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Digestive Diseases and Sciences May 2023The role of cholinergic receptors in the regulation of duodenal mucosal permeability in vivo is currently not fully described.
BACKGROUND
The role of cholinergic receptors in the regulation of duodenal mucosal permeability in vivo is currently not fully described.
AIMS
To elucidate the impact of nicotinic and muscarinic acetylcholine receptor signaling in response to luminal hypotonicity (50 mM NaCl) in the proximal small intestine of rat.
METHODS
The effect on duodenal blood-to-lumen clearance of Cr-EDTA (i.e., mucosal permeability) and motility was studied in the absence and presence of nicotinic and muscarinic receptor agonists and antagonists, a sodium channel blocker (tetrodotoxin), and after bilateral cervical vagotomy.
RESULTS
Rats with duodenal contractions responded to luminal hypotonicity by substantial increase in intestinal permeability. This response was absent in animals given a non-selective nicotinic receptor antagonist (mecamylamine) or agonist (epibatidine). Pretreatment with tetrodotoxin reduced the increase in mucosal permeability in response to luminal hypotonicity. Further, the non-selective muscarinic receptor antagonist (atropine) and agonist (bethanechol) reduced the hypotonicity-induced increase in mucosal permeability, while vagotomy was without an effect, suggesting that local enteric reflexes dominate. Finally, neither stimulating nor blocking the α7-nicotinic receptor had any significant effects on duodenal permeability in response to luminal hypotonicity, suggesting that this receptor is not involved in regulation of duodenal permeability. The effect of the different drugs on mucosal permeability was similar to the effect observed for duodenal motility.
CONCLUSIONS
A complex enteric intramural excitatory neural reflex involving both nicotinic and muscarinic receptor subtypes mediates an increase in mucosal permeability induced by luminal hypotonicity.
Topics: Rats; Animals; Receptors, Cholinergic; Tetrodotoxin; Duodenum; Permeability; Receptors, Nicotinic
PubMed: 36436156
DOI: 10.1007/s10620-022-07764-6 -
Brain Sciences Nov 2022cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving... (Review)
Review
BACKGROUND
cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving efficacy of pharmacotherapies tested for cocaine use disorder, in the context of randomized-controlled clinical trials.
OBJECTIVES
we assessed the databases of the U.S. National Library of Medicine, Google Scholar, and PsycINFO, without date restrictions up to August 2022, to identify relevant studies.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
we included double-blinded randomized-controlled trials investigating pharmacotherapies for cocaine craving and/or cocaine use disorder whose outcomes included cocaine craving.
STUDY APPRAISAL AND SYNTHESIS METHODS
Two authors screened studies' titles and abstracts for inclusion, and both read all the included studies. We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study set-ting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes.
RESULTS
Overall, we appraised 130 clinical trials, including 8137 participants. We further considered the drugs from the studies that scored equal to or greater than six points in the quality assessment. There was a correlation between craving and cocaine use outcomes (self-reports, timeline follow-back or urinary benzoylecgonine) in the vast majority of studies. In the short-term treatment, acute phenylalanine-tyrosine depletion, clonidine, fenfluramine, meta-chlorophenylpiperazine (m-CPP) and mecamylamine presented promising effects. In the long term, amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone presented promising anti-craving effects. Unfortunately, the highly tested medications were not successful in most of the trials, as follows: propranolol in the short term; amantadine, aripiprazole, bromocriptine, citicoline, ketamine, modafinil, olanzapine, topiramate in the long term. The remaining 52 medications had no positive anti-craving outcomes.
LIMITATIONS
Our review was limited by high heterogeneity of craving assessments across the studies and by a great range of pharmacotherapies. Further, the majority of the studies considered abstinence and retention in treatment as the main outcomes, whereas craving was a secondary outcome and some of the studies evaluated patients with cocaine use disorder with comorbidities such as opioid or alcohol use disorder, schizophrenia, bipolar disorder or attention deficit hyperactivity. Lastly, most of the studies also included non-pharmacological treatments, such as counseling or psychotherapy.
CONCLUSIONS
There is a direct association between craving and cocaine use, underscoring craving as an important treatment target for promoting abstinence among persons with cocaine use disorder. Clonidine, fenfluramine and m-CPP showed to be promising medications for cocaine craving in the short-term treatment, and amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone in the long-term treatment.
PubMed: 36421870
DOI: 10.3390/brainsci12111546 -
Frontiers in Pharmacology 2022A network meta-analysis based on randomized controlled trials was conducted to investigate the effects of pharmacological interventions on smoking cessation. English...
A network meta-analysis based on randomized controlled trials was conducted to investigate the effects of pharmacological interventions on smoking cessation. English databases were searched to obtain randomized controlled trials reporting the effect of pharmacological interventions on smoking cessation. The risk of bias for the included trials was assessed using Cochrane Handbook tool. Stata 15.1 software was used to perform network meta-analysis, and GRADE approach was used to assess the evidence credibility on the effects of different interventions on smoking cessation. A total of 159 studies involving 60,285 smokers were included in the network meta-analysis. The analysis involved 15 interventions and which yielded 105 pairs of comparisons. Network meta-analysis showed that varenicline was more helpful for smoking cessation than other monotherapies, such as nicotine replacement therapy [Odds Ratio (OR) = 1.42, 95% confidence interval (CI) (1.16, 1.73)] and bupropion [OR = 1.52, 95% CI (1.22, 1.89)]. Furthermore, combined interventions were superior to monotherapy in achieving smoking cessation, such as varenicline plus bupropion over bupropion [OR = 2.00, 95% CI (1.11, 3.61)], varenicline plus nicotine replacement therapy over nicotine replacement therapy [OR = 1.84, 95% CI (1.07, 3.18)], and nicotine replacement therapy plus mecamylamine over naltrexone [OR = 6.29, 95% CI (1.59, 24.90)]. Finally, the surface under the cumulative ranking curve value indicated that nicotine replacement therapy plus mecamylamine had the greatest probability of becoming the best intervention. Most pharmacological interventions demonstrated a benefit in smoking cessation compared with placebo, whether monotherapy or combination therapy. Moreover, confirmed evidence suggested that some combination treatments, such as varenicline plus bupropion and nicotine replacement therapy plus mecamylamine have a higher probability of being the best smoking cessation in.
PubMed: 36353488
DOI: 10.3389/fphar.2022.1012433 -
Bioscience Reports Dec 2022M2 macrophages have been reported to be important in the progression of coronary artery disease (CAD). Thus, the present study aims at exploring the diagnostic value of...
BACKGROUND
M2 macrophages have been reported to be important in the progression of coronary artery disease (CAD). Thus, the present study aims at exploring the diagnostic value of M2 macrophage-associated genes in CAD.
METHODS
Transcriptome profile of CAD and control samples were downloaded from Gene Expression Omnibus database. The proportion of immune cells was analyzed using cell type identification by estimating relative subsets of RNA transcripts. Weighted Gene Co-expression Network Analysis (WGCNA) was carried out to screen the relevant module associated with M2 macrophages. Differential CAD and control samples of expressed genes (DEGs) were identified by the limma R package. Functional enrichment analysis by means of the clusterProfiler R package. Least absolute shrinkage and selection operator (LASSO) and random forest (RF) algorithms were carried out to select signature genes. Receiver operating curves (ROC) were plotted to evaluate the diagnostic value of selected signature genes. The expressions of potential diagnostic markers were validated by RT-qPCR. The ceRNA network of diagnostic biomarkers was constructed via miRwalk and Starbase database. CMap database was used to screen candidate drugs in the treatment of CAD by targeting diagnostic biomarkers.
RESULTS
A total of 166 M2 macrophage-associated genes were identified by WGCNA. By intersecting those genes with 879 DEGs, 53 M2 macrophage-associated DEGs were obtained in the present study. By LASSO, RF, and ROC analyses, C1orf105, CCL22, CRYGB, FRK, GAP43, REG1P, CALB1, and PTPN21 were identified as potential diagnostic biomarkers. RT-qPCR showed the consistent expression patterns of diagnostic biomarkers between GEO dataset and clinical samples. Perhexiline, alimemazine and mecamylamine were found to be potential drugs in the treatment of CAD.
CONCLUSION
We identified eight M2 macrophage-associated diagnostic biomarkers and candidate drugs for the CAD treatment.
Topics: Humans; Coronary Artery Disease; Gene Regulatory Networks; Gene Expression Profiling; Transcriptome; Macrophages; Biomarkers
PubMed: 36222281
DOI: 10.1042/BSR20221394 -
Developmental Biology Dec 2022We recently described calcium signaling in the appendicularian tunicate Oikopleura dioica during pre-gastrulation stages, and showed that regularly occurring calcium...
We recently described calcium signaling in the appendicularian tunicate Oikopleura dioica during pre-gastrulation stages, and showed that regularly occurring calcium waves progress throughout the embryo in a characteristic spatiotemporal pattern from an initiation site in muscle lineage blastomeres. Here, we have extended our observations to the period spanning from gastrulation to post-hatching stages. We find that repetitive Ca2+ waves persist throughout this developmental window, albeit with a gradual increase in frequency. The initiation site of the waves shifts from muscle cells at gastrulation and early tailbud stages, to the central nervous system at late tailbud and post-hatching stages, indicating a transition from muscle-driven to neurally driven events as tail movements emerge. At these later stages, both the voltage gated Na+ channel blocker tetrodotoxin (TTX) and the T-type Ca2+ channel blocker and nAChR antagonist mecamylamine eliminate tail movements. At late post-hatching stages, mecamylamine blocks Ca2+ signals in the muscles but not the central nervous system. Post-gastrulation Ca2+ signals also arise in epithelial cells, first in a haphazard pattern in scattered cells during tailbud stages, evolving after hatching into repetitive rostrocaudal waves with a different frequency than the nervous system-to-muscle waves, and insensitive to mecamylamine. The desynchronization of Ca2+ waves arising in different parts of the body indicates a shift from whole-body to tissue/organ-specific Ca2+ signaling dynamics as organogenesis occurs, with neurally driven Ca2+ signaling dominating at the later stages when behavior emerges.
Topics: Animals; Gastrulation; Urochordata; Calcium Signaling; Calcium; Mecamylamine
PubMed: 36162551
DOI: 10.1016/j.ydbio.2022.09.004 -
American Journal of Physiology.... Nov 2022It has previously been shown that current smoking is protective against endoscopic retrograde cholangiopancreatography (ERCP)-induced acute pancreatitis, but the...
It has previously been shown that current smoking is protective against endoscopic retrograde cholangiopancreatography (ERCP)-induced acute pancreatitis, but the mechanism of this effect was not identified. We tested the hypothesis that nicotine is the active factor in this protection in a mouse model of ERCP. Pretreatment with nicotine dose dependently inhibited acute pancreatitis caused by infusion of ERCP contrast solution into the main pancreatic duct in mice. 3-2,4-Dimethoxybenzylidene anabaseine (GTS-21), a specific partial agonist of the α7 nicotinic cholinergic receptor (α7nAChR), also protected the pancreas against ERCP-induced acute pancreatitis. The effects of GTS-21 were abolished by pretreatment with the nicotinic receptor antagonist mecamylamine. Surgical splenectomy performed 7 days before ERCP-induced pancreatitis blocked the protective effects of GTS-21. Intravenous injection of a crude preparation of total splenocytes prepared from mice pretreated with GTS-21 inhibited ERCP-induced pancreatitis; splenocytes from mice treated with vehicle had no effect. When T cells were removed from the crude GTS-21-treated splenocyte preparation by immunomagnetic separation, the remaining non-T-cell splenocytes did not protect against ERCP-induced acute pancreatitis. We conclude that nicotine protects against ERCP-induced acute pancreatitis and that splenic T cells are required for this effect. Stimulation of α7 nicotinic cholinergic receptors may protect against ERCP-induced acute pancreatitis and may also be a novel approach to therapeutic reversal of ongoing acute pancreatitis. Epidemiological evidence indicated that acute smoking reduced the risk of endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis, but the mechanism has remained elusive. The current findings indicate the nicotine reduces the severity of ERCP-induced pancreatitis by stimulating a population of splenic T cells that exert a protective effect on the pancreas. These findings raise the possibility that nicotinic agonists might be useful in treating pancreatitis.
Topics: Mice; Animals; Cholangiopancreatography, Endoscopic Retrograde; Pancreatitis; Nicotine; Mecamylamine; Nicotinic Agonists; Acute Disease; alpha7 Nicotinic Acetylcholine Receptor; Spleen; T-Lymphocytes
PubMed: 36126221
DOI: 10.1152/ajpgi.00156.2022 -
Molecular Brain Sep 2022Nicotinic acetylcholine receptors are thought to be associated with a wide range of phenomena, such as movement, learning, memory, attention, and addiction. However, the...
Systemic injection of nicotinic acetylcholine receptor antagonist mecamylamine affects licking, eyelid size, and locomotor and autonomic activities but not temporal prediction in male mice.
Nicotinic acetylcholine receptors are thought to be associated with a wide range of phenomena, such as movement, learning, memory, attention, and addiction. However, the causal relationship between nicotinic receptor activity and behavior remains unclear. Contrary to the studies that examined the functions of muscarinic acetylcholine receptors, the role of the nicotinic acetylcholine receptors on behavior has not been examined as extensively. Here, we examined the effects of intraperitoneal injection of mecamylamine, a nicotinic acetylcholine receptor antagonist, on the performance of male mice in a head-fixed temporal conditioning task and a free-moving open-field task. The head-fixed experimental setup allowed us to record and precisely quantify the licking response while the mice performed the behavioral task with no external cues. In addition, by combining the utility of the head-fixed experimental design with computer vision analysis based on deep learning algorithms, we succeeded in quantifying the eyelid size of awake mice. In the temporal conditioning task, we delivered a 10% sucrose solution every 10 s using a blunt-tipped needle placed within the licking distance of the mice. After the training, the mice showed increased anticipatory licking toward the timing of sucrose delivery, suggesting that the mice could predict the timing of the reward. Systemic injection of mecamylamine decreased licking behavior and caused eye closure but had no effect on learned conditioned predictive behavior in the head-fixed temporal conditioning task. In addition, the injection of mecamylamine decreased spontaneous locomotor activity in a dose-dependent manner in the free-moving open-field task. The results in the open-field experiments further revealed that the effect of mecamylamine on fecal output and urination, suggesting the effects on autonomic activities. Our achievement of successful eyelid size recording has potential as a useful approach in initial screening for drug discovery. Our study paves a way forward to understanding the role of nicotinic acetylcholine receptors on learning and behavior.
Topics: Animals; Dose-Response Relationship, Drug; Eyelids; Male; Mecamylamine; Mice; Nicotinic Antagonists; Receptors, Nicotinic; Sucrose
PubMed: 36068635
DOI: 10.1186/s13041-022-00959-y -
Cells Aug 2022Mucociliary clearance is a primary defence mechanism of the airways consisting of two components, ciliary beating and transepithelial ion transport (I). Specialised...
Mucociliary clearance is a primary defence mechanism of the airways consisting of two components, ciliary beating and transepithelial ion transport (I). Specialised chemosensory cholinergic epithelial cells, named brush cells (BC), are involved in regulating various physiological and immunological processes. However, it remains unclear if BC influence I. In murine tracheae, denatonium, a taste receptor agonist, reduced basal I in a concentration-dependent manner (EC 397 µM). The inhibition of bitter taste signalling components with gallein (G subunits), U73122 (phospholipase C), 2-APB (IP3-receptors) or with TPPO (Trpm5, transient receptor potential-melastatin 5 channel) reduced the denatonium effect. Supportively, the I was also diminished in Trpm5 mice. Mecamylamine (nicotinic acetylcholine receptor, nAChR, inhibitor) and amiloride (epithelial sodium channel, ENaC, antagonist) decreased the denatonium effect. Additionally, the inhibition of G subunits (pertussis toxin) reduced the denatonium effect, while an inhibition of phosphodiesterase (IBMX) increased and of adenylate cyclase (forskolin) reversed the denatonium effect. The cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTR and the KCNQ1 potassium channel antagonist chromanol 293B both reduced the denatonium effect. Thus, denatonium reduces I via the canonical bitter taste signalling cascade leading to the Trpm5-dependent nAChR-mediated inhibition of ENaC as well as G signalling leading to a reduction in cAMP-dependent I. Therefore, BC activation contributes to the regulation of fluid homeostasis.
Topics: Animals; Cyclic AMP; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Sodium Channels; Mice; Quaternary Ammonium Compounds; Taste; Taste Buds
PubMed: 35954259
DOI: 10.3390/cells11152411 -
Neural Regeneration Research Feb 2023Therapeutic intervention for spinal cord injury is limited, with many approaches relying on strengthening the remaining substrate and driving recovery through...
Therapeutic intervention for spinal cord injury is limited, with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training. As compared with learning novel compensatory strategies, rehabilitation focuses on restoring movements lost to injury. Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning, or if it engages previously trained motor circuits without requiring novel learning remains an open question. In this study, mice were randomly assigned to receive intraperitoneal injection with the pan-nicotinic, non-competitive antagonist mecamylamine and the nicotinic α7 subunit selective antagonist methyllycaconitine citrate salt or vehicle (normal saline) prior to motor learning assays, then randomly reassigned after motor learning for rehabilitation study post-injury. Cervical spinal cord dorsal column lesion was used as a model of incomplete injury. Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury. Our findings indicate that critical differences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.
PubMed: 35900431
DOI: 10.4103/1673-5374.346544