Regular ArticleRole of Opioidergic and Serotonergic Mechanisms in Cough and Antitussives
Abstract
This paper provides an overview of our current understanding of the serotonergic and opioidergic mechanisms of cough and antitussives. Systemic administration of 8-OH-DPAT, at doses of 0.1 and 0.3 mg/kg, ip, markedly reduced the number of coughs in rats in a dose-dependent manner. The antitussive effects of 8-OH-DPAT, dihydrocodeine and dextromethorphan were significantly reduced by pretreatment with methysergide, but not with ketanserin. Therefore it is possible to speculate that 5-HT1receptors, in particular the 5-HT1Areceptors, may be more important than others with respect to the effect of antitussive drugs. DAMGO, a selective μ-opioid receptor agonist, and U-50,488H, a highly selective κ-opioid receptor agonist, have potent antitussive effects when administered either icv or ip. However, we did not observe a cough-depressant effect of DPDPE, a selective δ-opioid receptor agonist. These results indicate that the antitussive effects of opioids are mediated predominantly by μ- and κ-opioid receptors. On the other hand, naloxonazine, a selective μ1-opioid receptor antagonist, had no effect on the antitussive effects associated with icv DAMGO. These results indicate that μ2- rather than μ1-opioid receptors are involved in μ-opioid receptor-induced antitussive effects. Antitussive effects of dextromethorphan and noscapine were significantly and dose-dependently reduced by pretreatment with rimcazole, a specific antagonist of sites. However, rimcazole did not have a significant effect on the antitussive effect of morphine. These results suggest that sites may be involved in the antitussive mechanism of non-narcotic antitussive drugs.
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Chemical Space of Small Molecule Exploration for the Elucidation of Cough Suppressant Pharmacology of Ying Su Ke/Zi
2024, Journal of Herbal MedicineChronic cough, a prevalent condition, lacks effective medical solutions. Traditionally, Ying Su Ke/Zi (derived from Papaver somniferum L.) has been used in certain ethnic herbal formulas to address cough. However, there is a notable absence of molecular-level exploration regarding their mechanism for treating cough.
Starting with the chemical ingredients of Ying Su Ke/Zi, this study used principal component analysis to explore the chemical space of these compounds and set four rounds of screening criteria based on the chemical space distribution to quickly identify active compounds. Following that, their targets were predicted using the weighted ensemble system model, and target enrichment analysis was executed.
In total, 247 compounds in Ying Su Ke/Zi were data-mined from literature reports, based on which four rounds of screening yielded 88 potential active chemicals, mostly alkaloids. Besides, 168 target proteins, mostly G-protein-coupled receptors, were identified, and meanwhile the results of the enrichment analysis revealed that these target proteins are, mostly, localised at cell membranes, cell junctions, and cell projections, and they were primarily involved in biological processes ranging from stimulus response, signalling, and bioregulation, possessing molecular functions concerning altering molecular transduction activity and binding. Moreover, the key biological pathways covered by these target proteins are neuroactive receptor-ligand interaction pathway, serotonergic synapse pathway, etc.
Integrating the foregoing findings with the pathophysiological characteristics of cough, the current study reveals that Ying Su Ke/Zi exert their antitussive pharmacological effects primarily via opioidergic and serotonergic mechanisms.
Are noscapine and raloxifene ligands of the bradykinin B<inf>2</inf> receptor? An assessment based on the human umbilical vein contractility assay
2022, International ImmunopharmacologyThe centrally acting antitussive opiate derivative, noscapine, has been claimed to be a non-competitive bradykinin B2 receptor antagonist. Raloxifene, a selective estrogen receptor modulator, was predicted to bind the bradykinin B2 receptor and to exert a partial agonist activity. These intriguing claims suggest that new molecular scaffolds (“chemotypes”) may be identified for small molecule ligands of kinin receptors and that some off-target effects of noscapine or raloxifene may be mediated by bradykinin B2 receptors. An established contractile bioassay for ligands of the bradykinin B2 receptor, the isolated human umbilical vein, was exploited to characterize the inhibitory effect of noscapine and raloxifene on the B2 receptor-mediated contractile response to bradykinin. Observed effects were compared with those of the peptide antagonist icatibant, a potent, selective and competitive B2 receptor antagonist. Our results indicate that neither noscapine (2.5 µM) nor raloxifene (20 µM) behave as B2 receptor antagonists in concentrations that vastly exceeded an effective concentration of the control antagonist, icatibant; further, none of these drugs had direct contractile effects. It is suggested that the previously reported B2 receptor inhibitory effect of noscapine, a putative sigma-receptor agonist, might result from an indirect physiological antagonism, while raloxifene did not appear to have any significant affinity for the B2 receptors.
Physicochemical properties and in vitro digestion behavior of a new bioactive Tremella fuciformis gum
2022, International Journal of Biological MacromoleculesA new easy-dissolved Tremella fuciformis gum (TFG) from fruiting body was investigated in detail from three aspects: physicochemical characteristics, rheological behavior and in vitro digestion behavior. The results showed that TFG consisted of 73.9% polysaccharides, exhibiting easy solubility in water and good colloidal characteristics and stability. The physical and chemical treatments could decrease the apparent viscosity of TFG solution. The antioxidation activity of TFG remained constant at each static in vitro digestion phase, revealing that this gum could be used as a potential food thickener and antioxidant. The digestion behavior of TFG was also determined using a dynamic in vitro digestive system, DIVRS-II. The results demonstrated that the digestion behavior of TFG should be attributed to the morphology of digestive tracts, continuous secreting and continuous emptying. The antitussive effect of TFG was related to the increase in serum IL-10 content.
Effect of prolonged mechanical ventilation on cough function and TRPV1 expression
2022, Respiratory Physiology and NeurobiologyCough is a pivotal airway protective reflex, yet the effects of prolonged mechanical ventilation (PMV) on cough function are unknown. This study compared the cough function in subjects with PMV (≥ 21 days, n = 29) and those with short-term mechanical ventilation (SMV, ≤ 7 days, n = 27). Cough reflex sensitivity was measured by capsaicin provocation concentrations after extubation. The cough strength of respiratory muscles was assessed by involuntary cough peak expiratory flow (iCPEF). The mRNA expression of transient receptor potential vanilloid 1 (TRPV1), a cough sensor activated by capsaicin, in tracheal tissues was determined. We found that cough reflex sensitivity and iCPEF were significantly lower in the PMV group than in the SMV group. The tracheal expression of TRPV1 was similar in both groups, suggesting that changes in TRPV1 expression may not be a contributing factor. Our finding regarding the cough dysfunction after PMV highlights the need to implement effective airway clearance management and rehabilitation in this population.
Visible-light-mediated metal-free decarboxylative acylation of electron-deficient quinolines using α-ketoacids under ambient air
2022, TetrahedronA visible-light-promoted metal-free decarboxylative coupling protocol for the acylation of electron-deficient quinolines using ambient air as an oxidant has been disclosed. This environmental-friendly protocol takes place under mild conditions and is highlighted by using inexpensive photocatalyst and starting materials, thereby integrating C–H functionalization and recent photoredox scenario based on diaryl ketones. This work contributes to a more systematic utilization of α-ketoacids as an efficient source of acyl radicals in acylation of electron-deficient heteroaromatic compounds.
Biomimetic photooxidation of noscapine sensitized by a riboflavin derivative in water: The combined role of natural dyes and solar light in environmental remediation
2022, Journal of Photochemistry and Photobiology B: BiologyNoscapine (NSC) is a benzyl-isoquinoline alkaloid discovered in 1930 as an antitussive agent. Recently, NSC has also been reported to exhibit antitumor activity and, according to computational studies, it is able to attack the protease enzyme of Coronavirus (COVID-19) and thus could be used as antiviral for COVID-19 pandemic. Therefore, an increasing use of this drug could be envisaged in the coming years. NSC is readily metabolized with a half-life of 4.5 h giving rise to cotarnine, hydrocotarnine, and meconine, arising from the oxidative breaking of the CC bond between isoquinoline and phthalide moieties. Because of its potentially increasing use, high concentrations of NSC but also its metabolites will be delivered in the environment and potentially affect natural ecosystems. Thus, the aim of this work is to investigate the degradation of NSC in the presence of naturally occurring photocatalysts. As a matter of fact, the present contribution has demonstrated that NSC can be efficiently degraded in the presence of a derivative of the natural organic dye Riboflavin (RFTA) upon exposure to visible light. Indeed, a detailed study of the mechanism involved in the photodegradation revealed the similarities between the biomimetic and the photocatalyzed processes. In fact, the main photoproducts of NSC were identified as cotarnine and opianic acid based on a careful UPLC-MS2 analysis compared to the independently synthesized standards. The former is coincident with one of the main metabolites obtained in humans, whereas the latter is related to meconine, a second major metabolite of NSC. Photophysical experiments demonstrated that the observed oxidative cleavage is mediated mainly by singlet oxygen in a medium in which the lifetime of 1O2 is long enough, or by electron transfer to the triplet excited state of RFTA if the photodegradation occurs in aqueous media, where the 1O2 lifetime is very short.