Molecular Neurobiology

, Volume 25, Issue 2, pp 167–189 | Cite as

Neurobiology of nitrous oxide-induced antinociceptive effects

  • Masahiko FujinagaEmail author
  • Mervyn Maze


Nitrous oxide (N2O), or laughing gas, has been used for clinical anesthesia for more than a century and is still commonly used. While the anesthetic/hypnotic mechanisms of N2O remain largely unknown, the underlying mechanisms of its analgesic/antinociceptive effects have been elucidated during the last several decades. Evidence to date indicate that N2O induces opioid peptide release in the periaqueductal gray area of the midbrain leading to the activation of the descending inhibitory pathways, which results in modulation of the pain/nociceptive processing in the spinal cord. The types of opioid peptide induced by N2O and the subtypes of opioid receptors that mediate the antinociceptive effects of N2O appear to depend on various factors including the species and/or strain, the regions of the brain, and the paradigms of behavior testing used for the experiments. Among three types of descending inhibitory pathways, the descending noradrenergic inhibitory pathway seems to play the most prominent role. The specific elements involved are now being resolved.

Index Entries

Nitrous oxide analgesia antinociceptive effect descending inhibitory pathway opioid peptides adrenoceptor GABA 


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  1. 1.
    Frost E. A. (1985) A history of nitrous oxide, in Nitrous Oxide/N 2O (Eger E.I., eds), Elsevier, New York, NY, pp. 1–22.Google Scholar
  2. 2.
    Wynne J. M. (1985) Physics, chemistry, and manufacture of nitrous oxide, in Nitrous Oxide/N 2O (Eger E.I., eds.), Elsevier, New York, NY, pp. 23–39.Google Scholar
  3. 3.
    Maze M. and Fujinaga M. (2000) Recent advances in understanding the actions and toxicity of nitrous oxide. Anaesthesia 55, 311–314.PubMedGoogle Scholar
  4. 4.
    Basbaum A. L. and Fields H. L. (1978) Endogenous pain control mechanisms: review and hypothesis. Ann. Neurol. 4, 451–462.PubMedGoogle Scholar
  5. 5.
    Basbaum A. L. and Fields H. L. (1984) Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Ann. Rev. Neurosci. 7, 309–338.PubMedGoogle Scholar
  6. 6.
    Behbehani M. M. (1995) Functional characteristics of the midbrain periaqueductal gray. Prog. Neurobiol. 46, 575–605.PubMedGoogle Scholar
  7. 7.
    Fields H. L. and Basbaum A. L. (1999) Central nervous system mechanisms of pain modulation, in Textbook of Pain, 4th ed. (Wall P.D. and Melzack R., eds.), Churchill Livingstone, Edinburgh, pp. 309–329.Google Scholar
  8. 8.
    Holden J. E. and Proudfit H. K. (1998) Enkephalin neurons that project to the A7 catecholamin cell group are located in nuclei that modulate nociception: ventromedial medulla. Neuroscience 83, 929–947.PubMedGoogle Scholar
  9. 9.
    Bajic D. and Proudfit H. K. (1999) Projections of neurons in the periaqueductal gray to pontine and medullary catecholamine cell groups involved in the modulation of nociception. J. Comp. Neurol. 405, 359–379.PubMedGoogle Scholar
  10. 10.
    Kirifides M. L., Simpson K. L., Lin R. C.-S., and Waterhouse B. D. (2001) Topographic organization and neurochemical identity of dorsal raphe neurons that project to the trigeminal somatosensory pathway in the rat. J. Comp. Neurol. 435, 325–340.PubMedGoogle Scholar
  11. 11.
    Proudfit H. K. and Yeomans D. C. (1995) The modulation of nociception by enkephalin-containing neurons in the brainstem, in The Pharmacology of Opioid Peptides (Tseng L. F., eds.), Harwood Academic, Amsterdam, The Netherlands, pp. 197–217.Google Scholar
  12. 12.
    Finck A. D. (1985) Nitrous oxide analgesia, in Nitrous Oxide/N 2O (Eger, E.I. eds.), Elsevier, New York, NY, pp. 41–55.Google Scholar
  13. 13.
    Seevers M. H., Bennett J. H., Pohle H. W., and Reinardy E. W. (1937) The analgesia produced by nitrous oxide, ethylene and cyclopropane in the normal human subject. JPET 59, 291–300.Google Scholar
  14. 14.
    Berkowitz B. A., Ngai S. H., and Finck A. D. (1976) Nitrous oxide analgesia: resemblance to opiate action. Science 194, 967–968.PubMedGoogle Scholar
  15. 15.
    Chapman C. R. and Benedetti C. (1979) Nitrous oxide effects on cerebral evoked potential to pain: partial reversal with a narcotic antagonist. Anesthesiology 51, 135–138.PubMedGoogle Scholar
  16. 16.
    Yang J. C., Clark W. C., and Ngai S. H. (1980) Antagonism of nitrous oxide by naloxone in man. Anesthesiology 52, 414–417.PubMedGoogle Scholar
  17. 17.
    Berkowitz B. A., Finck A. D., and Ngai S. H. (1977) Nitrous oxide analgesia: reversal by naloxone and development of tolerance. JPET 203, 539–547.Google Scholar
  18. 18.
    Lawrence D. and Livingston A. (1981) Opiate-like analgesic activity in general anaesthetics. Br. J. Pharm. 73, 435–442.Google Scholar
  19. 19.
    Zuniga J., Joseph S., and Knigge K. (1987) Nitrous oxide analgesia. Partial antagonism by naloxone and total reversal after periaqueductal gray lesions in the rat. Eur. J. Pharm. 142, 51–60.Google Scholar
  20. 20.
    Quock R. M., Walczak C. K., Henry R. J., and Chen D. C. (1990) Effect of subtype-selective opioid receptor blockers on nitrous oxide antinociception in rats. Pharmacol. Res. 22, 351–357.PubMedGoogle Scholar
  21. 21.
    Hodges B. L., Gagnon M. J., Gillespie T. R., Breneisen J. R., O’Leary D. F., Hara S., and Quock R. M. (1994) Antagonism of nitrous oxide antinociception in the rat hot plate test by site-specific mu and epsilon opioid receptor blockage. JPET 269, 596–600.Google Scholar
  22. 22.
    Goto T., Marota J. J. A., and Crosby G. (1994) Nitrous oxide induces preemptive analgesia in the rat that is antagonized by halothane. Anesthesiology 80, 409–416.PubMedGoogle Scholar
  23. 23.
    Guo T.-Z., Poree L., Golden W., Stein J., Fujinaga M., and Maze M. (1996) Antinociceptive response to nitrous oxide is mediated by supraspinal opiate and spinal α2 adrenergic receptors in the rat. Anesthesiology 85, 846–852.PubMedGoogle Scholar
  24. 24.
    Smith E. H. and Rees J. M. H. (1981) The effects of naloxone on the analgesic activities of general anaesthetics. Experientia 37, 289–290.PubMedGoogle Scholar
  25. 25.
    Quock R. M. and Graczak L. M. (1988) Influence of narcotic antagonist drugs upon nitrous oxide analgesia in mice. Brain Res. 440, 35–41.PubMedGoogle Scholar
  26. 26.
    Quock R. M., Best J. A., Chen D. C., Vaughn L. K., Portoghese P. S., and Takemori A. E. (1990) Mediation of nitrous oxide analgesia in mice by spinal and supraspinal κ-opioid receptors. Eur. J. Pharm. 175, 97–100.Google Scholar
  27. 27.
    Quock R. M. and Mueller J. (1991) Protection by U-50,488H against β-chlornaltrexamine antagonism of nitrous oxide antinociception in mice. Brain Res. 549, 162–164.PubMedGoogle Scholar
  28. 28.
    Quock R. M., Curtis B. A., Reynolds B. J., and Mueller J. L. (1993) Dose-dependent antagonism and potentiation of nitrous oxide antinociception by naloxone in mice. JPET 267, 117–122.Google Scholar
  29. 29.
    Chen D. C. and Quock R. M. (1990) A study of central opioid receptor involvement in nitrous oxide analgesia in mice. Anesth. Prog. 37, 181–185.PubMedGoogle Scholar
  30. 30.
    Moody E. J., Mattson M, Newman A. H., Rice K. C., and Skolnick P. (1989) Stereospecific reversal of nitrous oxide analgesia by naloxone. Life Sci. 44, 703–709.PubMedGoogle Scholar
  31. 31.
    Levine J. D., Gordon N. C., and Fields H. L. (1982) Naloxone fails to antagonize nitrous oxide analgesia for clinical pain. Pain 13, 165–169.PubMedGoogle Scholar
  32. 32.
    Yagi M., Mashimo T., Kawaguchi T., and Yoshiya I. (1995) Analgesic and hypnotic effects of subanaesthetic concentrations of xenon in human volunteers: comparison with nitrous oxide. Br. J. Anaesth. 74, 670–673.PubMedGoogle Scholar
  33. 33.
    Zacny J. P., Conran A. Pardo H., Coalson D. W. Black M., Klock P. A., and Klaft J. M. (1999) Effects of naloxone on nitrous oxide actions in healthy volunteers. Pain 83, 411–418.PubMedGoogle Scholar
  34. 34.
    Ohara A., Mashimo T., Zhang P., Inagaki Y., Shibuta S., and Yoshiya I. (1997) A comparative study of the antinociceptive action of xenon and nitrous oxide in rats. Anesth. Analg. 85, 931–936.PubMedGoogle Scholar
  35. 35.
    Fukuhara N, Ishikawa T., Kinoshita H., Xiong L, and Nakanishi O. (1998) Central noradrenergic mediation of nitrous oxide-induced analgesia in rats. Can. J. Anaesth. 45, 1123–1129.PubMedGoogle Scholar
  36. 36.
    Gillman M. A., Kok L., and Lichtigfeld F. J. (1980) Paradoxical effect of naloxone on nitrous oxide analgesia in man. Eur. J. Pharm. 61, 175–177.Google Scholar
  37. 37.
    Gillman M. A. and Lightgfeld F. J. (1983) Letter to the editor. Pain 17, 103–104.PubMedGoogle Scholar
  38. 38.
    Gillman M. A. (1986) Pharmacokinetic differences could explain the lack of reversal of nitrous oxide analgesia by low-dose naloxone. Anesthesiology 65, 449–450.PubMedGoogle Scholar
  39. 39.
    Willer J.-C., Bergeret S., Gaudy J.-H., and Dauthier C. (1985) Failure of naloxone to reverse the nitrous oxide-induced depression of a brain stem reflex: an electrophysiologic and double-blind study in humans. Anesthesiology 63, 467–472.PubMedGoogle Scholar
  40. 40.
    Zacny J. P., Coalson D. W., Lichtor J. L., Yajnik S., and Thapar P. (1994) Effects of naloxone on the subjective and psychomotor effects of nitrous oxide in humans. Pharmacol. Biochem. Behav. 49, 573–578.PubMedGoogle Scholar
  41. 41.
    Smith R. A., Wilson M., and Miller K. W. (1978) Naloxone has no effect on nitrous oxide anesthesia. Anesthesiology 49, 6–8.PubMedGoogle Scholar
  42. 42.
    Hynes M. D. and Berkowitz B. A. (1979) Nitrous oxide stimulation of locomotor activity: Evidence for an opiate-like behavioral effect. JPET 209, 304–308.Google Scholar
  43. 43.
    Way W. L., Hosobuchi Y., Johnson B. H., Eger E. I., and Bloom F. E. (1984) Anesthesia does not increase opioid peptides in cerebrospinal fluid of humans. Anesthesiology 60, 43–45.PubMedGoogle Scholar
  44. 44.
    Morris B. and Livingston A. (1984) Effects of nitrous oxide exposure on met-enkephalin levels in discrete areas of rat brain. Neurosci. Lett. 45, 11–14.PubMedGoogle Scholar
  45. 45.
    Evans S. F., Stringer M., Bukht M. D. G., Thomas W. A., and Tomlin S. J. (1985) Nitrous oxide inhalation does not influence plasma concentrations of β-endorphin or metenkephalin-like immunoreactivity. Br. J. Anaesth. 57, 624–628.PubMedGoogle Scholar
  46. 46.
    Quock R. M., Kouchich F. J., and Tseng L. (1985) Does nitrous oxide induce release of brain opioid peptides? Pharmacology 30, 95–99.PubMedGoogle Scholar
  47. 47.
    Quock R. M., Kouchich F. J., and Tseng L. (1986) Influence of nitrous oxide upon regional brain levels of methionine-enkephalin-like immunoreactivity in rats. Brain Res. 16, 321–323.Google Scholar
  48. 48.
    Zuniga J. R., Knigge K. M., and Joseph S. A. (1986) Central β-endorphin release and recovery after exposure to nitrous oxide in rats. J. Oral Maxillofac. Surg. 44, 714–718.PubMedGoogle Scholar
  49. 49.
    Zuniga J. R., Joseph S. A., and Knigge K. M. (1987) The effects of nitrous oxide on the central endogenous pro-opiomelanocortin system in the rat. Brain Res. 420, 57–65.PubMedGoogle Scholar
  50. 50.
    Zuniga J. R., Joseph S. A., and Knigge K. M. (1987) 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. 420, 66–72.PubMedGoogle Scholar
  51. 51.
    Finck A. D., Samaniego E., and Ngai S. H. (1995) Nitrous oxide selectively releases met5-enkephalin and met5-enkephalin-arg6-phe7 into canine third ventricular cerebrospinal fluid. Anesth. Analg. 80, 664–670.PubMedGoogle Scholar
  52. 52.
    Fang F., Guo T. Z., Davies M. F., and Maze M. (1997) Opiate receptors in the periaqueductal gray mediate analgesic effect of nitrous oxide in rats. Eur. J. Pharm. 336, 137–141.Google Scholar
  53. 53.
    Hara S., Gagnon M. J., Quock R. M., and Shibuya T. (1994) Effect of opioid peptide antisera on nitrous oxide antinociception in rats. Pharmacol. Biochem. Behav. 48, 699–702.PubMedGoogle Scholar
  54. 54.
    Branda E. M., Ramza J. T., Cahill F. J., Tseng L. F., and Quock R. M. (2000). Role of brain dynorphin in nitrous oxide antinociception in mice. Pharmacol. Biochem. Behav. 65, 217–221.PubMedGoogle Scholar
  55. 55.
    Cahill F. J., Ellenberger E. A., Mueller J. L., Tseng L. F. and Quock R. M. (2000) Antagonism of nitrous oxide antinociception in mice by intrathecally administered antisera to endogenous opioid peptides. J. Biomed. Sci. 7, 299–303.PubMedGoogle Scholar
  56. 56.
    McDonald C. E., Gagnon M. J., Ellenberger E. A., Hodges B. L., Ream J. K., Tousman S. A., and Quock R. M. (1994) Inhibitors o nitric oxide synthesis antagonize nitrous oxide antinociception in mice and rats. JPET 269, 601–608.Google Scholar
  57. 57.
    Hara S., Kuhns E. R., Ellengerger E. A., Mueller J. L., Shibuya T., Endo T., and Quock R. M. (1995) Involvement of nitric oxide in intracerebroventricular β-endorphin-induced neuronal release of methionine-enkephalin. Brain Res. 675, 190–194.PubMedGoogle Scholar
  58. 58.
    Caton P. W., Tousman S. A., and Quock R. M. (1994) Involvement of nitric oxide in nitrous oxide anxiolysis in the elevated plus-maze. Pharmacol. Biochem. Behav. 48, 689–692.PubMedGoogle Scholar
  59. 59.
    Gillman M. A. (1984) Possible mechanisms of action of nitrous oxide at the opioid receptor. Med. Hypotheses 15, 109–114.PubMedGoogle Scholar
  60. 60.
    Ahmed M. S. and Byrne W. L. (1980) Opiate receptor binding studies influence of a reversible sulfhydryl agent, in Endogenous and Exogenous Opiate agonists and Antagonists (Way E. L., eds.), Pergamon, New York, NY, pp. 51–54.Google Scholar
  61. 61.
    Lawrence D. and Livingston A. (1981) Opiatelike analgesic activity in general anaesthetics. Br. J. Pharm. 73, 435–442.Google Scholar
  62. 62.
    Daras C., Cantrill R. C., and Gillman M. A. (1983) [3H]Naloxone displacement: evidence for nitrous oxide as opioid receptor agonist. Eur. J. Pharm. 89, 177–178.Google Scholar
  63. 63.
    Ori C., Ford-Rice F., and London E. D. (1989) Effects of nitrous oxide and halothane on μ and κ opioid receptors in guinea-pig brain. Anesthesiology 70, 541–544.PubMedGoogle Scholar
  64. 64.
    Komatsu T., Shingu K., Tomemori N., Urabe N., and Mori K. (1981) Nitrous oxide activates the supraspinal pain inhibition system. Acta Anaesth. Scand. 25, 519–522.PubMedGoogle Scholar
  65. 65.
    Nagasaka H., Taguchi M., Tsuchiyama M., Mizumoto Y., Hori K., Hayashi K., et al. (1997) Effect of nitrous oxide on spinal dorsal horn WDR neuronal activity in cats. Masui 46, 1190–1196.PubMedGoogle Scholar
  66. 66.
    Miyazaki Y., Adachi T., Utsumi J., Shichino T., and Segawa H. (1999) Xenon has greater inhibitory effects on spinal dorsal horn neurons than nitrous oxide in spinal cord transected cats. Anesth. Analg. 88, 893–897.PubMedGoogle Scholar
  67. 67.
    Zhang C., Davies M. F., Guo T.-Z., and Maze M. (1999) The analgesic action of nitrous oxide is dependent on the release of norepinephrine in the dorsal horn of the spinal cord. Anesthesiology 91, 1401–1407.PubMedGoogle Scholar
  68. 68.
    Ohara A., Zhang P., Inagaki Y., Mashimo T., and Yoshiya I. (1995) Nitrous oxide analgesia: existence of acute tolerance and complete antagonism by yohimbine. Anesth. Resusci. 31, 37–39.Google Scholar
  69. 69.
    Sawamura S., Kingery W. S., Davies M. F., Agashe G. S., Clark J. D., Kobilka B. K., et al. (2000) Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of α2B adrenoceptors. J. Neurosci. 20, 9242–9251.PubMedGoogle Scholar
  70. 70.
    Ohashi Y., Stowell J. M., Orii R., Maze M., and Fujinaga M. (2001) Neural nuclei activated by nitrous oxide in Fischer rats. Anesthesiology 95, A-721 (abstract).Google Scholar
  71. 71.
    Bourgoin S., Ternaux J. P., Boireau A., Héry F., and Hamon M. (1975) Effects of halothane and nitrous oxide anaesthesia on 5-HT turn-over in the rat brain. Naunyn-Schmiedeberg’s Arch. Pharmacol. 288, 109–121.Google Scholar
  72. 72.
    Mueller J. L. and Quock R. M. (1992) Contrasting influences of 5-hydroxytryptamine receptors in nitrous oxide antinociception in mice. Pharmacol. Biochem. Behav. 41, 429–432.PubMedGoogle Scholar
  73. 73.
    Gao K., Kim Y.-H. H., and Mason P. (1997) Serotonergic pontomedullary neurons are not activated by antinociceptive stimulation in the periaqueductal gray. J. Neurosci. 17, 3285–3292.PubMedGoogle Scholar
  74. 74.
    Gao K., Chen D. O., Genzen J. R., and Mason P. (1998) Activation of serotonergic neurons in the raphe magnus is not necessary for morphine analgesia. J. Neurosci. 18, 1860–1868.PubMedGoogle Scholar
  75. 75.
    de Jong R. H., Robles R., and Morikawa K. (1969) Actions of halothane and nitrous oxide on dorsal horn neurons (“The spinal gate”). Anesthesiology 31, 205–212.PubMedGoogle Scholar
  76. 76.
    de Jong R. H., Robles R., and Heavner J. E. (1970) Suppression of impulse transmission in the cat’s dorsal horn by inhalation anesthetics. Anesthesiology 32, 440–445.PubMedGoogle Scholar
  77. 77.
    Kitahata L. M., Taub A., and Sato I. (1971) Lamina-specific suppression of dorsal horn unit activity by nitrous oxide and by hyperventilation. JPET 176, 101–108.Google Scholar
  78. 78.
    Taub A., Hoffert M., and Kitahata L. M. (1974) Lamina-specific suppression and acceleration of dorsal-horn unit activity by nitrous oxide: a statistical analysis. Anesthesiology 40, 24–31.PubMedGoogle Scholar
  79. 79.
    Sugai N., Maruyama H., and Goto K. (1982) Effect of nitrous oxide alone or its combination with fentanyl on spinal reflexes in cats. Br. J. Anaesth. 54, 567–570.PubMedGoogle Scholar
  80. 80.
    Shingu K., Osawa M., Omatsu Y., Komatsu T., Urabe N., and Mori K. (1981) Naloxone does not antagonize the anesthetic-induced depression of nociceptor-driven spinal cord response in spinal cats. Acat Anaesth. Sacnd. 25, 526–532.Google Scholar
  81. 81.
    Adachi T., Miyazaki Y., Kurata J., Utsumi J., Shinomura T., Nakao S., et al. (1996) Nitrous oxide decreases somatocardiac sympathetic A-and C-reflexes in anesthetized rats. Neurosci. Lett. 213, 57–60.PubMedGoogle Scholar
  82. 82.
    Guo T.-Z., Davies M. F., Kingery W. S., Patterson A. J., Limbird L. E., and Maze M. (1999) Nitrous oxide produces antinociceptive response via α2B and/or α2C adrenoceptor subtypes in mice. Anesthesiology 90, 470–476.PubMedGoogle Scholar
  83. 83.
    Hashimoto T., Maze M., Ohashi Y., and Fujinaga M. (2001) Nitrous oxide activates GABAergic neurons in the spinal cord in Fischer rat. Anesthesiology 95, 463–469.PubMedGoogle Scholar
  84. 84.
    Nuseir K. and Proudfit H. K. (2000) Bidirectional modulation of nociception by GABA neurons in the dorsolateral pontine tegmentum that tonically inhibit spinally projecting noradrenergic A7 neurons. Neuroscience 96, 773–783.PubMedGoogle Scholar
  85. 85.
    Baba H., Goldstein P. A., Okamoto M., Kohno T. Ataka T., Yoshimura M., and Shimoji K. (2000) Norepinephrine facilitates inhibitory transmission in substantia gelatinosa of adult rat spinal cord (part 2). Effects on somatodendritic sits of GABAergic neurons. Anesthesiology 92, 485–492.PubMedGoogle Scholar
  86. 86.
    Orii R., Hashimoto T., Nelson L. M., Maze M., and Fujinaga M. (2001) Evidence for the involvement of spinal cord alpha-1 adrenoceptors in the antinociceptive effect of nitrous oxide in Fischer rats. Anesthesiology 95, A-745 (abstract).Google Scholar
  87. 87.
    Bylund D. B., Eikenberg D. C., Hieble J. P., Langer S. Z., Lefkowitz R. J., Minneman K. P., et al. (1994) International union of pharmacology nomenclature of adrenoceptors. Pharmacol. Rev. 46, 121–135.PubMedGoogle Scholar
  88. 88.
    Surprenant A., Horstman D. A., Akbarali H., and Limbird L. E. (1992) A point mutation of the alpha 2-adrenoceptor that blocks coupling to potassium but not calcium currents. Science 257, 977–980.PubMedGoogle Scholar
  89. 89.
    MacMillan L. B., Hein L., Smith M. S., Piascik M. T., and Limbird L. E. (1996) Central hypotensive effects of the α2a-adrenergic receptor subtype. Science 273, 801–803.PubMedGoogle Scholar
  90. 90.
    Link R. E., Dsai K., Hein L., Stevens M. E., Chruscinski A., Bernstein D., et al. (1996) Cardiovascular regulation in mice lacking α2-adrenergic receptor subtypes b and c. Science 273, 803–805.PubMedGoogle Scholar
  91. 91.
    Millan M. J. (1997) The role of descending noradrenergic and serotonergic pathways in the modulation of nociception: focus on receptor multiplicity. Handbook Exp. Pharm. 130, 385–446.Google Scholar
  92. 92.
    Bloom F. E., Battenberg E., Rossier J., Ling N., Guillemin R. (1978) Neurons containing β-endorphin in rat brain exist separately from those containing enkephalin: immunocytochemical studies. Proc. Natl. Acad. Sci. USA 75, 1591–1595.PubMedGoogle Scholar
  93. 93.
    Gyulai F. E., Firestone L. L., Mintun M. A., and Winter P. M. (1997) In vivo imaging of nitrous oxide-induced changes in cerebral activation during noxious heat stimuli. Anesthesiology 86, 538–548.PubMedGoogle Scholar
  94. 94.
    Quock R. M., Mueller J. L., and Vaughn L. K. (1993) Strain-dependent differences in responsiveness of mice to nitrous oxide (N2O) antinociception. Brain Res. 614, 52–56.PubMedGoogle Scholar
  95. 95.
    Vaughn L. K. and Pruhs R. J. (1995) Strain-dependent variability in nitrous oxide withdrawal seizure frequency. Life Sci. 57, 1125–1130.PubMedGoogle Scholar
  96. 96.
    Quock R. M., Mueller J. L., Vaughn L. K., and Belknap J. K. (1996) Nitrous oxide antinociception in BXD recombinant inbred mouse strains and identification of quantitative trait loci. Brain Res. 725, 23–29.PubMedGoogle Scholar
  97. 97.
    Fender C., Fujinaga M., and Maze M. (2000) Strain differences in antinociceptive effect of nitrous oxide on tail flick test in rats. Anesth. Analg. 90, 195–199.PubMedGoogle Scholar
  98. 98.
    Whitwam J. G., Morgan M., Hall G. M., and Petrie A. (1976) Pain during continuous nitrous oxide administration. Br. J. Anaesth. 48, 425–429.PubMedGoogle Scholar
  99. 99.
    Rupreht J., Dworacek B., Bonke B., Dzoljic M. R., Van Eijndhoven J. H. M., and De Vlieger M. (1985) Tolerance to nitrous oxide decreases in volunteers. Acta Anaesth. Scand. 29, 635–638.PubMedGoogle Scholar
  100. 100.
    Ramsay D. S., Brown A. C., and Woods S. C. (1992) Acute tolerance to nitrous oxide in humans. Pain 51, 367–373.PubMedGoogle Scholar
  101. 101.
    Pirec V., Patterson T. H., Thapar P., Apfelbaum J. L., and Zacny J. P. (1995) Effects of subanesthetic concentrations of nitrous oxide on coldpressor pain in humans. Pharmacol. Biochem. Behav. 51, 323–329.PubMedGoogle Scholar
  102. 102.
    Zacny J. P., Cho A. M., Coalson D. W., Rupani G., Young C. J., Klafta J. M., et al. (1996) Differential acute tolerance development to effects of nitrous oxide in humans. Neurosci. Lett. 209, 73–76.PubMedGoogle Scholar
  103. 103.
    Berkowitz B. A., Finck A. D., Hynes M. D., and Ngai S. H. (1979) Tolerance to nitrous oxide analgesia in rats and mice. Anesthesiology 51, 309–312.PubMedGoogle Scholar
  104. 104.
    Rupreht J., Ukponmwan O. E., Dworacek B., Admiraal P. V., and Dzoljic M. R. (1985) Enkephalinase inhibition prevented tolerance to nitrous oxide analgesia in rat. Acta Anaesth. Scand. 28, 617–620.Google Scholar
  105. 105.
    Avramov M. N., Shingu K., and Mori K. (1999) Progressive changes in electroencephalographic responses to nitrous oxide in humans: a possible acute drug tolerance. Anesth. Analg. 70, 369–374.Google Scholar
  106. 106.
    Mori K. and Winters W. D. (1975) Neural blockade of sleep and anesthesia. Int. Anesth. Clin. 13, 67–108.Google Scholar
  107. 107.
    Stevens J. E., Oshima E., and Mori K. (1983) Effects of nitrous oxide on the epileptogenic property of enflurane in cats. Br. J. Anaesth. 55, 145–154.PubMedGoogle Scholar
  108. 108.
    Smith R. A., Winter P. M., Smith M., and Eger E. I. (1979) Rapidly developing tolerance to acute exposures to anesthetic agents. Anesthesiology 50, 496–500.PubMedGoogle Scholar
  109. 109.
    Ramsay D. S., Omachi K., Leroux B. G., Seeley R. J., Prall C. W., and Woods S. C. (1999) Nitrous oxide-induced hypothermia in the rat: acute and chronic tolerance. Pharmacol. Biochem. Behav. 62, 189–196.PubMedGoogle Scholar
  110. 110.
    Shingu K., Osawa M., Fukuda K., and Mori K. (1985) Acute tolerance to the analgesic action of nitrous oxide does not develop in rats. Anesthesiology 62, 502–504.PubMedGoogle Scholar
  111. 111.
    Beitner-Johnson D., Guitart X., and Nestler E. J. (1991) Dopaminergic reward regions of Lewis and Fischer rats display different levels of tyrosine hydroxylase and other morphine-and cocaine-regulated phosphoproteins. Brain Res. 561, 147–150.PubMedGoogle Scholar
  112. 112.
    Guitart X., Beitner-Johnson D., Marby D. W., Kosten T. A., and Nestler E. J. (1992) Fischer and Lewis rat strains differ in basal levels of neurofilament proteins and their regulation by chronic morphine in the mesolimbic dopamine system. Synapse 12, 242–253.PubMedGoogle Scholar
  113. 113.
    Guitart X., Kogan J. H., Berhow M., Terwillinger R. Z., Aghajanian G. K., and Nestler E. J. (1993) Lewis and Fischer rat strains display differences in biochemical, electrophysiological and behavioral parameters: studies in the nucleus accumbens and locus coeruleus of drug naive and morphine-treated animals. Brain Res. 611, 7–17.PubMedGoogle Scholar
  114. 114.
    Nylander I., Vlaskovska M., and Terenius L. (1995) Brain dynorphin and enkephalin systems in Fishcer and Lewis rats: effects of morphine tolerance and withdrawal. Brain Res. 683, 25–35.PubMedGoogle Scholar
  115. 115.
    Vaccarino A. L. and Couret L. C. (1995) Relationship between hypothalamic-pituitary-adrenal activity and blockade of tolerance to morphine analgesia by pain: a strain comparison. Pain 63, 385–389.PubMedGoogle Scholar
  116. 116.
    Ngai S. H. and Finck A. D. (1982) Prolonged exposure to nitrous oxide decreases opiate receptor density in rat brainstem. Anesthesiology 57, 26–30.PubMedGoogle Scholar
  117. 117.
    Fitzgerald M. and Koltzenburg M. (1986) The functional development of descending inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal cord. Brain Res. 389, 261–270.PubMedGoogle Scholar
  118. 118.
    van Praag H. and Frenk H. (1991) The development of stimulation-produced analgesia (SPA) in the rat. Dev. Brain Res. 64, 71–76.Google Scholar
  119. 119.
    Fujinaga M., Doone R., Davies M. F., and Maze M. (2000) Nitrous oxide lacks antinociceptive effect on tail flick test in newborn rats. Anesth. Analg. 91, 6–10.PubMedGoogle Scholar
  120. 120.
    Ohashi Y., Stowell J. M., Hashimoto T., Nelson L. E., Maze M., and Fujinaga M. (2001) Effect of nitrous oxide on formalin-induced c-Fos expression in the spinal cord of adult and newborn Fischer rats. Anesthesiology 95, A-1287 (abstract).Google Scholar
  121. 121.
    Hashimoto T., Ohashi Y., Nelson L. E., Maze M., and Fujinaga M. (2002) Developmental variation in nitrous oxide induced c-Fos expression in Fischer rat spinal cord. Anesthesiology, 96, 249–251.PubMedGoogle Scholar
  122. 122.
    Narsinghani U. and Anand K. J. S. (2000) Developmental neurobiology of pain in neonatal rats. Lab. Animal 29, 27–39.PubMedGoogle Scholar
  123. 123.
    Goto T., Marota J. J. A., and Crosby G. (1996) Volatile anaesthetic antagonize nitrous oxide and morphine-induced analgesia in the rat. Br. J. Anesth. 76, 702–706.Google Scholar
  124. 124.
    Janiszewski D. J., Galinkin J. L., Klock P. A., Coalson D. W., Pardo H., and Zacny J. P. (1999) The effects of subanesthetic concentrations of sevoflurane and nitrous oxide, alone and in combination, on analgesia, mood, and psychomotor performance in healthy volunteers. Anesth. Analg. 88, 1149–1154.PubMedGoogle Scholar
  125. 125.
    Williams F. G. and Beitz A. J. (1990) Ultra-structural morphometric analysis of enkephalin-immunoreactive terminals in the ventrocaudal periaqueductal gray: analysis of their relationship to periaqueductal grayraphe magnus projection neurons. Neuroscience 38, 381–394.PubMedGoogle Scholar
  126. 126.
    Clark F. M. and Proudfit H. K. (1991) The projection of noradrenergic neurons in the A7 catecholamine cell group to the spinal cord in the rat demonstrated by anterograde tracing combined with immunocytochemistry. Brain Res. 547, 279–288.PubMedGoogle Scholar
  127. 127.
    Proudfit H. K. and Clark F. M. (1991) The projections of locus coeruleus neurons o the spinal cord. Prog. Brain Res. 88, 123–141.PubMedGoogle Scholar
  128. 128.
    Fritschy J. M. and Grzanna R. (1990) Demonstration of two separate descending noradrenergic pathways to the rat spinal cord: evidence for an intragriseal trajectory of locus coeruleus axons in the superficial layers of the dorsal horn. J. Comp. Neurol. 291, 553–582.PubMedGoogle Scholar
  129. 129.
    Clark F. M., Yeomans D. C., and Proudfit H. K. (1991) The noradrenergic innervation of the spinal cord: differences between two substrains of Sprague-Dawley rats determined using retrograde tracers combined with immunocytochemistry. Neurosci. Lett. 125, 155–158.PubMedGoogle Scholar
  130. 130.
    Clark F. M. and Proudfit H. K. (1992) Anatomical evidence for genetic differences in the innervation of the rat spinal cord by noradrenergic locus coeruleus neurons. Brain Res. 591, 44–53.PubMedGoogle Scholar
  131. 131.
    Sluka K. A. and Westlund K. N. (1992) Spinal projections of the locus coeruleus and the nucleus subcoeruleus in the Harlan and the Sasco Sprague-Dawley rat. Brain Res. 579, 67–73.PubMedGoogle Scholar
  132. 132.
    Clark F. M. and Proudfit H. K. (1993) The projections of noradrenergic neurons in the A5 catecholamine cell group to the spinal cord in the rat: anatomical evidence that A5 neurons modulate nociception. Brain Res. 616, 200–210.PubMedGoogle Scholar
  133. 133.
    Luppi P.-H., Aston-Jones G., Akaoka H., Chouvet G., and Jouvet M. (1995) Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus Vulgaris leucoagglutinin. Neuroscience 65, 119–160.PubMedGoogle Scholar
  134. 134.
    Aston-Jones G., Rajkowski J., Kubiak P., Valentino R. J., and Shipley M. T. (1996) Role of the locus coeruleus in emotional activation. Prog. Brain Res. 107, 379–402.PubMedGoogle Scholar
  135. 135.
    Singewald N. and Philippu A. (1998) Release of neurotransmitters in the locus coeruleus. Prog. Neurobiol. 56, 237–267.PubMedGoogle Scholar
  136. 136.
    Lowey A. D., Marson L., Parkinson D., Perry M. A., and Sawyer W. B. (1986) Descending noradrenergic pathways involved in the A5 depressor response. Brain Res. 386, 313–324.Google Scholar
  137. 137.
    Byrum C. E. and Guyenet P. G. (1987) Afferent and efferent connections of the A5 noradrenergic cell group in the rat. J. Comp. Neurol. 261, 529–542.PubMedGoogle Scholar
  138. 138.
    Bajic D., Van Bockstaele E. J., and Produfit H. K. (2001) Ultrastructural analysis of ventrolateral periaqueductal gray projections to the A7 catecholamine cell group. Neuroscience 104, 181–197.PubMedGoogle Scholar
  139. 139.
    Proudfit H. K. and Monsen M. (1999) Ultrastructural evidence that substance P neurons form synapses with noradrenergic neurons in the A7 catecholamine cell group that modulate nociception. Neuroscience 91, 1499–1512.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  1. 1.Magill Department of AnaesthesiaIntensive Care and Pain Management Chelsea and Westminster HospitalLondonUK
  2. 2.Department of Anaesthetics and Intensive Care Imperial College of Science, Technology and MedicineUniversity of LondonLondonUK

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