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ENeuro Jul 2022There are currently no Food and Drug Administration (FDA)-approved delta opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and...
There are currently no Food and Drug Administration (FDA)-approved delta opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and non-human primates compared to traditional mu opioid receptor (MOR) therapeutics (Vanderah, 2010). Targeting peripheral receptors is an attractive strategy to reduce abuse potential. However, peripheral opioid receptors do not readily respond to agonists unless primed by inflammation, which would limit their efficacy in non-inflammatory pain patients (Stein et al., 1989). It was recently identified that G protein-coupled receptor kinase 2 (GRK2) maintains DOR incompetence in non-inflamed nociceptors (Brackley et al., 2016; Brackley et al., 2017). Here, we report that paroxetine, a selective serotonin reuptake inhibitor and potent GRK2 inhibitor (Thal et al., 2012), reduces chronic GRK2 association with membrane DOR, thereby enhancing peripheral DOR-mediated analgesic competence in the absence of inflammation. Interestingly, paroxetine's effects on GRK2 are limited to peripheral tissues in the male rat. The effects of paroxetine on DOR competence are notably antagonized by GRK2 overexpression. This is the first study to suggest that paroxetine induces peripheral DOR analgesic competence through a GRK2-dependent mechanism, improving analgesic efficacy in non-inflamed tissue. Because paroxetine targets the protein that governs peripheral opioid receptor responsiveness, and does so in the absence of inflammation, we propose that paroxetine may be suitable as a co-therapy with peripherally-restrictive doses of opioids to improve analgesic efficacy in non-inflammatory pain conditions.Opioids that target MOR represent the gold-standard for analgesic healthcare, despite widespread abuse potential and the ongoing opioid-epidemic. Work herein uncovers the therapeutic potential of targeting peripheral DOR for analgesic utility with an FDA-approved GRK2 inhibitor paroxetine to boost efficacy and reduce side effect profiles. Analgesic pain management targeting DOR with increased efficacy through adjuvant paroxetine treatment could reduce over-reliance on MOR agonist opioids for pain relief and usher in new options for analgesia.
PubMed: 35882549
DOI: 10.1523/ENEURO.0063-22.2022 -
Frontiers in Psychiatry 2020Recent interest in the role of microbiota in health and disease has implicated gut microbiota dysbiosis in psychiatric disorders including major depressive disorder....
Recent interest in the role of microbiota in health and disease has implicated gut microbiota dysbiosis in psychiatric disorders including major depressive disorder. Several antidepressant drugs that belong to the class of selective serotonin reuptake inhibitors have been found to display antimicrobial activities. In fact, one of the first antidepressants discovered serendipitously in the 1950s, the monoamine-oxidase inhibitor Iproniazid, was a drug used for the treatment of tuberculosis. In the current study we chronically treated DBA/2J mice for 2 weeks with paroxetine, a selective serotonin reuptake inhibitor, and collected fecal pellets as a proxy for the gut microbiota from the animals after 7 and 14 days. Behavioral testing with the forced swim test revealed significant differences between paroxetine- and vehicle-treated mice. Untargeted mass spectrometry and 16S rRNA profiling of fecal pellet extracts showed several primary and secondary bile acid level, and microbiota alpha diversity differences, respectively between paroxetine- and vehicle-treated mice, suggesting that microbiota functions are altered by the drug. In addition to their lipid absorbing activities bile acids have important signaling activities and have been associated with gastrointestinal diseases and colorectal cancer. Antidepressant drugs like paroxetine should therefore be used with caution to prevent undesirable side effects.
PubMed: 32581888
DOI: 10.3389/fpsyt.2020.00518 -
Pain Research & Management 2016Serotonin is a monoamine neurotransmitter that plays a major role in both nociception and mood regulation. Alterations in the 5-hydroxytryptophan (5HT) system have been... (Review)
Review
Serotonin is a monoamine neurotransmitter that plays a major role in both nociception and mood regulation. Alterations in the 5-hydroxytryptophan (5HT) system have been reported in chronic pain patients. In recent years, Selective Serotonin Reuptake Inhibitors (SSRIs) have been suggested as an alternative treatment for chronic pain due to the fact that they are better tolerated presenting less secondary effects than other antidepressants such as tricyclic antidepressants. Although several clinical trials have been published, the effectiveness of SSRI as treatment for pain conditions is inconclusive. This review aims to summarise what is known, regarding the effectiveness of SSRI as a treatment for chronic pain conditions in adults. A total of 36 studies involving a total of 1898 participants were included in this review. Of the 36 trials included in the review, 2 used zimelidine as treatment, 3 used escitalopram, 4 used fluvoxamine, 4 used sertraline, 6 used citalopram, 8 used paroxetine, 9 used fluoxetine, and one used both citalopram and paroxetine. Because the trials included in this review are quite heterogeneous, only qualitative analyses were performed. SSRI seems to have an effect on most of chronic pain conditions; however, further clinical trials with good methodology leading to low risk of bias are needed in order to conclude once and for all the effect of this drug class as treatment for chronic pain conditions.
Topics: Chronic Pain; Databases, Factual; Double-Blind Method; Humans; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 27445601
DOI: 10.1155/2016/2020915 -
Frontiers in Public Health 2022Since December 2019, the Coronavirus Disease 2019 (COVID-19) pandemic has become a non-neglectable context for the whole healthcare system. Under the background of...
Since December 2019, the Coronavirus Disease 2019 (COVID-19) pandemic has become a non-neglectable context for the whole healthcare system. Under the background of COVID-19, the detection and diagnosis of malaria cases are under challenge. Here, we reported a COVID-19 and malaria co-infection traveler who has a long living history in Cameroon. The case was administered with dihydroartemisinin and piperaquine tablets for malaria, Lopinavir and Ritonavir tablets, Arbidol, recombinant human interferon α-2b and Compound Maxing Yifei mixture for COVID-19, and Zolpidem Tartrate tablets, Diazepam, Paroxetine Hydrochloride tablets, Thymosin α1, and Lianhua Qinwen Jiaonang during the second hospitalization of the patient since the patient has a certain level of anxiety and insomnia with no evidence of inflammatory reactions. After being tested negative two times for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 48 h, the patient met China's COVID-19 discharge standards and was discharged with stable vital signs and mental state. Since most countries in the sub-Saharan region have a fragile health system, co-infection for both and SARS-CoV-2 may not be uncommon, and raise a challenge in diagnosis, treatment, and prevention for both diseases. We add to the literature on co-infection of malaria and COVID-19 and offer operational advice on diagnosis, prevention, and treatment for the co-infection.
Topics: COVID-19; Coinfection; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum; SARS-CoV-2
PubMed: 35991037
DOI: 10.3389/fpubh.2022.871374 -
Sexual Health Apr 2016Eutectic Mixture of Local Anaesthetics (EMLA) is recommended for use off-label as a treatment for premature ejaculation (PE). Other topical anaesthetics are available,... (Meta-Analysis)
Meta-Analysis Review
Eutectic Mixture of Local Anaesthetics (EMLA) is recommended for use off-label as a treatment for premature ejaculation (PE). Other topical anaesthetics are available, some of which have been evaluated against oral treatments. The purpose of this systematic review was to evaluate the evidence from randomised controlled trials (RCTs) for topical anaesthetics in the management of PE. Bibliographic databases including MEDLINE were searched to August 2014. The primary outcome was intra-vaginal ejaculatory latency time (IELT). Methodological quality of RCTs was assessed. IELT and other outcomes were pooled across RCTs in a meta-analysis. Between-trial heterogeneity was assessed. Nine RCTs were included. Seven were of unclear methodological quality. Pooled evidence (two RCTs, 43 participants) suggests that EMLA is significantly more effective than placebo at increasing IELT (P<0.00001). Individual RCT evidence also suggests that Topical Eutectic-like Mixture for Premature Ejaculation (TEMPE) spray and lidocaine gel are both significantly more effective than placebo (P=0.003; P<0.00001); and lidocaine gel is significantly more effective than sildenafil or paroxetine (P=0.01; P=0.0001). TEMPE spray is associated with significantly more adverse events than placebo (P=0.003). More systemic adverse events are reported with tramadol, sildenafil and paroxetine than with lidocaine gel. Diverse methods of assessing sexual satisfaction and ejaculatory control with topical anaesthetics are reported and evidence is conflicting. Topical anaesthetics appear more effective than placebo, paroxetine and sildenafil at increasing IELT in men with PE. However, the methodological quality of the existing RCT evidence base is uncertain.
Topics: Anesthetics, Local; Humans; Male; Premature Ejaculation; Randomized Controlled Trials as Topic
PubMed: 26599522
DOI: 10.1071/SH15042 -
The Journal of Steroid Biochemistry and... Dec 2019Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via...
Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.
Topics: Aromatase; Cells, Cultured; Citalopram; Female; Fluoxetine; Humans; Molecular Docking Simulation; Paroxetine; Placenta; Pregnancy; Serotonin; Selective Serotonin Reuptake Inhibitors; Sertraline; Trophoblasts; Venlafaxine Hydrochloride
PubMed: 31509772
DOI: 10.1016/j.jsbmb.2019.105470 -
ELife Jul 2020Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of...
Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of ∆N72/∆C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.
Topics: Cryoelectron Microscopy; Crystallography, X-Ray; Humans; Molecular Structure; Paroxetine; Protein Structure, Tertiary; Serotonin; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 32618269
DOI: 10.7554/eLife.56427 -
Ugeskrift For Laeger Apr 2022Treatment with SSRI have a high frequency of treatment of emergent sexual dysfunction. The mechanism is thought to be through serotoninergic inhibition of the sexual... (Review)
Review
Treatment with SSRI have a high frequency of treatment of emergent sexual dysfunction. The mechanism is thought to be through serotoninergic inhibition of the sexual response. More than 70% of patients treated with sertraline, citalopram or paroxetine experience sexual side effects, while escitalopram and fluvoxamine yield the lowest degree of sexual dysfunction within the group. This review suggests management strategies including dose reduction, change of medication and add-on treatment. A small group of patients experience post-SSRI dysfunction, in which sexual dysfunction persists after treatment termination.
Topics: Citalopram; Humans; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Sexual Dysfunction, Physiological
PubMed: 35410653
DOI: No ID Found -
The International Journal of... Apr 2022Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter...
BACKGROUND
Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT).
METHODS
This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine.
RESULTS
All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout.
CONCLUSION
These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.
Topics: Antidepressive Agents, Second-Generation; Atomoxetine Hydrochloride; Cyclohexanols; Depressive Disorder, Major; Humans; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Paroxetine; Serotonin; Selective Serotonin Reuptake Inhibitors; Tyramine; Venlafaxine Hydrochloride
PubMed: 34958348
DOI: 10.1093/ijnp/pyab086 -
Frontiers in Immunology 2023Up to 40 per cent of people with active inflammatory bowel disease (IBD) also suffer from mood disorders such as anxiety and depression. Notwithstanding, the fundamental...
BACKGROUND
Up to 40 per cent of people with active inflammatory bowel disease (IBD) also suffer from mood disorders such as anxiety and depression. Notwithstanding, the fundamental biological pathways driving depression in IBD remain unknown.
METHODS
We identified 33 core genes that drive depression in IBD patients and performed consensus molecular subtyping with the NMF algorithm in IBD. The CIBERSORT were employed to quantify the immune cells. Metabolic signature was characterized using the "IOBR" R package. The scoring system (D. score) based on PCA. Pre-clinical models are constructed using DSS.
RESULTS
Using transcriptome data from the GEO database of 630 IBD patients, we performed a thorough analysis of the correlation between IBD and depression in this research. Firstly, the samples were separated into two different molecular subtypes (D. cluster1 and D. cluster2) based on their biological signatures. Moreover, the immunological and metabolic differences between them were evaluated, and we discovered that D. cluster2 most closely resembled IBD patients concomitant with depression. We also developed a scoring system to assess the IBD-related depression and predict clinical response to anti-TNF- therapy, with a higher D. score suggesting more inflammation and worse reaction to biological therapies. Ultimately, we also identified through animal experiments an antidepressant, paroxetine, has the added benefit of lowering intestinal inflammation by controlling microorganisms in the digestive tract.
CONCLUSIONS
This study highlights that IBD patients with or without depression show significant variations and antidepressant paroxetine may help reduce intestinal inflammation.
Topics: Humans; Paroxetine; Depression; Tumor Necrosis Factor Inhibitors; Inflammatory Bowel Diseases; Anti-Inflammatory Agents; Antidepressive Agents; Inflammation
PubMed: 36923403
DOI: 10.3389/fimmu.2023.1145070