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Neurobiology of Pain (Cambridge, Mass.) 2024Monoamine-targeting antidepressants serve as frontline medications for chronic pain and associated comorbidities. While persistent anti-allodynic properties of...
Monoamine-targeting antidepressants serve as frontline medications for chronic pain and associated comorbidities. While persistent anti-allodynic properties of antidepressants generally require weeks of treatment, several groups have demonstrated acute analgesic effects within hours of administration, suggesting a role in non-mesocorticolimbic pain processing regions such as the peripheral nervous system. To further explore this possibility, after four weeks of spared nerve injury or sham surgeries, we systemically administered desipramine or saline for an additional three weeks and performed whole transcriptome RNA sequencing on L3-6 dorsal root ganglia. Along with alterations in molecular pathways associated with neuronal activity, we observed a robust immunomodulatory transcriptional signature in the desipramine treated group. Cell subtype deconvolution predicted that these changes were associated with A- and C-fibers. Of note, differentially expressed genes from the dorsal root ganglia of DMI-treated, injured mice were largely unique compared to those from the nucleus accumbens of the same animals. These observations suggest that, under peripheral nerve injury conditions, desipramine induces specific gene expression changes across various regions of the nociceptive circuitry.
PubMed: 38549875
DOI: 10.1016/j.ynpai.2024.100153 -
Medicine Mar 2024Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was... (Review)
Review
Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was to examine the effect of lipid emulsions on neuropsychiatric drug-induced toxicity using relevant case reports of human patients, with a particular focus on the Glasgow Coma Scale (GCS) score and corrected QT interval, to analyze drugs that frequently require lipid emulsion treatment. The following keywords were used to retrieve relevant case reports from PubMed: "antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone" and "lipid emulsion or Intralipid." Lipid emulsion treatment reversed the corrected QT interval prolongation and decreases in Glasgow Coma Scale scores caused by toxic doses of neuropsychiatric drugs, especially lipid-soluble drugs such as amitriptyline, trazodone, quetiapine, lamotrigine, and citalopram. The log P (octanol/water partition coefficient) of the group which required more than 3 lipid emulsion treatments was higher than that that of the group which required less than 3 lipid emulsion treatments. The main rationale to administer lipid emulsion as an adjuvant was as follows: hemodynamic depression intractable to supportive treatment (88.3%) > lipophilic drugs (8.3%) > suspected overdose or no spontaneous breathing (1.6%). Adjuvant lipid emulsion treatment contributed to the recovery of 98.30% of patients with neuropsychiatric drug-induced toxicity. However, further analyses using many case reports are needed to clarify the effects of lipid emulsion resuscitation.
Topics: Humans; Quetiapine Fumarate; Amitriptyline; Citalopram; Fat Emulsions, Intravenous; Trazodone; Drug-Related Side Effects and Adverse Reactions; Dothiepin
PubMed: 38489675
DOI: 10.1097/MD.0000000000037612 -
Talanta Jun 2024This article describes the synthesis of sorptive phases for bioanalysis based on the modification of cellulose paper with natural beeswax as sorbent, resulting in a...
This article describes the synthesis of sorptive phases for bioanalysis based on the modification of cellulose paper with natural beeswax as sorbent, resulting in a substrate completely renewable and sustainable. The preparation of the sorptive phases consisted of the dissolution of beeswax in hexane, followed by its drop-casting on cellulose paper and subsequent evaporation of the solvent. The beeswax modification of paper renders it hydrophobic, enabling the extraction of the target analytes, i.e., imipramine, desipramine, amitriptyline and trimipramine, via hydrophobic interactions. The main variables affecting the extraction performance were investigated (e.g., pH, ionic strength, extraction time, eluent composition, agitation speed). The analytical workflow combines a straightforward sampling, simultaneous extraction of 30 samples in 1 h, and the rapid (<2 min) determination of the analytes via direct infusion mass spectrometry. The method provided limits of detection in the range 2.0 and 3.2 μg L, and the precision, expressed as relative standard deviation, was better than 5.4 % and 8.5 % for intra and inter-day analyses, respectively. The accuracy, in terms of relative recovery, ranged from 90 % to 121 % using saliva as model biofluid.
Topics: Antidepressive Agents, Tricyclic; Cellulose; Amitriptyline; Waxes
PubMed: 38479029
DOI: 10.1016/j.talanta.2024.125860 -
Sleep Medicine Mar 2024The hippocampus (HPC) plays a pivotal role in fear learning and memory. Our two recent studies suggest that rapid eye movement (REM) sleep via the HPC downregulates fear...
The hippocampus (HPC) plays a pivotal role in fear learning and memory. Our two recent studies suggest that rapid eye movement (REM) sleep via the HPC downregulates fear memory consolidation and promotes fear extinction. However, it is not clear whether and how the dorsal and the ventral HPC regulates fear memory differently; and how the HPC in wake regulates fear memory. By chemogenetic stimulating in the HPC directly and its afferent entorhinal cortex that selectively activated the HPC in REM sleep for 3-6 h post-fear-acquisition, we found that HPC activation in REM sleep consolidated fear extinction memory. In particular, dorsal HPC (dHPC) stimulation in REM sleep virtually eliminated fear memory by enhancing fear extinction and reducing fear memory consolidation. By contrast, chemogenetic stimulating HPC afferent the supramammillary nucleus (SUM) induced 3-hr wake with HPC activation impaired fear extinction. Finally, desipramine (DMI) injection that selectively eliminated REM sleep for >6 h impaired fear extinction. Our results demonstrate that the HPC is critical for fear memory regulation; and wake HPC and REM sleep HPC have an opposite role in fear extinction of respective impairment and consolidation.
Topics: Humans; Fear; Extinction, Psychological; Sleep; Learning; Hippocampus; Memory Consolidation
PubMed: 38367358
DOI: 10.1016/j.sleep.2024.02.022 -
Recording ten-fold larger I conductances with automated patch clamping using equimolar Cs solutions.Frontiers in Physiology 2024The rapid delayed rectifier potassium current (I) is important for cardiac repolarization and is most often involved in drug-induced arrhythmias. However, accurately...
The rapid delayed rectifier potassium current (I) is important for cardiac repolarization and is most often involved in drug-induced arrhythmias. However, accurately measuring this current can be challenging in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes because of its small current density. Interestingly, the ion channel conducting I, hERG channel, is not only permeable to K ions but also to Cs ions when present in equimolar concentrations inside and outside of the cell. In this study, I was measured from Chinese hamster ovary (CHO)-hERG cells and hiPSC-CM using either Cs or K as the charge carrier. Equimolar Cs has been used in the literature in manual patch-clamp experiments, and here, we apply this approach using automated patch-clamp systems. Four different (pre)clinical drugs were tested to compare their effects on Cs- and K-based currents. Using equimolar Cs solutions gave rise to approximately ten-fold larger hERG conductances. Comparison of Cs- and K-mediated currents upon application of dofetilide, desipramine, moxifloxacin, or LUF7244 revealed many similarities in inhibition or activation properties of the drugs studied. Using equimolar Cs solutions gave rise to approximately ten-fold larger hERG conductances. In hiPSC-CM, the Cs-based conductance is larger compared to the known K-based conductance, and the Cs hERG conductance can be inhibited similarly to the K-based conductance. Using equimolar Cs instead of K for I measurements in an automated patch-clamp system gives rise to a new method by which, for example, quick scans can be performed on effects of drugs on hERG currents. This application is specifically relevant when such experiments are performed using cells which express small I current densities in combination with small membrane capacitances.
PubMed: 38328302
DOI: 10.3389/fphys.2024.1298340 -
International Journal of Molecular... Jan 2024Astrocytes are crucial in the regulation of neurotransmitter homeostasis, and while their involvement in the dopamine (DA) tripartite synapse is acknowledged, it...
Astrocytes are crucial in the regulation of neurotransmitter homeostasis, and while their involvement in the dopamine (DA) tripartite synapse is acknowledged, it necessitates a more comprehensive investigation. In the present study, experiments were conducted on primary astrocyte cultures from the striatum and cortex of neonatal rats. The pharmacological intricacies of DA uptake, including dependence on time, temperature, and concentration, were investigated using radiolabelled [H]-DA. The mRNA expression of transporters DAT, NET, PMAT, and OCTs was evaluated by qPCR. Notably, astrocytes from both brain regions exhibited prominent mRNA expression of NET and PMAT, with comparatively lower expression of DAT and OCTs. The inhibition of DA uptake by the DAT inhibitor, GBR12909, and NET inhibitors, desipramine and nortriptyline, impeded DA uptake in striatal astrocytes more than in cortical astrocytes. The mRNA expression of NET and PMAT was significantly upregulated in cortical astrocytes in response to the DA receptor agonist apomorphine, while only the mRNA expression of NET exhibited changes in striatal astrocytes. Haloperidol, a DA receptor antagonist, and L-DOPA, a DA precursor, did not induce significant alterations in transporter mRNA expression. These findings underscore the intricate and region-specific mechanisms governing DA uptake in astrocytes, emphasizing the need for continued exploration to unravel the nuanced dynamics of astrocytic involvement in the DA tripartite synapse.
Topics: Animals; Rats; Dopamine; Animals, Newborn; Astrocytes; Corpus Striatum; Membrane Transport Proteins; RNA, Messenger
PubMed: 38255983
DOI: 10.3390/ijms25020911 -
Journal of Pharmacological Sciences Feb 2024Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset psychiatric disorder. We investigated the effects of systemic administration of...
Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset psychiatric disorder. We investigated the effects of systemic administration of monoamine reuptake inhibitors on long-term potentiation (LTP) formation and monoamine release in the medial prefrontal cortex (mPFC) of the stroke-prone spontaneously hypertensive rat (SHRSP)/Ezo, an animal model of ADHD, and its genetic control, Wistar Kyoto (WKY)/Ezo, to elucidate the functional changes in the mPFC monoamine neural system. Methylphenidate (dopamine (DA) and noradrenaline (NA) reuptake inhibitor) and desipramine (NA reuptake inhibitor) improved LTP formation defects in the mPFC of SHRSP/Ezo, suggesting that NA or both DA and NA are required for improvement of impaired LTP. Methylphenidate increased mPFC DA in both WKY/Ezo and SHRSP/Ezo, but the increase was greater in the former. GBR-12909 (DA reuptake inhibitor) increased mPFC DA in WKY/Ezo but had no effect in SHRSP/Ezo. This may be because DA transporter in SHRSP/Ezo is functionally impaired and contributes less to DA reuptake, so its inhibition did not increase DA level. Meanwhile, basal DA levels in the mPFC of SHRSP/Ezo were paradoxically decreased. These results suggest that functional changes in the DA and NA neural system in the frontal lobe are involved in the pathology of ADHD.
Topics: Humans; Rats; Animals; Child; Rats, Inbred WKY; Attention Deficit Disorder with Hyperactivity; Rats, Inbred SHR; Amines; Methylphenidate; Models, Animal; Dopamine
PubMed: 38246729
DOI: 10.1016/j.jphs.2023.12.002 -
Molecular Pharmaceutics Feb 2024Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life...
Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life quality and complicates the treatment of both conditions. Antidepressants are less effective for pain and depression than for depression alone and they induce severe side effects. Opioids are highly efficacious analgesics, but rapid development of tolerance, dependence, and debilitating side effects limit their efficacy and safe use. Leucine-enkephalin (Leu-ENK), the endogenous delta opioid receptor agonist, controls pain and mood and produces potent analgesia with reduced adverse effects compared to conventional opioids. High proteolytic instability, however, makes Leu-ENK ineffective after systemic administration and limits its clinical usefulness. KK-103, a Leu-ENK prodrug, was developed to overcome these limitations of Leu-ENK via markedly increased plasma stability in mice. We showed rapid and substantially increased systemic adsorption and blood plasma exposure of KK-103 compared to Leu-ENK. We also observed brain uptake of radiolabeled KK-103 after systemic administration, indicating a central effect of KK-103. We then established KK-103's prolonged antinociceptive efficacy in the ramped hot plate and formalin test. In both models, KK-103 produced a comparable dose to the maximum antinociceptive-effect relationship. The pain-alleviating effect of KK-103 primarily resulted from activating the delta opioid receptor after the likely conversion of KK-103 to Leu-ENK in vivo. Finally, KK-103 produced an antidepressant-like activity comparable to the antidepressant desipramine, but with minimal gastrointestinal inhibition and no incidence of sedation.
Topics: Mice; Animals; Enkephalin, Leucine; Receptors, Opioid, delta; Prodrugs; Pain; Analgesics; Antidepressive Agents
PubMed: 38243899
DOI: 10.1021/acs.molpharmaceut.3c00807 -
The Australian and New Zealand Journal... Apr 2024Binge spectrum disorders are prevalent worldwide. Psychiatric and medical comorbidities are common, and societal costs are significant. Evidence-based treatment remains... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Binge spectrum disorders are prevalent worldwide. Psychiatric and medical comorbidities are common, and societal costs are significant. Evidence-based treatment remains underutilized. Cognitive behavioral therapy is the recommended first-line treatment, but pharmacotherapy may be easier to access.
INTERVENTIONS
Meta-analytic evidence directly comparing cognitive behavioral therapy with pharmacotherapy is lacking. We aimed to compare the effects of cognitive behavioral therapy interventions with any pharmacological treatment for binge spectrum disorders. We searched PubMed, Embase, CENTRAL, ClinicalTrials.gov and reference lists for randomized controlled trials comparing cognitive behavioral therapy with any pharmacotherapy for bulimia nervosa/binge eating disorder and performed pairwise meta-analytic evaluations.
PRIMARY OUTCOMES
Primary outcomes are remission and frequency of binges. Secondary outcomes are frequency of purges, response, eating disorder psychopathology, weight/body mass index, depression, anxiety, quality of life and dropouts.
RESULTS
Eleven randomized controlled trials comparing cognitive behavioral therapy with fluoxetine/imipramine/desipramine/methylphenidate/sibutramine were identified ( = 531). Cognitive behavioral therapy was superior to antidepressants in terms of remission, frequency of binges and eating disorder psychopathology. There were no statistically significant differences for any of the individual cognitive behavioral therapy vs drug comparisons in terms of response/depression/anxiety/weight/quality of life/dropouts. Cognitive behavioral therapy was not superior to sibutramine/methylphenidate for the primary outcomes.
CONCLUSIONS
Data are scarce, comparisons underpowered and, considering the inherent methodological limitations of psychotherapy trials, questions arise regarding the presumed superiority of cognitive behavioral therapy. Further research is needed.
Topics: Humans; Quality of Life; Cognitive Behavioral Therapy; Psychotherapy; Methylphenidate; Treatment Outcome; Cyclobutanes
PubMed: 38179705
DOI: 10.1177/00048674231219593 -
Ecotoxicology and Environmental Safety Jan 2024Recent research has highlighted a correlation between exposure to ambient fine particulate matter (PM) and the development of systemic insulin resistance (IR) along with...
Recent research has highlighted a correlation between exposure to ambient fine particulate matter (PM) and the development of systemic insulin resistance (IR) along with an elevated risk of diabetes. Ceramide has emerged as one of the pathogenic mechanisms contributing to IR. The inhibition of acid sphingomyelinase (ASMase) activity by desipramine (DES) has been shown to effectively reduce ceramide levels. In the present study, 24 female C57BL/6 N mice were randomized into one of the four groups: the filtered air exposure (FA) group, the concentrated PM exposure (PM) group, the concentrated PM treated with low-dose DES (DL) group, and the concentrated PM treated with high-dose DES (DH) group. The PM, DL and DH groups were exposed to PM for an 8-week period within a whole-body exposure system. The study encompassed extensive examinations of glucose homeostasis, liver lipid profile, ceramide pathway, and insulin signaling pathway. Our results demonstrated that PM exposure caused impaired glucose tolerance, elevated ceramide levels, increased phosphorylation PP2A, reduced Akt phosphorylation, and hindered GLUT2 expression. Remarkably, DES administration mitigated PM-induced IR by effectively lowering ceramide levels. In conclusion, the reduction of ceramide levels by DES may be a promising therapeutic strategy for coping PM-induced IR.
Topics: Female; Animals; Mice; Particulate Matter; Insulin Resistance; Desipramine; Mice, Inbred C57BL; Liver; Air Pollutants
PubMed: 38134639
DOI: 10.1016/j.ecoenv.2023.115849