Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2003 Sep;111(12):1461–1464. doi: 10.1289/ehp.5935

Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity: central role of N-methyl-D-aspartate receptors in the sensitivity mechanism.

Martin L Pall 1
PMCID: PMC1241647  PMID: 12948884

Abstract

The elevated nitric oxide/peroxynitrite and the neural sensitization theories of multiple chemical sensitivity (MCS) are extended here to propose a central mechanism for the exquisite sensitivity to organic solvents apparently induced by previous chemical exposure in MCS. This mechanism is centered on the activation of N-methyl-D-aspartate (NMDA) receptors by organic solvents producing elevated nitric oxide and peroxynitrite, leading in turn to increased stimulating of and hypersensitivity of NMDA receptors. In this way, organic solvent exposure may produce progressive sensitivity to organic solvents. Pesticides such as organophosphates and carbamates may act via muscarinic stimulation to produce a similar biochemical and sensitivity response. Accessory mechanisms of sensitivity may involve both increased blood-brain barrier permeability, induced by peroxynitrite, and cytochrome P450 inhibition by nitric oxide. The NMDA hyperactivity/hypersensitivity and excessive nitric oxide/peroxynitrite view of MCS provides answers to many of the most puzzling aspects of MCS while building on previous studies and views of this condition.

Full Text

The Full Text of this article is available as a PDF (119.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abou-Donia M. B., Goldstein L. B., Dechovskaia A., Bullman S., Jones K. H., Herrick E. A., Abdel-Rahman A. A., Khan W. A. Effects of daily dermal application of DEET and epermethrin, alone and in combination, on sensorimotor performance, blood-brain barrier, and blood-testis barrier in rats. J Toxicol Environ Health A. 2001 Apr 6;62(7):523–541. doi: 10.1080/152873901300007824. [DOI] [PubMed] [Google Scholar]
  2. Bascom R., Meggs W. J., Frampton M., Hudnell K., Killburn K., Kobal G., Medinsky M., Rea W. Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation. Environ Health Perspect. 1997 Mar;105 (Suppl 2):531–537. doi: 10.1289/ehp.97105s2531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bell I. R., Baldwin C. M., Schwartz G. E. Illness from low levels of environmental chemicals: relevance to chronic fatigue syndrome and fibromyalgia. Am J Med. 1998 Sep 28;105(3A):74S–82S. doi: 10.1016/s0002-9343(98)00162-4. [DOI] [PubMed] [Google Scholar]
  4. Bell I. R., Miller C. S., Schwartz G. E. An olfactory-limbic model of multiple chemical sensitivity syndrome: possible relationships to kindling and affective spectrum disorders. Biol Psychiatry. 1992 Aug 1;32(3):218–242. doi: 10.1016/0006-3223(92)90105-9. [DOI] [PubMed] [Google Scholar]
  5. Bell I. R., Schwartz G. E., Baldwin C. M., Hardin E. E. Neural sensitization and physiological markers in multiple chemical sensitivity. Regul Toxicol Pharmacol. 1996 Aug;24(1 Pt 2):S39–S47. doi: 10.1006/rtph.1996.0075. [DOI] [PubMed] [Google Scholar]
  6. Bell I. R., Szarek M. J., Dicenso D. R., Baldwin C. M., Schwartz G. E., Bootzin R. R. Patterns of waking EEG spectral power in chemically intolerant individuals during repeated chemical exposures. Int J Neurosci. 1999 Mar;97(1-2):41–59. doi: 10.3109/00207459908994302. [DOI] [PubMed] [Google Scholar]
  7. Bliss T. V., Collingridge G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993 Jan 7;361(6407):31–39. doi: 10.1038/361031a0. [DOI] [PubMed] [Google Scholar]
  8. Boczkowski J., Lisdero C. L., Lanone S., Carreras M. C., Aubier M., Poderoso J. J. Peroxynitrite-mediated mitochondrial dysfunction. Biol Signals Recept. 2001 Jan-Apr;10(1-2):66–80. doi: 10.1159/000046876. [DOI] [PubMed] [Google Scholar]
  9. Cullen M. R. The worker with multiple chemical sensitivities: an overview. Occup Med. 1987 Oct-Dec;2(4):655–661. [PubMed] [Google Scholar]
  10. Dailey H. A., Dailey T. A., Wu C. K., Medlock A. E., Wang K. F., Rose J. P., Wang B. C. Ferrochelatase at the millennium: structures, mechanisms and [2Fe-2S] clusters. Cell Mol Life Sci. 2000 Dec;57(13-14):1909–1926. doi: 10.1007/PL00000672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Deschoolmeester M. L., Eastmond N. C., Dearman R. J., Kimber I., Basketter D. A., Coleman J. W. Reciprocal effects of interleukin-4 and interferon-gamma on immunoglobulin E-mediated mast cell degranulation: a role for nitric oxide but not peroxynitrite or cyclic guanosine monophosphate. Immunology. 1999 Jan;96(1):138–144. doi: 10.1046/j.1365-2567.1999.00662.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Downey D. Porphyria: the road not traveled. Med Hypotheses. 2001 Jan;56(1):73–76. doi: 10.1054/mehy.2000.1114. [DOI] [PubMed] [Google Scholar]
  13. Forsythe P., Gilchrist M., Kulka M., Befus A. D. Mast cells and nitric oxide: control of production, mechanisms of response. Int Immunopharmacol. 2001 Aug;1(8):1525–1541. doi: 10.1016/s1567-5769(01)00096-0. [DOI] [PubMed] [Google Scholar]
  14. Hahn M., Bonkovsky H. L. Multiple chemical sensitivity syndrome and porphyria. A note of caution and concern. Arch Intern Med. 1997 Feb 10;157(3):281–285. [PubMed] [Google Scholar]
  15. Haley J. E., Sullivan A. F., Dickenson A. H. Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Res. 1990 Jun 4;518(1-2):218–226. doi: 10.1016/0006-8993(90)90975-h. [DOI] [PubMed] [Google Scholar]
  16. Kajekar R., Moore P. K., Brain S. D. Essential role for nitric oxide in neurogenic inflammation in rat cutaneous microcirculation. Evidence for an endothelium-independent mechanism. Circ Res. 1995 Mar;76(3):441–447. doi: 10.1161/01.res.76.3.441. [DOI] [PubMed] [Google Scholar]
  17. Kawauchi S., Sugamoto S., Furukawa O., Mimaki H., Takeuchi K. Stimulation by nitric oxide of gastric acid secretion in bullfrog fundic mucosa in vitro. J Physiol Pharmacol. 2001 Mar;52(1):93–105. [PubMed] [Google Scholar]
  18. Kim Y. M., Bergonia H. A., Müller C., Pitt B. R., Watkins W. D., Lancaster J. R., Jr Loss and degradation of enzyme-bound heme induced by cellular nitric oxide synthesis. J Biol Chem. 1995 Mar 17;270(11):5710–5713. doi: 10.1074/jbc.270.11.5710. [DOI] [PubMed] [Google Scholar]
  19. Konopka T. E., Barker J. E., Bamford T. L., Guida E., Anderson R. L., Stewart A. G. Nitric oxide synthase II gene disruption: implications for tumor growth and vascular endothelial growth factor production. Cancer Res. 2001 Apr 1;61(7):3182–3187. [PubMed] [Google Scholar]
  20. Lafon-Cazal M., Culcasi M., Gaven F., Pietri S., Bockaert J. Nitric oxide, superoxide and peroxynitrite: putative mediators of NMDA-induced cell death in cerebellar granule cells. Neuropharmacology. 1993 Nov;32(11):1259–1266. doi: 10.1016/0028-3908(93)90020-4. [DOI] [PubMed] [Google Scholar]
  21. Meggs W. J. Neurogenic inflammation and sensitivity to environmental chemicals. Environ Health Perspect. 1993 Aug;101(3):234–238. doi: 10.1289/ehp.93101234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Miller C. S., Mitzel H. C. Chemical sensitivity attributed to pesticide exposure versus remodeling. Arch Environ Health. 1995 Mar-Apr;50(2):119–129. doi: 10.1080/00039896.1995.9940889. [DOI] [PubMed] [Google Scholar]
  23. Murray C. W., Cowan A., Larson A. A. Neurokinin and NMDA antagonists (but not a kainic acid antagonist) are antinociceptive in the mouse formalin model. Pain. 1991 Feb;44(2):179–185. doi: 10.1016/0304-3959(91)90135-K. [DOI] [PubMed] [Google Scholar]
  24. Novelli A., Reilly J. A., Lysko P. G., Henneberry R. C. Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res. 1988 Jun 7;451(1-2):205–212. doi: 10.1016/0006-8993(88)90765-2. [DOI] [PubMed] [Google Scholar]
  25. Pall M. L. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses. 2000 Jan;54(1):115–125. doi: 10.1054/mehy.1998.0825. [DOI] [PubMed] [Google Scholar]
  26. Pall M. L., Satterlee J. D. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and posttraumatic stress disorder. Ann N Y Acad Sci. 2001 Mar;933:323–329. doi: 10.1111/j.1749-6632.2001.tb05836.x. [DOI] [PubMed] [Google Scholar]
  27. Prast H., Philippu A. Nitric oxide as modulator of neuronal function. Prog Neurobiol. 2001 May;64(1):51–68. doi: 10.1016/s0301-0082(00)00044-7. [DOI] [PubMed] [Google Scholar]
  28. Rafferty S. P., Domachowske J. B., Malech H. L. Inhibition of hemoglobin expression by heterologous production of nitric oxide synthase in the K562 erythroleukemic cell line. Blood. 1996 Aug 1;88(3):1070–1078. [PubMed] [Google Scholar]
  29. Reynolds I. J., Hastings T. G. Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J Neurosci. 1995 May;15(5 Pt 1):3318–3327. doi: 10.1523/JNEUROSCI.15-05-03318.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ruocco I., Cuello A. C., Shigemoto R., Ribeiro-da-Silva A. Light and electron microscopic study of the distribution of substance P-immunoreactive fibers and neurokinin-1 receptors in the skin of the rat lower lip. J Comp Neurol. 2001 Apr 16;432(4):466–480. doi: 10.1002/cne.1114. [DOI] [PubMed] [Google Scholar]
  31. Smirnova Iva V., Pall Martin L. Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients. Mol Cell Biochem. 2003 Jun;248(1-2):93–95. doi: 10.1023/a:1024176016962. [DOI] [PubMed] [Google Scholar]
  32. Snyder S. H. Nitric oxide and neurons. Curr Opin Neurobiol. 1992 Jun;2(3):323–327. doi: 10.1016/0959-4388(92)90123-3. [DOI] [PubMed] [Google Scholar]
  33. Sorg B. A. Multiple chemical sensitivity: potential role for neural sensitization. Crit Rev Neurobiol. 1999;13(3):283–316. doi: 10.1615/critrevneurobiol.v13.i3.30. [DOI] [PubMed] [Google Scholar]
  34. Szabó C., Billiar T. R. Novel roles of nitric oxide in hemorrhagic shock. Shock. 1999 Jul;12(1):1–9. doi: 10.1097/00024382-199907000-00001. [DOI] [PubMed] [Google Scholar]
  35. Sörensen J., Bengtsson A., Bäckman E., Henriksson K. G., Bengtsson M. Pain analysis in patients with fibromyalgia. Effects of intravenous morphine, lidocaine, and ketamine. Scand J Rheumatol. 1995;24(6):360–365. doi: 10.3109/03009749509095181. [DOI] [PubMed] [Google Scholar]
  36. Turski L., Turski W. A. Towards an understanding of the role of glutamate in neurodegenerative disorders: energy metabolism and neuropathology. Experientia. 1993 Dec 15;49(12):1064–1072. doi: 10.1007/BF01929915. [DOI] [PubMed] [Google Scholar]
  37. Uma S., Yun B. G., Matts R. L. The heme-regulated eukaryotic initiation factor 2alpha kinase. A potential regulatory target for control of protein synthesis by diffusible gases. J Biol Chem. 2001 Feb 5;276(18):14875–14883. doi: 10.1074/jbc.M011476200. [DOI] [PubMed] [Google Scholar]
  38. Yonehara N., Yoshimura M. Effect of nitric oxide on substance P release from the peripheral endings of primary afferent neurons. Neurosci Lett. 1999 Aug 27;271(3):199–201. doi: 10.1016/s0304-3940(99)00533-9. [DOI] [PubMed] [Google Scholar]
  39. Ziem G., McTamney J. Profile of patients with chemical injury and sensitivity. Environ Health Perspect. 1997 Mar;105 (Suppl 2):417–436. doi: 10.1289/ehp.97105s2417. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES