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Neuropharmacology Of Respiration
Published in Alan D. Miller, Armand L. Bianchi, Beverly P. Bishop, Neural Control of the Respiratory Muscles, 2019
Monique Denavit-Saubié, Arthur S. Foutz
Iontophoretic applications in adult animals in vivo61 have shown that a large proportion of respiratory neurons of various types respond to ACh and to muscarinic and nicotinic agonists, and thus have both receptor types. The effects of the agonists were antagonized by atropine or nicotinic antagonists, but the effects of the antagonists applied alone were inconsistent. However, in decerebrate cats, atropine applied extracellularly by iontophoresis partly or totally suppresses the depolarizing response to hypercapnia of neurons in the ventral respiratory group.91 The proportion of respiratory neurons inhibited by ACh is much greater in anesthetized than in decerebrated animals,61 and this might explain inconsistencies in the literature. Similarly, after a systemic injection of a Cholinesterase inhibitor, the respiratory output is either depressed or stimulated, depending on whether the animal is anesthetized or decerebrated. Therefore, most anesthetics may precipitate respiratory failure by inverting the response of some respiratory neurons to ACh.
Metabolic Mapping with Deoxyglucose Autoradiography as an Approach for Assessing Drug Action in the Central Nervous System
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Akeo Kurumaji, Deborah Dewar, James McCulloch
The effects of nicotine on cerebral glucose use are both dose dependent and reversed by the nicotinic antagonist, mecamylamine (London et al., 1988). Moreover, nicotine doses that effect metabolic changes compare favorably with those that produced behavioral effects. Glucose use is increased in the majority of responsive areas by 0.3 mg/kg nicotine, which is similar to doses used in training rats to discriminate nicotine (Overton, 1979). Increases in glucose use in response to nicotine were observed in the Papez circuit, and these actions may be involved in the effects nicotine has on cognitive performance. Similarly, the motor effects of nicotine could be due to the increases in glucose use observed in areas known to be involved in motor control, namely, cerebellar vermis, red nucleus, substantia nigra, pars compacta, and paramedian nucleus. The response of the nucleus of the spinal tract of the trigeminal nerve (Sp5) is consistent with the antinociceptive effects of nicotine, as are the responses seen in the nucleus ambiguus and nucleus of the solitary tract with its ability to increase blood pressure. While these correlations between the physiological and behavioral effects of nicotine and its ability to enhance glucose use in brain structures implicated in these effects do not prove causal relationships, they provide insight into the possible mechanisms by which nicotine produces its effects.
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
Nicotinic antagonists, at the present time, may be divided into two general categories: 1) those that are muscle nicotinic receptor antagonists or so-called neuromuscular blockers, such as d-tubocurarine (curare, the South American arrow poison), and 2) the neuronal nicotinic antagonists or so-called ganglionic blockers, such as hexamethonium, mecamylamine (Inversine®), and trimethaphan. The only ganglionic blocker still available in the United States is mecamylamine. Neuromuscular and ganglionic blockers interfere with neurotransmission by acting on the postsynaptic nicotinic receptor (an ion channel) and binding to it in a competitive or noncompetitive manner to prevent the binding of ACh to the receptor. The drugs that act at the neuromuscular junction to produce muscle paralysis bind directly to the nicotinic receptor, preventing access of ACh. This is also how some of the ganglionic blocking agents work (e.g., mecamylamine, trimethaphan). However, some of the ganglionic blockers (e.g., hexamethonium) enter the ion channel and form a plug, which also effectively interferes with neurotransmission by preventing influx of sodium ions.42
Influence of experimental end point on the therapeutic efficacy of the antinicotinic compounds MB408, MB442 and MB444 in treating nerve agent poisoned mice – a comparison with oxime-based treatment
Published in Toxicology Mechanisms and Methods, 2020
Jiri Kassa, Christopher M. Timperley, Mike Bird, A. Christopher Green, John E. H. Tattersall
The nicotinic antagonists would be an addition to antidotal treatment of nerve agent-induced poisoning (Sheridan et al. 2005), because atropine sufficiently antagonizes nerve agent-induced overstimulation of mAChRs but has no therapeutic effect at nAChRs (McDonough and Shih 2007). Until now, nicotinic antagonists have not been used to treat nerve agent poisoning because of the difficulties of administering a dose sufficient to alleviate the effects of excessive ACh without causing neuromuscular paralysis (Sheridan et al. 2005). However, noncompetitive nicotinic antagonists are considered relatively safe because they do not compete with acetylcholine binding and their effects will not be overcome by increasing concentrations of ACh. Certain bispyridinium compounds have beneficial effects in poisoning with organophosphorus compounds through their ability to affect the open ion channel of the nAChR and/or nAChR orthosteric sites (Tattersall 1993; Niessen et al. 2013).
Cell signal transduction: hormones, neurotransmitters and therapeutic drugs relate to purine nucleotide structure
Published in Journal of Receptors and Signal Transduction, 2018
Molecular structure has a direct bearing on ligand specificity in regard to the interaction of purine nucleotides and G-proteins with cell membrane receptors. Equilibrium binding studies on the M2 acetylcholine receptor demonstrate that depletion of membrane-bound GDP increases the proportion of high-affinity agonist sites, and carbachol accelerates the dissociation of GDP [14]. The binding of α7 nicotinic acetylcholine receptors to Gα and Gβγ proteins decreases in the presence of ligand [15]. Some commonality in the functional properties of receptor ligands extends across receptor classes. Antiarrhythmics, anesthetics, antidepressants, histamine (H1) and calcium channel antagonists all block the glibenclamide sensitive K+ current [16]. Nicotinic ligands such as epibatidine and tubocurarine bind with high potency to a serotonin (5-HT3) receptor and serotonin acts as a nicotinic antagonist [17]. The therapeutic consequences of poor drug-receptor specificity are evident in the concepts of pharmacological promiscuity and network pharmacology [18,19].
Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study
Published in Scandinavian Journal of Rheumatology, 2021
AM Drewes, C Brock, SE Rasmussen, HJ Møller, B Brock, BW Deleuran, AD Farmer, M Pfeiffer-Jensen
The autonomic nervous system serves to maintain homoeostasis. It is broadly comprised of two opposing branches: the sympathetic and the parasympathetic nervous systems, with the vagus nerve representing the main neural substrate of the latter. The vagus nerve has a pivotal role in modulating inflammation (4). There is supported evidence that the vagus nerve, through the cholinergic anti-inflammatory pathway, suppresses the production of pro-inflammatory cytokines, such as TNF-α, by direct inhibition of peripheral macrophages mediated through lymphocytes, and indirectly via the splenic coeliac ganglion, leading to release of acetylcholine from the distal vagus nerve (4, 5). TNF-α is a central pathophysiological mediator in RA and is the target of monoclonal antibodies (6). α7-Nicotinic acetylcholine receptors (α7nAChR), expressed on cytokine-producing macrophages, monocytes, and in the synovium of patients with RA, are activated by acetylcholine, which inhibits nuclear factor-κB activation and other pro-inflammatory factors (7–9). Studies in vagotomized mice demonstrate that electrical vagal stimulation applied to the distal end of the nerve ameliorates the pro-inflammatory cytokine response to lipopolysaccharide (LPS) (10). Vagotomy also induces the proliferation of splenic CD4 T lymphocytes and proinflammatory cytokines after in vitro stimulation. It is also shown that nicotine can counteract the consequences of vagotomy and nicotinic antagonists can mimic these effects. These findings imply that the vagus nerve may affect the threshold for activation of CD4+ T cells, and increased activity in the vagus nerve may counteract the lowered threshold of CD4+ T cells (11, 12).