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From the Townsend Letter
October 2006


Recent Progress in Clinical Applications
and Research in Fibromyalgia

by Robert W. Bradford, Professor of Medicine, D. Sc. NMD, and Henry W. Allen, Director of Clinical Biochemistry, BRI

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Continued. . . 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12


Serotonin is the neurotransmitter involved with the sensation of pain. When serotonin is bound by its receptor in the postsynaptic membrane, an 11-amino acid peptide known as "substance P" is released, which, in turn, is bound by its receptor and activates "protein Gq." Protein Gq is a GTPase: that is, it utilizes GTP (guanosine triphosphate) and degrades it to GDP (guanosine diphosphate), thereby activating the enzyme phospholipase C. This enzyme then cleaves inositol triphosphate (IP3) from a specific phospholipid found in the bilayer lipid membrane. IP3 then binds to its receptor found in the membrane of a subcellular organelle functioning as a calcium storage chamber (sarcoplasmic reticulum), thereby releasing calcium into the cytoplasm. The influx of calcium sends a signal to certain portions of the brain which interpret that impulse as pain.21 See Figure 3. (13KB .pdf)

Substance P

The neuropeptide "substance P" is an 11-amino acid peptide (protein) having the sequence: (N-terminal) Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-(NH2) (C-terminal). The abbreviations for the amino acids are Arg – arginine; Pro – proline; Lys – lysine; Gln – glutamine, the amide form of glutamic acid; Phe – phenylalanine; Gly – glycine; Leu – leucine; and Met-(NH2) – the amide form of methionine.22

The important characteristics of these amino acid residues are that arginine and lysine are water-soluble (hydrophilic) and positively charged; glutamine is neutral and water-soluble; phenylalanine is water insoluble (hydrophobic); glycine and leucine are neutral; and methionine amide is water-soluble.

As previously described, substance P binds to its receptor and forms one link in the chain of the normal pain sequence. It was realized that if a mimic of substance P could be found that would also bind to this receptor and block the entry of substance P, this substance would act as a pain inhibitor. For this reason, a great effort has been made to determine the shape or configuration of substance P when bound by the receptor. If substance P is dissolved in various solvents, including water, DMSO, oils, Proprietary Stabilized Alkanylated Sulfur Compound, and others, it assumes various configurations depending on the solvent and pH of the medium into which it is placed.23,24

Hydrogen Bond
The structure of substance P is related to the formation of the "hydrogen bond," a weak bond found in most proteins, peptides, enzymes, nucleic acids (RNA and DNA), and other molecules. In its simplest form, a hydrogen bond is formed between a hydroxy group (-OH) attached to a carbon atom (1) and the oxygen of another hydroxy group bound to a second carbon atom (2). The "H" of the first hydroxy group is simply a proton (p) bound to an oxygen atom. The oxygen atom of the second hydroxy group has in its outer shell two pairs of unused electrons, only one of which is required to form a hydrogen bond between the two oxygen atoms. Simply put, a hydrogen bond is the sharing of a proton by two oxygen atoms. This arrangement may be seen in Figure 4.

  \    /                  /  
                    - C – O:- - - - - p ------O – C -
  /                       \
     (2)                (1)

Figure 4: A hydrogen bond

Proprietary Stabilized Alkanylated Sulfur Compound
If a chemical substance that has the ability to form a stronger hydrogen bond with the oxygen atoms comes in close contact with this system, the bond will be broken through the formation of hydrogen bonds with the extraneous substance. Proprietary Stabilized Alkanylated Sulfur Compound, researched and developed by the Bradford Research Institute, is an example of a strong hydrogen bond-breaker of this nature. It has been used clinically at the Ingles Integrative Hospital and elsewhere with a high degree of success in the management of the pain associated with fibromyalgia. Disrupting the normal structure of substance P, and the subsequent inability to bind to the receptor, represents a break in the sequence of biochemical events leading to pain and a reduction of pain. Proprietary Stabilized Alkanylated Sulfur Compound is also instrumental in the breaking of hydrogen bonds holding together the polysaccharide cell wall of certain infectious fungal forms and spores found in fibromyalgia patients, described in greater detail below. Through disruption of the cell walls of mycelia and spores, these fungi are destroyed, partly accounting for the relief from pain in fibromyalgia patients.

Some peptides or segments of peptides are capable of assuming a helical or spiral configuration (alpha-helix), held in this position by hydrogen bonds oriented in the direction of the helix. It has been found that a section of substance P including the sequence -Gln-Gln-Phe-Phe-, assumes the configuration of an alpha-helix in which the residues extend outward from the helical backbone.25 In addition, the C-terminal amide group of methionine folds back onto the chain and forms hydrogen bonds with the amide groups of two glutamine residues, -Gln-Gln-.26 See Figure 5. (13KB .pdf)

Benzene Rings
Structural analysis has shown that it is highly likely the two benzene rings of two phenylalanine residues (-Phe-Phe-) are perpendicular to each other rather than parallel when bound in the receptor site.27 The configuration of substance P when bound to the receptor is of extreme importance in relation to its ability to be bound. If, for any reason, the configuration is altered, the likelihood of binding is doubtful and highly unlikely.28

Structural analysis has also shown that the configuration of substance P is determined by the presence of critical hydrogen bonds holding together not only the alpha-helix but the folding of the chain upon itself.25,26 If these hydrogen bonds are broken by an agent capable of breaking such bonds, it becomes highly unlikely that substance P will be bound by the receptor or result in pain.

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