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Mechanism of Action of Nitrous Oxide

  • Dimitrios Emmanouil
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Abstract

The use of nitrous oxide sedation can reduce anxiety and pain associated with the treatment in a dental office. But how and what does nitrous oxide do? In fact, for more than 120 years, nitrous oxide was being used without a clear understanding of its mechanism of actions. This chapter will take our readers “backstage” where they will develop a better understanding on how nitrous oxide brings about its effects and what makes it useful in dentistry. A detailed description will be given on the way nitrous oxide interacts at a molecular level to bring about its anxiolytic, euphoric, sedative, and anesthetic effects. Bringing all this back to clinical setting, different stages of anesthesia, levels of sedation, and signs which suggest normal sedation vs oversedation shall be discussed.

Keywords

Mechanism of action of nitrous oxide Levels of sedation Relative analgesia Conscious sedation Signs and symptoms of nitrous oxide in children 
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Supplementary material

978-3-030-29618-6_3_MOESM1_ESM.mov (168.5 mb)
Video 3.1 This video presents the eye response during inhalation sedation. The clip shows reduced blink rate, decreased movement of eye balls, and drooping upper eye lids. After the inhalation sedation procedure ends, eyes appear brighter, with a normal blink rate and movement of eye balls (MOV 185752 kb)
978-3-030-29618-6_3_MOESM2_ESM.mov (136 mb)
Video 3.2 This video describes what a child feels when inhaling nitrous oxide sedation. The first child says that she feels that her entire body is numb. The second child talks about his imagination while watching a cartoon show on screen while inhaling the gas. Changes in voice are well appreciated in this clip with pitch of voice higher and slight pauses while speaking. The third child has a euphoric effect and later describes the surroundings, indicating that the child is well aware about the surroundings (MOV 139308 kb)

References

  1. 1.
    Musselman RJ, McClure DB. Chapter 8. Pharmacotherapeutic approaches to behavior management. In: Wright GZ, editor. Behavior management in dentistry for children. Philadelphia: W.B. Saunders Co; 1975. p. 146–77.Google Scholar
  2. 2.
    American Society of Anesthesiologists. Practice guidelines for sedation and analgesia by nonanesthesiologists: an updated report by the American Society of Anesthesiologists task force on sedation and analgesia by nonanesthesiologists. Anesthesiology. 2002;96:1004–17.Google Scholar
  3. 3.
    Emmanouil DE, Quock RM. Advances in understanding the actions of nitrous oxide. Anesth Prog. 2007;54:9–18.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Rosen MA. Nitrous oxide for relief of labor pain: a systematic review. Am J Obstet Gynecol. 2002;186:110–26.Google Scholar
  5. 5.
    Parlow JL, Milne B, Tod DA, Stewart GI, Griffiths JM, Dudgeon DJ. Self-administered nitrous oxide for the management of incident pain in terminally ill patients: a blinded case series. Palliat Med. 2005;19:3–8.PubMedGoogle Scholar
  6. 6.
    Baskett PJ. Use of Entonox in the ambulance service. Br Med J. 1970;2:41–3.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Dundee JW, Moore J. Alterations in response to somatic pain associated with anaesthesia. IV. The effect of subanaesthetic concentrations of inhalation agents. Br J Anaesth. 1960;32:453–9.PubMedGoogle Scholar
  8. 8.
    Gillmam M. Minimal sedation required with nitrous oxide-oxygen treatment of the alcohol withdrawal state. Br J Psychiatry. 1986;148:604–6.Google Scholar
  9. 9.
    Chapman WP, Arrowood JG, Beecher HK. The analgetic effects of low concentrations of nitrous oxide compared in man with morphine sulphate. J Clin Invest. 1943;22(6):871–5.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Berkowitz BA, Ngai SH, Finck AD. Nitrous oxide “analgesia”: resemblance to opiate action. Science. 1976;194:967–8.PubMedGoogle Scholar
  11. 11.
    Berkowitz BA, Finck AD, Ngai SH. Nitrous oxide analgesia: reversal by naloxone and development of tolerance. J Pharmacol Exp Ther. 1977;203:539–47.PubMedGoogle Scholar
  12. 12.
    Gillman MA, Kok L, Lichtigfeld FJ. Paradoxical effect of naloxone on nitrous oxide analgesia in man. Eur J Pharmacol. 1980;61:175–7.PubMedGoogle Scholar
  13. 13.
    Lawrence D, Livingston A. Opiate-like analgesic activity in general anaesthetics. Br J Pharmacol. 1981;73(2):435–42.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Yang JC, Clark WC, Ngai SH. Antagonism of nitrous oxide analgesia by naloxone in man. Anesthesiology. 1980;52(5):414–7.PubMedGoogle Scholar
  15. 15.
    Quock RM, Kouchich FJ, Tseng LF. Does nitrous oxide induce release of brain opioid peptides? Pharmacology. 1985;30(2):95–9.PubMedGoogle Scholar
  16. 16.
    Sanders RD, Weimann J, Maze M. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. Anesthesiology. 2008;109:707–22.PubMedGoogle Scholar
  17. 17.
    Emmanouil DE, Quock RM. Modification of nitrous oxide analgesia by benzodiazepine receptors. Anesthesiol Prog. 1989;36:5–8.Google Scholar
  18. 18.
    Okuda T, Wakita K, Tsuchiya N, Hatsuoka K, Koga Y. Yohimbine and flumazenil: effect on nitrous oxide-induced suppression of dorsal horn neurons in cats. J Anesth. 1997;11:198–201.PubMedGoogle Scholar
  19. 19.
    Hashimoto T, Maze M, Ohashi Y, Fujinaga M. Nitrous oxide activates GABAergic neurons in the spinal cord in Fischer rats. Anesthesiology. 2001;95:463–49.PubMedGoogle Scholar
  20. 20.
    Fujinaga M, Doone R, Davies MF, Maze M. Nitrous oxide lacks the antinociceptive effect on the tail flick test in newborn rats. Anesth Analg. 2000;91:6–10.PubMedGoogle Scholar
  21. 21.
    Sawamura S, Kingery WS, Davies MF, Agashe GS, Clark JD, Kobilka BK, Hashimoto T. Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of α2B-adrenoreceptors. J Neurosci. 2000;20:9242–925.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Orii R, Ohashi Y, Guo T, Nelson LE, Hashimoto T, Maze M, Fujinaga M. Evidence for the involvement of spinal cord α1-adrenoreceptors in nitrous oxide-induced antinociceptive effects in Fischer rats. Anesthesiology. 2002;97:1458–65.PubMedGoogle Scholar
  23. 23.
    Zhang C, Davies MF, Guo TZ, Maze M. The analgesic action of nitrous oxide is dependent on the release of norepinephrine in the dorsal horn of the spinal cord. Anesthesiology. 1991;91:1401–7.Google Scholar
  24. 24.
    Guo TZ, Poree L, Golden W, Fujinaga M, Maze M. Antinociceptive response to nitrous oxide is mediated by supraspinal opiate and spinal alpha2-adrenergic receptors in the rat. Anesthesiology. 1996;85:846–52.PubMedGoogle Scholar
  25. 25.
    Ohara A, Mashimo T, Zhang P, Inagaki Y, Shibuta S, Yoshiya I. A comparative study of the antinociceptive action of xenon and nitrous oxide in rats. Anesth Analg. 1997;85:931–6.PubMedGoogle Scholar
  26. 26.
    Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists their pharmacology and therapeutic role. Anaesthesia. 1999;54:146–65.PubMedGoogle Scholar
  27. 27.
    Dawson C, Ma D, Chow A, Maze M. Dexmedetomidine enhances analgesic action of nitrous oxide. Anesthesiology. 2004;100:894–904.PubMedGoogle Scholar
  28. 28.
    Guo TZ, Davies F, Kingery WS, Patterson AJ, Limbird LE, Maze M. Nitrous oxide produces antinociceptive response via α2B- and/or α2C-adrenoreceptor subtypes in mice. Anesthesiology. 1999;90:470–6.PubMedGoogle Scholar
  29. 29.
    Mueller JL, Quock RM. Contrasting influences of 5-hydroxytryptamine receptors in nitrous oxide antinociception in mice. Pharmacol Biochem Behav. 1992;41:429–32.PubMedGoogle Scholar
  30. 30.
    Fitzgerald M, Koltzenburg M. The functional development of descending inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal cord. Brain Res. 1986;389:261–70.PubMedGoogle Scholar
  31. 31.
    Fitzgerald M, Shaw A, Macintosh N. Postnatal development of the cutaneous flexor reflex: comparative study of preterm infants and newborn rat pups. Dev Med Child Neurol. 1988;30:520–6.PubMedGoogle Scholar
  32. 32.
    Ohashi Y, Stowell JM, Nelson LE, Hashimoto T, Maze M, Fujinaga M. Nitrous oxide exerts age-dependent antinociceptive effects in Fischer rats. Pain. 2002;100:7–18.PubMedGoogle Scholar
  33. 33.
    Georgiev SK, Kohno T, Ikoma M, Yamakura T, Baba H. Nitrous oxide inhibits glutamatergic transmission in spinal dorsal horn neurons. Pain. 2008;134:24–31.PubMedGoogle Scholar
  34. 34.
    Prast H, Philippu A. Nitric oxide as modulator of neuronal function. Prog Neurobiol. 2001;64:51–68.PubMedGoogle Scholar
  35. 35.
    McDonald CE, Gagnon MJ, Ellenberger EA, Hodges BL, Ream JK, Tousman SA, Quock RM. Inhibitors of nitric oxide synthesis antagonize nitrous oxide antinociception in mice and rats. J Pharmacol Exp Ther. 1994;269(2):601–8.PubMedGoogle Scholar
  36. 36.
    Henry ED, Ohgami Y, Li S, Chung E, Quock RM. Correlation of inbred mouse sensitivity to nitrous oxide antinociception with brain nitric oxide synthase activity following exposure to nitrous oxide. Pharmacol Biochem Behav. 2005;81:764–8.PubMedGoogle Scholar
  37. 37.
    Ishikawa M, Quock RM. N2O stimulates NOS enzyme activity in C57BL/6 but not DBA/2 mice. Brain Res. 2003;976:262–3.PubMedGoogle Scholar
  38. 38.
    Ishikawa M, Quock RM. Role of nitric-oxide synthase isoforms in nitrous oxide antinociception in mice. J Pharmacol Exp Ther. 2003;306:484–9.PubMedGoogle Scholar
  39. 39.
    Li S, Bieber AJ, Quock RM. Antagonism of nitrous oxide antinociception in mice by antisense oligodeoxynucleotide directed against neuronal nitric oxide synthase enzyme. Behav Brain Res. 2004;152:361–3.PubMedGoogle Scholar
  40. 40.
    Quock RM, Mueller JL, Vaughn LK, Belknap JK. Nitrous oxide antinociception in BXD recombinant inbred mouse strains and identification of quantitative trait loci. Brain Res. 1996;725:23–9.PubMedGoogle Scholar
  41. 41.
    Mueller JL, Ellenberger EA, Vaughn LK, Belknap JK, Quock RM. Detection and mapping of quantitative trait loci that determine responsiveness of mice to nitrous oxide antinociception. Neuroscience. 2004;123:743–9.PubMedGoogle Scholar
  42. 42.
    Lee CGL, Gregg AR, O’Brien WE. Localization of the neuronal form of nitric oxide synthase to mouse chromosome 5. Mamm Genome. 1995;6:56–7.PubMedGoogle Scholar
  43. 43.
    Tseng LF, Higgins MJ, Hong JS, Hudson PM, Fujimoto JM. Release of immunoreactive met-enkephalin from the spinal cord by intraventricular β-endorphin but not by morphine in anesthetized rats. Brain Res. 1985;343:60–9.PubMedGoogle Scholar
  44. 44.
    Tseng LF. Intracerebroventricular administration of β-endorphin releases immunoreactive met-enkephalin from the spinal cord in cats, guinea pigs and mice. Neuropharmacology. 1989;28:1333–9.PubMedGoogle Scholar
  45. 45.
    Hara S, Kuhns WR, Ellenberger EA, Mueller JL, Shibuya T, Endo T, Quock RM. Involvement of nitric oxide in intracerebroventricular β-endorphin-induced neuronal release of methionine-enkephalin. Brain Res. 1995;675:190–4.PubMedGoogle Scholar
  46. 46.
    Ohgami Y, Li S, Chung E, Quock RM. Exposure to nitrous oxide [N2O] causes a nitric oxide [NO]-dependent release of β-endorphin in the rat arcuate nucleus. Proc West Pharmacol Soc. 2007;50:194.Google Scholar
  47. 47.
    Zelinski M, Ohgami Y, Quock RM. Exposure to nitrous oxide stimulates a nitric oxide-dependent neuronal release of β-endorphin in ventricular-cisternally-perfused rats. Brain Res. 2009;1300:37–40.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Cope JL, Chung E, Ohgami Y, Quock RM. Antagonism of the antinociceptive effect of nitrous oxide by inhibition of enzyme activity expression of neuronal nitric oxide synthase in mouse brain and spinal cord. Eur J Pharmacol. 2010;626:234–8.PubMedGoogle Scholar
  49. 49.
    Emmanouil DE, Dickens AS, Heckert RW, Ohgami Y, Chung E, Han S, Quock RM. Nitrous oxide-antinociception is mediated by opioid receptors and nitric oxide in the periaqueductal gray region of the brain. Eur Neuropsychopharmacol. 2008;18:194–9.PubMedGoogle Scholar
  50. 50.
    Zuniga JR, Joseph SA, Knigge KM. The effects of nitrous oxide on the secretory activity of pro-opiomelanocortin peptides from basal hypothalamic cells attached to cytodex beads in a superfusion in vitro system. Brain Res. 1987;420:66–72.PubMedGoogle Scholar
  51. 51.
    Rupreht J, Dworacek B, Bonke B, Dzoljic MR, Van Eijndhoven JH, De Vlieger M. Tolerance to nitrous oxide in volunteers. Acta Anaesthesiol Scand. 1985;29:635–8.PubMedGoogle Scholar
  52. 52.
    Berkowitz BA, Finck AD, Hynes MD, Ngai SH. Tolerance to nitrous oxide analgesia in rats and mice. Anesthesiology. 1979;51:309–12.PubMedGoogle Scholar
  53. 53.
    Emmanouil DE, Quock RM. Effects of benzodiazepine agonist, inverse agonist and antagonist drugs in the mouse staircase test. Psychopharmacology. 1990;102:95–7.PubMedGoogle Scholar
  54. 54.
    Quock RM, Emmanouil DE, Vaughn LK, Pruhs RJ. Benzodiazepine receptor mediation of behavioral effects of nitrous oxide in mice. Psychopharmacology. 1992;107:310–4.PubMedGoogle Scholar
  55. 55.
    Emmanouil DE, Johnson CH, Quock RM. Nitrous oxide anxiolytic effect in mice in the elevated plus maze: mediation by benzodiazepine receptors. Psychopharmacology (Berl). 1994;115:167–72.Google Scholar
  56. 56.
    Czech DA, Green DA. Anxiolytic effects of nitrous oxide in mice in the light-dark and holeboard exploratory tests. Psychopharmacology. 1992;109:315–20.PubMedGoogle Scholar
  57. 57.
    Li S, Quock RM. Comparison of N2O- and chlordiazepoxide-induced behaviors in the light/dark exploration test. Pharmacol Biochem Behav. 2001;68:789–96.PubMedGoogle Scholar
  58. 58.
    Li S, Ohgami Y, Dai Y, Quock RM. Antagonism of nitrous oxide-induced anxiolytic-like behavior in the mouse light/dark exploration procedure by pharmacologic disruption of endogenous nitric oxide function. Psychopharmacology. 2003;166:366–72.PubMedGoogle Scholar
  59. 59.
    Li S, Quock RM. Effects of a nitric oxide donor on behavior and interaction with nitrous oxide in the mouse light/dark exploration test. Eur J Pharmacol. 2002;447(1):75–8.PubMedGoogle Scholar
  60. 60.
    Hornbein TF, Eger EI, Winter PM, Smith G, Wetstone D, Smith KH. The minimum alveolar concentration of nitrous oxide in man. Anesth Analg. 1982;61:553–6.PubMedGoogle Scholar
  61. 61.
    Epstein RM, Rackow H, Salanitre E, Wolf GL. Influence of the concentration effect on the uptake of anesthetic mixtures: the second gas effect. Anesthesiology. 1964;25:364–71.PubMedGoogle Scholar
  62. 62.
    Jevtovic-Todorovic V, Todorovic ÅL, Mennerick SM, Powell S, Dikranian S, Benshoff K. Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998;4(4):460–3.PubMedGoogle Scholar
  63. 63.
    Emmanouil D, Quock RM. Effects of stress on nitrous oxide-induced anxiolytic action. Int J Paediatr Dent. 2007;17(1):25.Google Scholar
  64. 64.
    Jevtovic-Todorovic V, Benshoff N, Olney JW. Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats. Br J Pharmacol. 2000;130:1692–8.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Wesnes KA, Warburton DM. Stress, drugs and performance. In: Hockey GRJ, editor. Stress and fatigue in human performance. London: Wiley; 1983. p. 203–44.Google Scholar
  66. 66.
    Kovacs WJ, Ojeda SR. Textbook of endocrine physiology. 6th ed. New York: Oxford University; 2011.Google Scholar
  67. 67.
    Gillman MA, Katzeff IE. Does opioid uncoupling of the adrenal responses mediate opioid anti-stress effects? Med Sci Res. 1998;16:207–9.Google Scholar
  68. 68.
    Torner L, Toschi N, Pohlinger A, Landgraf R, Neumann ID. Anxiolytic and anti-stress effects of brain prolactin: improved efficacy of antisense targeting of the prolactin receptor by molecular modelling. J Neurosci. 2001;21:3207–14.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Emmanouil DE, Yeon J, Quock RM. Effects of chronic stress on nitrous oxide induced antinociceptive and anxiolytic effects in mice. FASEB J. 2012;26:662–6.Google Scholar
  70. 70.
    Dindi H, Tsai HM, Branch MC. Combustion mechanism of carbon monoxide-nitrous oxide flames. Combust Flame. 1991;87:13–20.Google Scholar
  71. 71.
    Meisch RA. Factors controlling drug reinforced behavior. Pharmacol Biochem Behav. 1987;27:367–71.PubMedGoogle Scholar
  72. 72.
    Walker DJ, Zacny JP. Bitonic dose–response functions for reinforcing and self-reported effects of nitrous oxide in humans. Pharmacol Biochem Behav. 2003;74:851–7.PubMedGoogle Scholar
  73. 73.
    Biersner RJ. Selective performance effects of nitrous oxide. Hum Factors. 1972;14:187–94.PubMedGoogle Scholar
  74. 74.
    Block RL, Ghoneim MM, Hinrichs JV, Kumar V, Pathak D. Effects of a subanaesthelic concentration of nitrous oxide on memory and subjective experience: influence of assessment procedures and types of stimuli. Human Psychopharmacol J. 1998;3(4):257–65.Google Scholar
  75. 75.
    Ramsay DS, Leonesio RJ, Whitney CW, Jones BC, Samson HH, Weinstein P. Paradoxical effects of nitrous oxide on human memory. Psychopharmacology. 1992;106:370–4.PubMedGoogle Scholar
  76. 76.
    Culley DJ, Raghavan SD, Baxter MG, Yukhananov R, Deth RC, Crosby G. Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg. 2007;105:83–8.PubMedGoogle Scholar
  77. 77.
    Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994;79:59–68.PubMedGoogle Scholar
  78. 78.
    Klein ED, Emmanouil D, Zhang Y, Shirachi DY, Quock RM. A mechanistic study of the effects of nitrous oxide (N2O) on spatial working memory in mice (Abstract). Int J Paediatr Dent. 2015;25(1):1–251.Google Scholar
  79. 79.
    Maze M, Fujinaga M. Editorial. Recent advances in understanding the actions and toxicity of nitrous oxide. Anaesthesia. 2000;55:311–4.PubMedGoogle Scholar
  80. 80.
    Tsao JC, Myers CD, Craske MG, et al. Role of anticipatory anxiety and anxiety sensitivity in children’s and adolescents’ laboratory pain responses. J Pediatr Psychol. 2004;29:379–88.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Weinstein P, Domoto PK, Holleman E. The use of nitrous oxide in the treatment of children: results of a controlled study. J Am Dent Assoc. 1986;112:325–31.PubMedGoogle Scholar
  82. 82.
    Hogue D, Ternisky M, Iranpour B. The response of nitrous oxide analgesia in children. J Dent Child. 1971;38:129–35.Google Scholar
  83. 83.
    Langa H. Relative analgesia in dental practice: inhalation analgesia with nitrous oxide. Philadelphia, PA: W B Saunders; 1986.Google Scholar
  84. 84.
    Malamed S. Sedation: guide to patient management. 5th ed. St. Louis: Elsevier; 2010.Google Scholar
  85. 85.
    Guedel AE. Inhalation anesthesia. New York: McMillan Co; 1937.Google Scholar
  86. 86.
    Carnow R. An analysis of patient reaction under N2O + O2 analgesia. J Oreg Dent Assoc. 1969;38:13–6.PubMedGoogle Scholar
  87. 87.
    Gillman MA, Lichtigfeld FJ. Opioid properties of psychotropic analgesic nitrous oxide (laughing gas). Perspect Biol Med. 1994;38:125–38.PubMedGoogle Scholar
  88. 88.
    Roberts GJ. Inhalation sedation (relative analgesia) with oxygen/nitrous oxide gas mixture: 1. Principles. Dent Update. 1990;17:139–46.PubMedGoogle Scholar
  89. 89.
    Parbrook GD. Therapeutic uses of nitrous oxide. Br J Anaesth. 1968;40:365–72.PubMedGoogle Scholar
  90. 90.
    Thompson JN, Neave N, Moss MC, Scholey AB, Wesnes K, Girdler NM. Cognitive properties of sedation agents and comparison of the effects of nitrous oxide and midazolam on memory and mood. Br Dent J. 1999;187(10):557–62.PubMedGoogle Scholar
  91. 91.
    Stach DJ. Nitrous oxide sedation: understanding the benefit and risks. Am J Dent. 1995;8:47–50.PubMedGoogle Scholar

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Authors and Affiliations

  • Dimitrios Emmanouil
    • 1
  1. 1.Department of Pediatric DentistryDental School, National and Kapodistrian University of AthensAthensGreece

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