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Instituto Nacional de Neurología y Neurocirugía

2018, Number 2

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Arch Neurocien 2018; 23 (2)

In silico evaluation of benzodiacepine, ketamine and temperature effect on pre-Bötzinger neuronal discharge patterns of respiratory control

Martínez-Reyes H, Eblen-Zajjur A

Language: Spanish
References: 36
Page: 25-35
PDF size: 676.08 Kb.


ABSTRACT

Introduction: Fever and the use of drugs such as benzodiazepines (GABAA agonists) and ketamine (NMDA antagonist) occur relatively frequently in anesthesiology. Breathing is a pattern generated in the brain stem, product of a complex ponto-medullary networks, which control the respiratory motoneurons thanks to the interaction of the inspiratory neurons of the pre-Bötzinger complex and the espiratory ones of the Bötzinger complex. These neurons have membrane receptors of the GABAA and NMDA type, which show high thermo-dependence, however, the changes in the pattern of neuronal discharge induced by these drugs and changes in body temperature are unknown.
Materials and methods: A validated model of pre-inspiratory neuron (pre-Bötzinger complex) was generated, increasing the synaptic GABAA weight equivalent to the effect of benzodiazepines or reducing the NMDA synaptic weight equivalent to the effect of ketamine in hypo- (35°C), normo- (37°C) or hyperthermia (40°C) quantifying the number and amplitude of neuronal discharges.
Results: Increase in GABAA or reduction of NMDA synaptic weights at temperatures of 35°C, 37°C or 40°C proportionally reduced the number of spikes and the amplitude of the action potential of the Pre-I neuronal, showing dose-response 2nd order polynomial curves with increased slopes at 35°C and 40°C.
Conclusion: benzodiazepines or ketamine through its receptors GABAA) and NMDA modify in silico the discharge pattern of Pre-I neuron from Pre-Bötzinger nucleus, showing more gabaergic effect and higher thermo-dependence in the dose-response curves during hypo and hyperthermia which are relevant for clinical practice.


REFERENCES

  1. Bianchi AL, Denavit-Saubie M, Champagnat J. Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. Physiol Rev 1995;75(1):1-45.

  2. Cohen MI. Neurogenesisof respiratory rhythm in the mammal. Physiol Rev 1979;59:1105-73.

  3. Richter DW. Neural regulation of respiration: rhythmogenesis and afferent control. In: comprehensive human Physiology 1996; 2079-95.

  4. Hilaire G, Duron B. Maturation of the mammalian respiratory system. Physiol Rev 1999;79(2):325-60.

  5. Smith JC, Ellenberger HH, Ballanyi K, Richter DWA, Feldman JL. Pre-Botzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 1991;254:726-9.

  6. Rekling JC, Feldman JL. PreBotzinger complex and pacemaker neurons hypothesized site and kernel for respiratory rhythm generation. Annu Rev Physiol 1998; 60:385-405.

  7. Koshiya N, Smith JC. Neuronal pacemaker for breathing visualized in vitro. Nature 1999;400(6742):360–3.

  8. Ezure K. Synaptic connections between medullary respiratory neurons and considerations on the genesis of respiratory rhythm. Prog Neurobiol 1990;35:429–50.

  9. Bianchi AL, Denavit-Saubié M, Champagnat J. Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters. Physiol Rev 1995;75(1):1–45.

  10. Ezure K, Tanaka I, Saito Y. Brainstem and spinal projections of augmenting expiratory neurons in the rat. Neurosci Res 2003;45(1):41–51.

  11. Rybak IA. Late expiratory activity emergence and interactions with the respiratory CPG. J Neurophysiol 2010;104:2713–29.

  12. Rubin JE, Shevtsova NA, Ermentrout GB, Smith JC, and Rybak IA. Multiple rhythmic states in a model of the respiratory central pattern generator. J Neurophysiol 2009;101:2146–65.

  13. Rybak IA, Molkov YI, Paton JF, Abdala AP, Zoccal DB. Modeling the autonomic nervous system, in primer on the autonomic nervous system. 3rd Edition. Robertson, Biagioni, Burnstock, Lowe, Paton, Editors. Oxford Academic Press 2012; 681–7.

  14. Rybak IA, Paton JFR, Schwaber J. Modeling neural mechanisms for genesis of respiratory rhythm and pattern: II. Network models of the central respiratory pattern generator. J Neurophysiol 1997;77:2007–26.

  15. Fietkiewicz C, Loparo K, Wilson CG. Drive latencies in hypoglossal motoneurons indicate developmental change in the brainstem respiratory network. J Neural Eng 2011;8(6):65011.

  16. Molkov YI, Bacak BJ, Dick TE, Rybak IA. Control of breathing by interacting pontine and pulmonary feedback loops. 2013; 7:1–18.

  17. Loewy AD, Spyer KM. Central regulation of autonomic functions. NewYork Oxford University Press1990.

  18. Rybak IA, Ptak K, Shevtsova NA, McCrimmon D. Sodium currents in neurons from the rostroventrolateral medulla of the rat. J Neurophysiol 2003;90:1635–42.

  19. Smith JC, Abdala PL, Koizumi H, Rybak IA, Paton JFR. Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms. J Neurophysiol 2007;98(6):3370–87.

  20. Butera RJ, Rinzel JR, Smith J. Models of respiratory rhythm generation in the pre-Bötzinger complex: II. Populations of coupled pacemaker neurons. J Neurophysiol 1999;82:398–415.

  21. Butera RJ, Rinzel JR, Smith J. Models of respiratory rhythm generation in the pre-Bötzinger complex: I. Populations of coupled pacemaker neurons. J Neurophysiol 1999;82:382–97.

  22. Rybak IA, Paton JF, Schwaber SJ. Modeling neural mechanisms for genesis of respiratory rhythm and pattern: I. Network models of the central respiratory pattern generator. J Neurophysio 1997;77:1994–2006.

  23. Rybak IA, Shevtsova NA, Paton JFR, Dick TE, et al. Modeling the ponto-medullary respiratory network. Respir Physiol Neurobiol 2004;143:307–19.

  24. Frermann D, Keller BU, Richter D. Calcium oscillations in rhythmically active respiratory neurones in the brainstem of the mouse. J Physiol 1999;515:119–31.

  25. Elsen FP, Ramirez J. Calcium currents of rhythmic neurons recorded in the isolated respiratory network of neonatal mice. J Neurosci. 1998;18:10652–62.

  26. Martinez H, Eblen-Zajjur A. Termodependencia en rango clinico de las descargas neuronales individuales y colectivas en el complejo nuclear pre Bötzinger responsable del ritmo respiratorio. LXV Conv Anu ASOVAC. Caraca 2015.

  27. Huguenard J, McCormick D. Electrophysiology of the neuron. New York Oxford: Oxford University Press; 1994.

  28. Hammer O, Harper DAT, Ryan PD. PAST-palaeontological statistics, ver.1.89. Palaeontol electron 2001; 4(1):1-9.

  29. Vasilenko VY. Thermosensitivity: an intrinsic property of hypothalamic neurons. J Therm Biol 1994; 19: 219-236.

  30. Belluzzi O, Sacchi O.A five-conductance model of the action potential in the rat sympathetic neurone. Prog Biophys Mol Biol 1994; 55:1-30.

  31. Alfonsi E, Merlini G, Giorgetti A, Ceroni M, Piccolo G, Agostinis C, Savoldi F. Temperature-related changes in sensory nerve conduction: studies in normal subjects and in patients with paraproteinaemia. Electromyogr Clin Neurophysiol 1987; 27: 277-82.

  32. Chaudhry V, Crawford TO, Derossett SE. 1993. Thermal sensitivity in demyelinating neuropathy. Muscle Nerve 1993; 16: 301–6.

  33. Rutkove S, Kothari M, Shefner J. Nerve, muscle, and neuromuscular junction electrophysiology at high temperature. Muscle and Nerve 1997; 20(4):431–6.

  34. Bevan S. TRP channels as thermosensors. Current Topics in Membranes, 2006; 57: 199-239.

  35. Huang J, Zhang X, Mcnaughton PA. Modulation of temperature-sensitive TRP channels. Cell Dev Biol 2006; 17: 638–45.

  36. Montell C, Caterina MJ. Thermoregulation: channels that are cool to the core. Curr Biol 2007;17: 885–87.




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