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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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