Continued.
. . 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12
PAIN
MECHANISM OF FIBROMYALGIA
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.
H
\ / /
- 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. Peptides
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.
Continued. . . 1, 2,
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11, 12 |