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      History of Respiratory Stimulants

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          The interest in substances that stimulate respiration has waxed and waned throughout the years, intensifying following the introduction of a new class of drugs that causes respiratory depression, and diminishing when antidotes or better drug alternatives are found. Examples include the opioids––deaths increasing during overprescribing, diminishing with wider availability of the opioid receptor antagonist naloxone, increasing again during COVID-19; the barbiturates––until largely supplanted by the benzodiazepines; propofol; and other central nervous system depressants. Unfortunately, two new troubling phenomena force a reconsideration of the status-quo: (1) overdoses due to highly potent opioids such as fentanyl, and even more-potent licit and illicit fentanyl analogs, and (2) overdose due to polysubstance use (the combination of an opioid plus one or more non-opioid drug, such as a benzodiazepine, sedating antidepressant, skeletal muscle relaxant, or various other agents). Since these now represent the majority of cases, new solutions are again needed. An interest in respiratory stimulants has been revived. This interest can be informed by a short review of the history of this interesting class of medications. We present a short history of the trajectory of advances toward more selective and safer respiratory stimulants.

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          Most cited references 57

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          Inspiratory bursts in the preBötzinger complex depend on a calcium-activated non-specific cation current linked to glutamate receptors in neonatal mice.

          Inspiratory neurons of the preBötzinger complex (preBötC) form local excitatory networks and display 10-30 mV transient depolarizations, dubbed inspiratory drive potentials, with superimposed spiking. AMPA receptors are critical for rhythmogenesis under normal conditions in vitro but whether other postsynaptic mechanisms contribute to drive potential generation remains unknown. We examined synaptic and intrinsic membrane properties that generate inspiratory drive potentials in preBötC neurons using neonatal mouse medullary slice preparations that generate respiratory rhythm. We found that NMDA receptors, group I metabotropic glutamate receptors (mGluRs), but not group II mGluRs, contributed to inspiratory drive potentials. Subtype 1 of the group I mGluR family (mGluR1) probably regulates a K+ channel, whereas mGluR5 operates via an inositol 1,4,5-trisphosphate (IP3) receptor-dependent mechanism to augment drive potential generation. We tested for and verified the presence of a Ca2+-activated non-specific cation current (I(CAN)) in preBötC neurons. We also found that high concentrations of intracellular BAPTA, a high-affinity Ca2+ chelator, and the I(CAN) antagonist flufenamic acid (FFA) decreased the magnitude of drive potentials. We conclude that I(CAN) underlies robust inspiratory drive potentials in preBötC neurons, and is only fully evoked by ionotropic and metabotropic glutamatergic synaptic inputs, i.e. by network activity.
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            Inhibitory glycine receptors: an update.

            Strychnine-sensitive glycine receptors (GlyRs) mediate synaptic inhibition in the spinal cord, brainstem, and other regions of the mammalian central nervous system. In this minireview, we summarize our current view of the structure, ligand-binding sites, and chloride channel of these receptors and discuss recently emerging functions of distinct GlyR isoforms. GlyRs not only regulate the excitability of motor and afferent sensory neurons, including pain fibers, but also are involved in the processing of visual and auditory signals. Hence, GlyRs constitute promising targets for the development of therapeutically useful compounds.
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              Generation and transmission of respiratory oscillations in medullary slices: role of excitatory amino acids.

              1. The involvement of excitatory amino acid (EAA) receptors in the generation of respiratory rhythm and transmission of inspiratory drive to hypoglossal (XII) motoneurons was examined in an in vitro neonatal rat medullary slice preparation. Slices generated rhythmic inspiratory activity in XII nerves. The role of EAAs in rhythm generation was determined by analyzing perturbations of respiratory network activity after bath application of EAA receptor antagonists or local microinjection of antagonists into the main column of respiratory neurons in the ventrolateral medulla (ventral respiratory group), particularly in the pre-Bötzinger complex (pre-BötC). The involvement of EAAs in drive transmission to XII motoneurons was examined by recording perturbations in XII nerve discharge or motoneuron synaptic inputs after microinjection of EAA receptor antagonists into either the XII motor nuclei or sites in the ventrolateral medulla containing interneurons of the drive transmission circuit. 2. Block of non-N-methyl-D-aspartate (non-NMDA) receptors by bath application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reversibly reduced XII nerve burst frequency and amplitude in a concentration-dependent manner, completely blocking respiratory motor output at concentrations > 4 microM. Activation of 2-amino-4-phosphonobutyric acid (AP-4)-sensitive receptors with D,L AP-4 reduced XII nerve burst amplitude by 30% but did not alter burst frequency. Block of NMDA receptor channels by bath application of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-iminemaleate (MK-801) did not perturb the frequency or amplitude of motor output. Inhibition of EAA uptake in the slices by bath application of dihydrokainic acid reversibly increased the frequency and amplitude of XII motor discharge. 3. Block of non-NMDA receptors at multiple sites along the main column of respiratory neurons in the ventrolateral medulla, including the pre-BötC, by unilateral microinjection of CNQX produced a dose-dependent, bilateral reduction in XII nerve burst amplitude without substantial perturbations of the frequency of respiratory oscillations. Block of non-NMDA receptors within the pre-BötC at sites ventral to amplitude altering sites produced a reduction in frequency and ultimately bilateral block of respiratory network oscillations. 4. Non-NMDA receptor block within the XII motor nucleus by unilateral microinjection of CNQX produced a dose-dependent reduction in ipsilateral XII nerve discharge amplitude without perturbing the frequency of respiratory oscillations. Perturbations of contralateral XII nerve burst amplitude were significantly smaller. NMDA channel block within the XII motor nucleus did not affect inspiratory burst amplitude, whereas activation of AP-4 receptors caused a 30% reduction in amplitude.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                16 April 2021
                : 14
                : 1043-1049
                [1 ]Marian University College of Osteopathic Medicine , Indianapolis, IN, USA
                [2 ]Pikeville University College of Osteopathic Medicine , Pikeville, KY, USA
                [3 ]Enalare Therapeutics Inc ., Princeton, NJ, USA
                [4 ]NEMA Research Inc ., Naples, FL, USA
                [5 ]Neumentum Inc ., Summit, NJ, USA
                [6 ]Western New England College of Pharmacy , Springfield, MA, USA
                [7 ]Albany College of Pharmacy & Health Sciences Union University , Albany, NY, USA
                [8 ]Remitigate Therapeutics , Delmar, NY, USA
                [9 ]Texas A&M College of Medicine , Bryan, TX, USA
                [10 ]University of Arizona College of Pharmacy , Tucson, AZ, USA
                [11 ]Temple University School of Pharmacy , Philadelphia, PA, USA
                Author notes
                Correspondence: Robert B Raffa Tel +1 610-291-7019 Email robert.raffa@temple.edu
                © 2021 Peppin et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

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                Figures: 0, References: 60, Pages: 7


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