NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity.

Multiple chemical sensitivity (MCS) is a condition where previous exposure to hydrophobic organic solvents or pesticides appears to render people hypersensitive to a wide range of chemicals, including organic solvents. The hypersensitivity is often exquisite, with MCS individuals showing sensitivity that appears to be at least two orders of magnitude greater than that of normal individuals. This paper presents a plausible set of interacting mechanisms to explain such heightened sensitivity. It is based on two earlier theories of MCS: the elevated nitric oxide/peroxynitrite theory and the neural sensitization theory. It is also based on evidence implicating excessive NMDA activity in MCS. Four sensitization mechanisms are proposed to act synergistically, each based on known physiological mechanisms: Nitric oxide-mediated stimulation of neurotransmitter (glutamate) release; peroxynitrite-mediated ATP depletion and consequent hypersensitivity of NMDA receptors; peroxynitrite-mediated increased permeability of the blood-brain barrier, producing increased accessibility of organic chemicals to the central nervous system; and nitric oxide inhibition of cytochrome P450 metabolism. Evidence for each of these mechanisms, which may also be involved in Parkinson's disease, is reviewed. These interacting mechanisms provide explanations for diverse aspects of MCS and a framework for hypothesis-driven MCS research.