We are happy to comment on resiniferatoxin and fatty acids. Very early on, Painonline editors concluded the central pains might not actually be bizarre. EVERY person surveyed has been able to accept, “like acid” as a description of burning dysesthesia. This, as well as the location of the burning, “just deep to the skin” is almost a universal. It is not necessary or desirable to improve on what CP sufferers themselves are comfortable with.
When acid leukotrienes were discovered in the thalamus of CP animals, we concluded the nerves were actually feeling acid. Now we encounter yet another study indicating we were right.
This author once sat privately with Dr. Patrick Wall, and pondered what sort of sensation could cause a metallic quality to accompany burning. Dr. Wall had a particularly articulate and reliable patient mention the “metallic” quality of dysesthesia. The latest answer to this returns to what CP patients have been saying from the first, “acid”.
It now appears sound to posit a question to the CP subject: Can you feel it now? The acid? Can you feel it where it resides, like a layer of burning just under your skin?
That “layer” is the collective feeling of acid at myriad VR1 receptors. Can they be persuaded to stop? It appears increasingly likely that the ansewr is “yes, and quickly”. Resiniferatoxin is one of the fastest drugs ever studied.
The heroes in this approach are Karai and Iadarola at NIH. Both have pioneered the use of resiniferatoxin (RTX), a derivative of euphorbium, which comes from Euphorbia resinifera, a cactus which was noted for medicinal purposes as far back as Augustus.
Its use is presently limited to infusion of it into the bladder for neurogenic pain, where it kills the pain nerves almost instantly without particular discomfort. There being no particular reason to regard the bladder pain found in CP as unrelated to the “centralization pain” of neurogenic bladder, we have suggested that (resiniferatoxin) RTX should be tested on CP bladder.
That work may transpire soon, and be followed by use in the spinal fluid to treat the chronic pain of CP. Short of that, local applications via various endoscopes may have application for CP gut, or even application to nerves or ganglia. There may even be resort to open iontophoresis. Equally possible is laparoscopic application for endomedtriosis It is our hope that the budget directors at NIH will fund this incredibly important work.
Resiniferatoxin kills the cells too rapidly to create the burn that is characteristic of capsaicin. With the bladder as a model, the approach is to inject resiniferatoxin into the spinal fluid in order to kill cells expressing the VR1 receptor, which mediates chronic pain. The acids mentioned above force VR1 to admit calcium, causing pain.
Resiniferatoxin does it one better and forces so much calcium inward that the cell dies. This important breakthrough is possibly the first big stick against Central Pain. The condition has been a nightmare of attempted therapies and failed results. Now at last, something good appears close.
The VR1 receptor, a calcium channel embedded in the cell membrane of pain neurons, and activated by fatty acids linked to arachidonic acid, is currently thought to be responsible for chronic pain, including the central pains. VR1 is also known as the capsaicin receptor.
Recently we reviewed the effect of NMDA on superoxide dismutase, causing an interruption of DNA precursors. We also reviewed the changes in fatty acid amide hydrolase (FAAH), an important enzyme in pain. (see Neuropathic Pain is not the same as Thermal Allodynia).
Now we come to what may be the central point of a CP therapy. We are convinced that the sensation of “acid under the skin” is not bizarre. We had suspected this when scientists at Harvard and Massachutsetts General found high levels of leukotrienes in the thalamus of nerve injured animals. Let us then assume that patients are accurate, and that acid really IS present around the pain nerves. Studies by Karai, Iadarola, and others are now confirming our earlier clinical impressions.
Organic chemistry is the study of carbon compounds. Carbon tends to arrange itself in six sided or five sided rings. Actual molecules may have substitutions, but we postulate a hypothetical structure with carbon at each position and then consider structurally related compounds and give them a name.
The Greek word for twenty is “eikosi”. All twenty carbon compounds are known as eicosonoids, which means similar to an hypothetical ideal C20 compound which is named prostanoic acid (a fatty acid). The twenty carbon atoms are arranged in four pentagons connected side to side with a carbohydrate (COOH) at one end. The positions are counted from the first carbon next to the carbohydrate, going counterclockwise. This puts position 9 at the top of the first pentagon and position 11 two places counterclockwise. If an oxygen or a hydroxide (OH) is put at these positions, we get different types of prostaglandins.
Although named for the prostate, prostaglandin is found in all mammalian cells except red blood cells. Eicosonoids are similar to hormones in that they cause action via ATP in the cell, which acts locally. ATP stores energy but also appears to signal pain–it is a neurotransmitter in its own right, especially to the acid sensitive ion channels (ASIC). The VR1 (TRPV-1) receptor is activated by the well known pain kinase, Protein Kinase C (PKC), which attaches the high energy phosphate bonds to VR1. PKC knockout rats cannot get Central Pain. Eicosonoids do not circulate in the blood, but are produced right where they exert action, such as at the neuronal membrane.
The link to ATP is even more profound in eicosanoids than it is for hormones.. As stated, the work of Keele and others indicates ATP is actually involved in pain signaling. Cell extracts with ATP cause the injectee to have greater pain. Equally convincing are the Souslova VR1 knockout rats (missing the gene for an ATP dependent pain receptor) who cannot feel pleasant warming.
Cockayne database has shown CP patients also do not properly sense the discomfort of a full bladder. Patients with CP bladder report failure to sense a full bladder to a point, at which time the sensation overshoots and they must void immediately at all costs. Whether this is due to the same failure to perceive the ATP spill from cells io the distended bladder epithelium is not known.
The most important prostaglandin precursor is 5,8,11,14 eicosotetranoic acid, with the numbers pointing out double bonds at the position listed. You have heard of Omega -3 fatty acids in fish. Arachidonic acid is an omega-6 fatty acid since the double bond at position 14 is six carbon atoms from the terminal end. The fatty acid ingested determines whether a person makes series 3 prostaglandins (cause pain and inflammation) or series 5 prostaglandins (do not attract inflammatory cells in the brain)
Diets rich in marine lipids prevent the formation of leukotrienes involved in inflammation and pain. Although we have not seen pain lessen on marine fats, no studies have addressed it. It appears that the type of fatty acids we consume makes a difference in our body, where inflammation or tissue reaction is important.
For example, some have claimed pain relief from flaxseed oil applied topically and docohexaenoic acid is thought to protect against Alzheimer’s. Both contain omega-3 fatty acids. Still, proinflammatory fatty acids seem likely to override dietary impact, at least over the short haul. Perhaps we already have plenty of Omega6 fatty acids stored away and need more time for the effect to be demonstrated.
Aspirin inhibits the synthesis of prostaglandin from arachidonic acid. Arachidonic acid is a precursor of the leukotrienes, which is increased in the skin, cord, and thalamus of nerve injured subjects. Aspirin does NOT inhibit the conversion of arachidonic acid to leukotrienes.
Leukotrienes are ten thousand times more potent than histamine. Like superoxide, the formation of a leukotrience requires an iron and sulfur. Both substances are concerned with free radicals.
Acidity at irritated nerve endings is caused by many factors, including potassium, leukotrienes, histamine, other cytokines etc. The acidity of the skin under blister fluid can reach a pH of 5. This is incredibly acidic compared to the physiologic pH of 7.4. The human body favors homeostasis or a stable “golden mean” and deviations of this magnitude are very uncommon.
The evidence is mounting that the so-called “bizarre” pain of dysesthesia is nothing more than the way a neuron surrounded by acid, perceives acid. Acid undoutedly changes the shape of any proteins in the membrane, such as make up the ion channels. Changes in shape will cause changes in function. Attempts to study the shape of NMDA receptors have not succeeded because we lack sufficient computing power. Bonding angles require heavy math and the configurations fold rapidly (1/100ms) from shape to shape until they reach a stable situation. Reactions may occur in only one configuration of many along the path to stability.
In followup work from the use of resiiferatoxin to stop neuropathic in the bladder, Karai and Iadarola showed in August 2001 J. Biol. Chem, that the VR1 receptor interacts with anandamide(see below) and inflammatory metabolites of arachidonic acid in a pH DEPENDANT MANNER. Anandamide, functioning similarly to capsaicin, activates the Vanilloid-1 receptor to cause pain. This means that ACID causes pain due to the influence on the VR1 receptor. Thus, we not only percieve acid at he skin, cord and brain, we experience its effects at the VR1 receptor. This is a kind of closed loop, with positive feedback. The end result of a positive feedback in any pain loop is torture, as Patrick Wall stated to this author and also emphasized in the “Textbook of Pain”.
Cells in the dorsal root ganglion, a collection of sensory neuron cell bodies just outside the cord, express the vanilloid receptor-1. Among vanilloids in the body is anandamide, sometimes also called a cannabinoid. The VR1 receoptor allows calcium to flow into the cell. Just as too much calcium can stop the heart, too much calcium can kill any cell expressing the VR1 receptor. Karai et al have shown (J. Biol. Chem) and JCI) that resiniferatoxin can kill pain neurons by allowing too much calcium to enter too rapidly.
Resiniferatoxin forces the VR1 receptor channel to permit lethal amounts of calcium to enter. Cell lysis (death) occurs within a minute or so.
We anticipate that resiniferatoxin studies will explode and that we may finally have a shot at stopping the positive loop. Complicated as it is, it is nothing more than the chemical behavior of a series of acid related events. We may possibly be looking at a new horizon in treatment. Calcium flooding may stop chronic pain by destroying the cells which mediate it. This may end the merciless exploitation of the VR1 receptor by prostanoids.