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Neurochemistry and Clinical Aspects of Pain
Majid Ali,
M.D.
Oxygen
is the organizing influence of human biology and
governs the aging process. In 2000, I began
Oxygen and Aging1 with those words.
Oxygen is a master work of nature—an
enduring tribute to Nature's preoccupation with
complementarity and contrariety. It is an elixir of
life and a hemlock for death — the ultimate
molecular Dr. Jekyll and Mr. Hyde. Sometimes by its
presence and sometimes by its absence, oxygen
initiates signaling for cellular life as well as
demise. In that context, it is important to
recognize that oxygen drives chronic pain pathways
primarily by its absence.
A large number of pain
neurotransmitters are involved in clinical pain
syndromes, including: substance P; enkephalins;
neurokinin 1, 2, and 3; serotonin; adenosine
triphosphate (ATP); nitric oxide; calcitonin;
vasoactive intestinal peptides; epinephrine,
norepinephrine, and related sympathomimetic agents;
glutamic acid, aspartic acid, and related excitatory
transmitters; and GABA, glycine, and related
inhibitory transmitters.2-4 Some
excitatory transmitters concerned with chronic pain
include glutamic acid and aspartic acid, which are
involved with dorsal horn sensitization through
activation of NMDA receptors, while inhibitory
transmitters participate in mechanisms that prevent
or diminish pain. It seems safe to predict that
future work will establish that, directly and
indirectly, all those molecular species are
triggered or influenced by oxygen deficit.
Oxygen and
Pain Neurotransmitters
Neurotransmitters transmit
information across synapses
—
regions separating neurons from
adjoining neurons, as well as neurons from the
muscle cells. These substances are stored in the
bulbous ends of axons, and are released by
electrical impulses traveling along the nerves to
those ends. Upon their release, neurotransmitter
either facilitate or inhibit continued electrical
impulses along the nerve fibers on the other side of
the synapse. Over 300 molecular species have been
recognized to be involved in neurotransmission.5
Some of the best known of those over 300
neurotransmitters have been listed in a preceding
section. It is regrettable that all neurologists and
others in the headache industry I know limit their
work only to serotonin and a few related
neurotransmitters.
Next to oxygen and serotonin,
substance P (SP) is the best examined of all the
pain neurotransmitters, and its relationship with
oxygen deficit has been most clearly delineated.6-11It
is an 11-residue peptide belonging to the tachykinin
sub-family of G-protein-coupled receptors (GPCR).
Those receptors form a class of integral membrane
proteins. Serotonin in the mammalian brain and
receptors of the olfactory epithelium that binds
odorants are two other members of this family are
receptors.
Oxygen deficit triggers the
release of substance P. There are several lines
of direct and indirect evidence for it.12,13
Direct evidence for that comes from experiments in
which decreasing concentrations of oxygen were
associated with the release of increasing amounts of
SP.12 Specifically, the carotid bodies
contain SP — in concentrations ranging from 1.4 to
1.6 ng/mg protein — that is released in response to
tissue hypoxia. The amount of SP released from the
carotid bodies increases in proportion to the
severity of hypoxia. It is noteworthy that the
release of SP by hypoxia is a calcium-dependent
process, and is primarily mediated by N- and L-type
Ca2+ channels. 13
Other lines of evidence for the
fundamental role of oxygen deficit in the
causation of pain include the following: (1) skin
lactate levels are increased in complex regional
pain14; (2) SP increases protein
extravasation in regional chronic pain states15 ;
(3) intradermal injection of epinephrine causes
local pain (due to vasoconstriction and consequent
oxygen deficit)16;
(4) a tissue hypoxia occurs in complex regional pain
syndrome17;
(5) ascorbic acid reduces pain
in reflex sympathetic dystrophy18; and
(6) certain other free radial scavengers also reduce
pain in complex regional pain states19
— the
mechanism of action of antioxidants being
restoration of local oxygen homeostasis.
Substance P
Substance P exerts varied effects
on different tissues. 20-24
It is
excitatory to the carotid body. Release of larger
amounts of SP in the lungs is associated with
pulmonary hypertension, an effect that is attenuated
by antioxidants. In the nasal mucosa, hyperbaric
oxygen decreases immunoreactivity to substance P.25
Not unexpectedly in light of the oxygen/SP
dynamics, oxyradicals under certain conditions also
trigger the release of substance P. By contrast,
antioxidants, such as ascorbic acid, inhibit the
release of SP.18 However, the
relationships between antioxidants and SP are
complex. For instance, capsaicin increases regional
perfusion — and oxygen delivery, inhibiting the
release of SP — but is also known to increase SP
release in the lung. Oxidants also have complex
relationships with SP. For example, nitric oxide
serving as an oxidant modulates histamine release
from tissue mast cell and circulating basophils, and
so contributes to pain caused by histamine.26-27
On the
other hand, nitric oxide, through its vasodilator
role, improves oxygen transport, decreases the
release of SP, and mitigates some pain syndromes.
(See Nature's Preoccupation With Complementarity
and Contrariety, the first volume of The
Principles and Practice of Medicine,28
for an
in-depth treatment of the subject).
Substance P also has complex
relationships with certain other physiologic
compounds, including enzymes and hormones. 29,30
For instance, increased amounts of erythrocyte
2,3-diphosphoglycerate
(2,3 DPG) caused by chronic hypoxia is associated
with increased release of SP. Since chronic hypoxia
increases the concentration of 2,3-DPG, this
provides yet another mechanims by which oxygen
deficit causes pain. Fascinating! How oxygen, by its
absence, both triggers a mechanism for correcting
that problem (by increasing 2,3-DGP production) and
sends out messages to other cellular systems for
participation in that effort (by inducing the
production of SP). An example of the involvement of
enzyme system with SP is that acute depressor
actions of angiotensin II in the nucleus of the
solitary tract are mediated by SP. An insight into
the possible interactions between SP and hormones is
provided by the complementary roles of SP and
calcitonin gene-related peptide in the causation of
phantom and ischemic pains.
An interesting aspect of the oxygen/substance P
dynamics is revealed by the case of the East
African naked mole-rats
(Heterocephalus glaber). This rat species
lacks substance P and does not appear to suffer pain
when tormented.31
The rats feel no immediate pain when cut,
scraped or subjected to heat stimuli. They only feel
some aches. But when the rats get a shot of SP, pain
signaling resumes working as in other mammals. One
can only wonder about what other defense mechanisms
exist in this rat species that compensate for
substance P.
Related Tutorials
Tutorial P1.
What Is Pain?
Tutorial P2.
The Oxygen Model
of Pain
Tutorial P3.
Migraine Migraine - Please Say Yes to Detection and
No to Diagnosis
Tutorial P4.
Migraine Labels That
Reveal Nothing and Hide Much
Tutorial.P5.
Neurochemistry
and Clinical Aspects of Pain
Tutorial P6. A Pathologist’s
Migraine
Tutorial P7. A President’s
Migraine
Tutorial.P8. A Politician’s
Migraine
Tutorial.P9. Short-term Use
of Migraine Attacks With Drugs Concurrent With
Nondrug Natural Remedies
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