with p62, ubiquitin, and phosphorylated pancreatic eukaryotic translation initiation factor-2-α kinase in NSC-34 cells but not in HEK293T cells. The aggregates had significantly lower recovery in fluorescence recovery after photobleaching. Acute treatment with σ1R agonist SA4503 failed to improve recovery, whereas prolonged treatment for 48 h significantly decreased σ1RE102Q-mCh insolubility and inhibited apoptosis. Whereas σ1R-mCh formed monomers and dimers, σ1RE102Q-mCh also formed trimers and tetramers. SA4503 reduced accumulation of the four types in the insoluble fraction and increased monomers in the soluble fraction. The σ1RE102Q insolubility was diminished by σ1R-mCh co-expression. These results suggest that the agonist and WT σ1R modify the detergent insolubility, toxicity, and oligomeric state of σ1RE102Q, which may lead to promising new treatments for σ1R-related ALS.

Interplay between 5-HT4 Receptors and GABAergic System within CA1 Hippocampal Synaptic Plasticity.

The type 4 serotonin receptor (5-HT4R) is highly involved in cognitive processes such as learning and memory. Behavioral studies have shown a beneficial effect of its activation and conversely reported memory impairments by its blockade. However, how modulation of 5HT4R enables modifications of hippocampal synaptic plasticity remains elusive. To shed light on the mechanisms at work, we investigated the effects of the 5-HT4R agonist RS67333 on long-term potentiation (LTP) within the hippocampal CA1 area. Although high-frequency stimulation-induced LTP remained unaffected by RS67333, the magnitude of LTP induced by theta-burst stimulation was significantly decreased. This effect was blocked by the selective 5-HT4R antagonist RS39604. Further, 5-HT4R-induced decrease in LTP magnitude was fully abolished in the presence of bicuculline, a GABAAR antagonist; hence, demonstrating involvement of GABA neurotransmission. In addition, we showed that the application of a GABABR antagonist, CGP55845, mimicked the effect of 5-HT4R activation, whereas concurrent application of CGP55845 and RS67333 did not elicit an additive inhibition effect on LTP. To conclude, through investigation of theta burst induced functional plasticity, we demonstrated an interplay between 5-HT4R activation and GABAergic neurotransmission within the hippocampal CA1 area.

Lessons on the Sigma-1 Receptor in TNBS-Induced Rat Colitis: Modulation of the UCHL-1, IL-6 Pathway.

Inflammatory Bowel Disease (IBD) is an autoimmune ailment of the gastrointestinal (GI) tract, which is characterized by enhanced activation of proinflammatory cytokines. It is suggested that the sigma-1 receptor (σ1R) confers anti-inflammatory effects. As the exact pathogenesis of IBD is still unknown and treatment options are limited, we aimed to investigate the effects of σ1R in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis. To this end, male Wistar–Harlan rats were used to model colitic inflammation through the administration of TNBS. To investigate the effects of σ1R, Fluvoxamine (FLV, σ1R agonist) and BD1063 (σ1R antagonist) were applied via intracolonic administration to the animals once a day for three days. Our radioligand binding studies indicated the existence of σ1Rs as [3H](+)-pentazocine binding sites, and FLV treatment increased the reduced σ1R maximum binding capacity in TNBS-induced colitis. Furthermore, FLV significantly attenuated the colonic damage, the effect of which was abolished by the administration of BD1063. Additionally, FLV potentially increased the expression of ubiquitin C-terminal hydrolase ligase-1 (UCHL-1) and the levels of endothelial nitric oxide synthase (eNOS), and decreased the levels of interleukin-6 (IL-6) and inducible NOS (iNOS) expression. In summary, our study offers evidence for the anti-inflammatory potential of FLV and σ1R in experimental colitis, and our results present a promising approach to the development of new σ1R-targeted treatment options against IBD.

Exploiting the Power of Stereochemistry in Drug Action: 3-[(2S,6S,11S)-8-Hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide as Potent Sigma-1 Receptor Antagonist.

(+)-(2S,6S,11S)- and (-)-(2R,6R,11R)-Benzomorphan derivatives have a different binding affinity for sigma-1 (σ1R) and opioid receptors, respectively. In this study, we describe the synthesis of the (+)-enantiomer [(+)-LP1] of the benzomorphan MOR agonist/DOR antagonist LP1 [(-)-LP1]. The binding affinity of both (+)-LP1 and (-)-LP1 for σ1R and sigma-2 receptor (σ2R) was tested. Moreover, (+)-LP1 opioid receptor binding affinity was also investigated. Finally, (+)-LP1 was tested in a mouse model of inflammatory pain. Our results showed a nanomolar σ1R and binding affinity for (+)-LP1. Both (+)-LP1 and (-)-LP1 elicited a significant analgesic effect in a formalin test. Differently from (-)-LP1, the analgesic effect of (+)-LP1 was not reversed by naloxone, suggesting a σ1R antagonist profile. Furthermore, σ1R agonist PRE-084 was able to unmask the σ1R antagonistic component of the benzomorphan compound. (+)-LP1 could constitute an useful lead compound to develop new analgesics based on mechanisms of action alternative to opioid receptor activation.

4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual μ-Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain.

The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ1R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ1R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics.

The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism.

AimSigma-1 receptors have been investigated and shown to play a protective role in both depression and cardiovascular disease. SA4503, known as a σ1 receptor agonist, regulates cardiac calcium and potassium channels in rat models of depression. However, it remains unknown whether SA4503 can alleviate myocardial inflammation or conduction junctions in the atrium after exposure to chronic mild stress.Methods and ResultsSprague-Dawley male rats received 28-day treatment with SA4503, simultaneously with chronic mild stress. Behavior measurements were assessed after the daily doses. Additionally, a multielectrode array assessment, electrophysiological study, immunohistochemistry analysis, histological analysis, and Western blot analysis were performed. Depression rats’ hearts showed abnormal electrical activity, including disordered excitation propagation and prolonged total activation time (TAT). In addition, atrial arrhythmias (AAs), induced by burst stimulation, showed higher incidence and longer duration in the depression group compared to the control group. These changes were related to reduced conduction junctions and enhanced spatial heterogeneity. Importantly, depressed rat hearts showed greater expression of inflammatory factors (TGF-α, IL-6, and TGF-β), more collagen distribution in the extracellular matrix, and lower expression of gap junction proteins (CX40 and CX43). Furthermore, SA4503 partially mitigated the above indices in the depression group (P < 0.01 for all groups).ConclusionThese findings show the effects of the σ1R agonist SA4503; it alleviates atrial myocardial inflammation and conduction junctions after chronic mild stress. SA4503 may be the promising pharmacological agent to treat depression-related AAs by increasing conduction function, improving the expression of connexin 40 and 43, and reducing cardiac myocardial inflammation.

Role of serotonin 4 receptor in the growth of hippocampal neurons during the embryonic development in mice

Serotonin (5-HT) homeostasis is critical for the brain development which influences neurogenesis, neuronal migration, and circuit formation. Distinctive distribution patterns of serotonin receptors (5-HTRs) in the brain govern various physiological activities. Amongst the 5-HTRs, serotonin 4 receptor (5-HT4R) is widely expressed in embryonic forebrain and affects neuronal development, synaptogenesis, and behavior, but its specific role in brain development is still not completely understood. Therefore, in the present study, we addressed the roles of 5-HT4R in the growth of hippocampal neurons during the development of mice brain. We cultured hippocampal neurons of the mouse at embryonic day 18 and then treatment of 5-HT4R agonist RS67333 was employed. We found RS67333 significantly increased the axonal length, diameter and branching along with total dendritic length, number of primary dendrites and their branching. In addition, these effects were neutralized by the concomitant treatment of 5-HT4R antagonist GR125487, which confirmed the specific role of the 5-HT4R in the growth of axon and dendrites. Further, the treatment of RS67333 upregulated the mRNA expression of collapsin response mediator protein-2 (CRMP2) and non-phosphorylated CRMP2 (npCRMP2) together with neurotrophic factors (BDNF, NT-3, NGF) and TRK-A. Additionally, the current research findings reveal that the knockdown of CRMP2 inhibited RS67333-induced growth of the axons and dendrites, which indicates that CRMP2 is required for the 5-HT4R-mediated growth of the axons and dendrites. Overall, the findings of the present in vitro study enrich the understanding and provide insight roles of 5-HT4R in embryonic brain development by promoting the growth of hippocampal neurons.

Novel radioligands for imaging sigma-1 receptor in brain using positron emission tomography (PET)

The sigma-1 receptor (σ1R) is a unique intracellular protein. σ1R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of σ1R in the brain using positron emission tomography (PET) could serve as a noninvasively tool for enhancing the understanding of the disease's pathophysiology. Moreover, σ1R PET tracers can be used for target validation and quantification in diagnosis. Herein, we describe the radiosynthesis, in vivo PET/CT imaging of novel σ1R 11C-labeled radioligands based on 6-hydroxypyridazinone, [11C]HCC0923 and [11C]HCC0929. Two radioligands have high affinities to σ1R, with good selectivity. In mice PET/CT imaging, both radioligands showed appropriate kinetics and distributions. Additionally, the specific interactions of two radioligands were reduced by compounds 13 and 15 (self-blocking). Of the two, [11C]HCC0929 was further investigated in positive ligands blocking studies, using classic σ1R agonist SA 4503 and σ1R antagonist PD 144418. Both σ1R ligands could extensively decreased the uptake of [11C]HCC0929 in mice brain. Besides, the biodistribution of major brain regions and organs of mice were determined in vivo. These studies demonstrated that two radioligands, especially [11C]HCC0929, possessed ideal imaging properties and might be valuable tools for non-invasive quantification of σ1R in brain.

Ligands Exert Biased Activity to Regulate Sigma 1 Receptor Interactions With Cationic TRPA1, TRPV1, and TRPM8 Channels.

The sigma 1 receptor (σ1R) and the mu-opioid receptor (MOR) regulate the transient receptor potential (TRP) V1 calcium channel. A series of proteins are involved in the cross-regulation between MORs and calcium channels like the glutamate N-methyl-D-aspartate receptor (NMDAR), including the histidine triad nucleotide-binding protein 1 (HINT1), calmodulin (CaM), and the σ1R. Thus, we assessed whether similar mechanisms also apply to the neural TRP ankyrin member 1 (TRPA1), TRP vanilloid member 1 (TRPV1), and TRP melastatin member 8 (TRPM8). Our results indicate that σ1R and CaM bound directly to cytosolic regions of these TRPs, and this binding increased in the presence of calcium. By contrast, the association of HINT1 with these TRPs was moderately dependent on calcium. The σ1R always competed with CaM for binding to the TRPs, except for its binding to the TRPA1 C-terminal where σ1R binding cooperated with that of CaM. However, σ1R dampened HINT1 binding to the TRPA1 N-terminal. When the effect of σ1R ligands was addressed, the σ1R agonists PRE084 and pregnenolone sulfate enhanced the association of the σ1R with the TRPM8 N-terminal and TRPV1 C-terminal in the presence of physiological calcium, as seen for the σ1R–NMDAR interactions. However, these agonists dampened σ1R binding to the TRPA1 and TRPV1 N-terminal domains, and also to the TRPA1 C-terminal, as seen for σ1R–binding immunoglobulin protein (BiP) interactions in the endoplasmic reticulum (ER). By contrast, the σ1R antagonists progesterone and S1RA reduced the association of σ1R with TRPA1 and TRPV1 C-terminal regions, as seen for the σ1R–NMDAR interactions. Conversely, they enhanced the σ1R interaction with the TRPA1 N-terminal, as seen for σ1R–BiP interactions, whereas they barely affected the association of σ1R with the TRPV1 N-terminal. Thus, depending on the calcium channel and the cytosolic region examined, the σ1R agonists pregnenolone sulfate and PRE084 opposed or collaborated with the σ1R antagonists progesterone and S1RA to disrupt or promote such interactions. Through the use of cloned cytosolic regions of selected TRP calcium channels, we were able to demonstrate that σ1R ligands exhibit biased activity to regulate particular σ1R interactions with other proteins. Since σ1Rs are implicated in essential physiological processes, exploiting such ligand biases may represent a means to develop more selective and efficacious pharmacological interventions.

Psychiatric comorbidities in high functioning autism: Polygenic overlap with major depression and attention deficit hyperactivity disorder

In early Alzheimer's disease (AD) brain, reduction of sigma-1 receptors (σ1R) is detected. In this study, we employed male heterozygous σ1R knockout (σ1R+/–) mice showing normal cognitive performance to investigate association of σ1R deficiency with AD risk. Herein we report that a single injection (i.c.v.) of Aβ25–35 impaired spatial memory with approximately 25% death of pyramidal cells in the hippocampal CA1 region of WT mice (Aβ25–35-WT mice), whereas it did not cause such impairments in σ1R+/– mice (Aβ25–35-σ1R+/– mice). Compared with WT mice, Aβ25–35-WT mice showed increased levels of NMDA-activated currents (INMDA) and NR2B phosphorylation (phospho-NR2B) in the hippocampal CA1 region at 48 h after Aβ25–35-injection (post-Aβ25–35) followed by approximately 40% decline at 72 h post-Aβ25–35 of their respective control levels, which was inhibited by the σ1R antagonist NE100. In Aβ25–35-WT mice, the administration of NR2B inhibitor Ro25-6981 or NE100 on day 1–4 post-Aβ25–35 attenuated the memory deficits and loss of pyramidal cells. By contrast, Aβ25–35-σ1R+/– mice showed a slight increase in the INMDA density and the phospho-NR2B at 48 h or 72 h post-Aβ25–35 compared to σ1R+/– mice. Treatment with σ1R agonist PRE084 in Aβ25–35-σ1R+/– mice caused the same changes in the INMDA density and the phospho-NR2B as those in Aβ25–35-WT mice. Furthermore, Aβ25–35-σ1R+/– mice treated with the NMDA receptor agonist NMDA or PRE084 on day 1–4 post-Aβ25–35 showed a loss of neuronal cells and memory impairment. These results indicate that the σ1R deficiency can reduce Aβ25–35-induced neuronal cell death and cognitive deficits through suppressing Aβ25–35-enhanced NR2B phosphorylation.

Cocaine Blocks Effects of Hunger Hormone, Ghrelin, Via Interaction with Neuronal Sigma-1 Receptors.

Despite ancient knowledge on cocaine appetite-suppressant action, the molecular basis of such fact remains unknown. Addiction/eating disorders (e.g., binge eating, anorexia, bulimia) share a central control involving reward circuits. However, we here show that the sigma-1 receptor (σ1R) mediates cocaine anorectic effects by interacting in neurons with growth/hormone/secretagogue (ghrelin) receptors. Cocaine increases colocalization of σ1R and GHS-R1a at the cell surface. Moreover, in transfected HEK-293T and neuroblastoma SH-SY5Y cells, and in primary neuronal cultures, pretreatment with cocaine or a σ1R agonist inhibited ghrelin-mediated signaling, in a similar manner as the GHS-R1a antagonist YIL-781. Results were similar in G protein-dependent (cAMP accumulation and calcium release) and in partly dependent or independent (ERK1/2 phosphorylation and label-free) assays. We provide solid evidence for direct interaction between receptors and the functional consequences, as well as a reliable structural model of the macromolecular σ1R-GHS-R1a complex, which arises as a key piece in the puzzle of the events linking cocaine consumption and appetitive/consummatory behaviors.

Sigma 1 Receptor Antagonists Inhibit Manic-Like Behaviors in Two Congenital Strains of Mice.

BackgroundSeveral currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3β that accompanies this disease.MethodsIn this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the “manic” Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors.ResultsThe activity of control mice, which do not exhibit manic-like behaviors in the forced swim test, was significantly enhanced by MK801, an inhibitor of glutamate N-methyl-D-aspartate receptor activity, an effect that was not or barely observed in manic-like mice. Typical mood stabilizers, such as glycogen synthase kinase 3β inhibitors, but not σ1R ligands, reduced the N-methyl-D-aspartate receptor-mediated behaviors in control mice. Notably, σ1R antagonists S1RA, PD144418, BD1047, and BD1063, but not σ1R agonists PRE084 and PPCC, attenuated the manic-like behaviors of BStac and HINT1-/- mice by increasing antiactivity behaviors. The antimanic effects of a single administration of σ1R antagonists persisted for at least 24 hours, and these drugs did not alter the behavior of the “bipolar” HINT1−/− mice during pro-depressive episodes.Conclusionsσ1R antagonists exhibit a selective normalizing effect on specific behavioral domains of mania without altering control (normal) or depressive-like behaviors.