Genetic Predisposition and Pain

Snails do it and so do humans. They make MULTIPLE varieties of pain chemicals.

Always differentiate between true central pain (constant burning dysesthesia and intermittent lightning pains) and mechanical pain which sets off weird sensations, but is basically meant to be painful, as opposed to central pain, which comes from harmless benign events. Central pain always involves superficial sensibilities, while mechanical pain can be anything. Mechanical pain may be treatable and may respond to opioids. Study of the snails gives us an idea of differences.

Once the Utah biochemist who patented conus regius pain blocking toxin, (ziconotide) got fifty million dollars for the patent, other scientists began to pay attention. In particular, it must have felt unsettling for the Australian biochemists, who sit just onshore from the Great Barrier Reef, where snails number like dandelions in the front yard, to hear of some mountain bound researcher getting rich off sea snails. Other species already known to possess neurotoxins include: Conus geographus*, Conus aulicus, Conus gloria-maris, Conus omaria, Conus striatus, Conus tulipa, Conus marmoreus* and Conus textile*.

These are all mollusks which produce various neurotoxins, including, but not limited to:

A-conotoxin – Blocks nicotinic acetylcholine receptors

W-conotoxin – blocks voltage gated calcium channels which prevents movement of calcium and also reduces release of acetylcholine (Ach), Ach drives cholinergic synapses (ziconotide belongs here at calcium channel activity)

M-conotoxin – affects sodium channels in muscle in a manner similar to tetrodotoxin or saxotoxin. (The source of the first is the Tetrodon or puffer fish, but the toxin’s origin is probably Vibrio or Pseudomonas bacteria ingested by the pufferfish) Tetrodoxin (Fugu poisoning comes from eating the puffer fish) blocks the opening of voltage gated ion channels. Saxotoxin comes from dinoflagellates ingested by oysters etc and also blocks voltage gated sodium ion channels. Recall that sodium ion channels are needed for influx of sodium ions into the neuron to accomplish an action potential or neuron firing. Neurons are polarized, ie. positive ions outside and negative ions inside, like a battery, and opening ion channels allows a “depolarization” or firing.

And of course there is the very interesting “Sleeper peptide” produced by Conus geographus, which causes a deep sleep. Everyone wants a piece of this one, but Conus geographus is very dangerous to study. it is estimated there are 250,000 graduates in marine biology every year but only 40 new jobs. Maybe now these grads will have somewhere to go, on the hunt of the deadly mollusks.

It takes little imagination to realize how significant the potential for pharmacologic discovery is from these species.

Mollusks are carnivorous. When it hunts, the snail extends its siphon by which it detects prey. Amazingly, this siphon is covered with neuroreceptors which assess nearly everything about the prey. Venom is stored in a wide variety in a venom bulb. The snail concocts almost instantaneously a special mixture using various amounts of its’ hundreds of toxins to deliver just the right dose to the prey.

Very quickly, the milky venom is chemically changed to a clear liquid which is injected in a radula or barb, which is more or less a detachable harpoon which comes out through the proboscis of the snail. The snail even exceeds the elephant for the relative length of the proboscis, which may be as long as the entire length of the snail body. Out it comes and in goes to the radula into the prey.

In the venom bulb, the pre-toxins are not yet poisonous. They are peptides (simple in chemistry if not in shape, they are short sequences of amino acids–usually about thirty amino acids in length). They must be mixed in a complicated formula to be deadly. A peptide can be viewed as a short protein. There are many sulphide to sulphide bonds which occur in cone peptides, which suggests a large variety of potential shapes, since peptides, usually held in one configuration, are able to rotate into chinese puzzle like arrangements around any disulphide bonds, creating a great variety of peptides which could match the vulnerability of a variety of animals. The snail rapidly formulates and mixes the peptides on the fly and delivers it very rapidly to the prey. It is like creating a bunch of rocks and throwing them at a perforated shield so as to match variously shaped holes in the barrier.

This kind of pharmacologic weapon is unusual for other species, which generally have an old reliable poison, which is preferred above others.

Being so slow, snails have to include an anti-pain peptide in the poison so the prey doesn’t panic and swim off. Here is where we come in. We would perhaps like a helping of the anti-pain peptide without the stuff that makes us quit breathing.

Acetylcholine is the neurotransmitter in all autonomic ganglia. Remember however that it is the receptor which actually makes the difference, NOT the neurotransmitter. There are two types of acetylcholine (Ach) receptors, nicotinic and muscarinic. There are four major types of muscarinic receptors and at least ten varieties of them.

The nicotinic receptor relate to the junction of nerve and muscle (blocking this blocks all muscle function, eg breathing) Ganglia are where cell bodies collect to which axons funnel information or distribute it by synapsing with another neuron. The neuron AFTER the synapse is called postganglionic. Ach moves into the synapse, does its job and is then reabsorbed to do its job over again.

Nicotinic receptors are the postganglionic receptors responsible for EXCITATORY, FAST post-synaptic potentials (fast EPSP). A potential is a firing or depolarizing of neurons. You will recall that when the polar voltage difference between the inside and outside of the neuron disappears (depolarizes), an action potential or nerve firing is generated along the neuron.

The Muscarinic Ach receptors pertain to the slow repolarization leading to hyperpolarization, or INHIBITORY postsynaptic potential (IPSP) which redevelops after a firing. The next step involves a slow hyperpolarization which then permits a SLOW EXCITATORY postsynaptic firing potential (slow EPSP). Just remember that no action potential can be generated until the inside of the neuron is polarized compared to the outside, ie. until there are positive ions to rush into the cell, creating a current flow, or nerve firing.

In the sympathetic nervous system, where we are no longer talking about nerve to nerve synapse, but instead where the nerves actually contact the tissue to be stimulated (such as connection of nerve to muscle), neither nicotinic nor muscarinic receptors are used (except in sweating). Instead, noradrenaline (norepinephrine) is used and dedicated receptors to it are the path of the neurotransmitter.

Muscarinic acetylcholine receptors are “metabotropic receptors” which means they use G proteins to act. G proteins couple to their receptor to facilitate their signalling mechanism. There are a very large vareity of G proteins. The signalling molecule, which is Ach, binds to the receptor crossing the membrane, (transmembrane receptor) which is itself bound to intracellular proteins–which ARE the G proteins. The G proteins then permit further binding and activity to occur, including the opening of certain ion channels.

Nicotinic receptors use ION GATED receptors, NOT metabotropic. Ions such as Sodium, Potassium, chloride, or calcium open these ion channels and one ion, such as calcium, may be required to open another, such as the potaasium channel. Since there are many varieties of muscarinic receptors, we can see that the magic of the cone shell in formulating the correct neuropeptide is nothing short of a miracle. Although we do not believe ziconotide will completely block N type calcium channels (the ones in pain fibers), we do believe more specific drugs can be found which do block the N type calcium channel specifically. From the responses in the surveys, we are not confident that ziconotide stops classic central pain. It does seem to stop pain from peripheral nerve injury, but we need more clinical studies to be more conclusive on this.

It just keeps getting better and better in the marine toxin world. For snail researchers, the “future’s so bright I gotta wear shades”. These amazing creatures, slow as molasses, nevertheless are chemical turbomachines, which CATCH nimble, flashing fish. How do they do it?

If you were harpooned by the nose of a snail, wouldn’t you get away as fast as possible. Well, Nature has equipped the lowly snail with a huge pharmacopoieia of toxins. The more scientists look, the more neuroactive drugs they find in the toxin glands of the various snails. Conus regius, the original contributor of ziconotide model pain relievers (the commercial product, Prialt, is now synthetic) is so beautiful that ecologists are begging shell collectors to stop gathering them. Sea snails are becoming scarce owing to the high price their large shells bring. In a recent visit to a Hawaiian shell shop, a nice big Conus Regius was priced at $200.00. They look magnificent, light cream with variegated red pattern.

There are a number of other snails which also do the “kill the pain” bit. Two with apparently equal potentcy to the Conus Regius have been found now on the Great Barrier Reef. Dozens more are likely to follow. Chemists simply cannot believe how many different neurotoxins are in one, single snail. It is like walking into a warehouse of drugs which alter neurotransmission. Snails already are big business and are going to become huge, provided shell collectors don’t kill the species off before we can study them.

The secret of the snail’s success at hunting is the inclusion in the venom of their proboscis ingredients to block pain. The little reef fish which has been speared by the harpooned proboscis feel NO pain and may not realize it is time to get away, even as Ach blockade is making it hard for muscles to act. Just like us, fish think they know pain and may not be alarmed by the dulling sensations which are sinking in.

The number of nerve toxins discovered so far among snails is around 400 and growing. Astoundingly, the snail assesses its prey and produces a mixture of toxins tailor made for whatever prey it is after. How it knows which nerve toxins will work on which sea creature is a total mystery. The point is that their pain blockers are chemically different, implying that pain receptor systems are different also.

Do you suppose that if Nature has given the snail hundreds or even thousands of pain blockers to reach the large number of chemical cascades possible, that Nature would give man one and ONLY one chemical pathway for pain. If you do, you are wrong.

If there is one thing clearly demonstrated by the surveys at painonline, it is that there is genetic variation from person to person and from gender to gender in response to medication.

The sequence of amino acids which make up the proteins from which ion channels and receptors are formed reflect the genetic background of the individual. Not only is the genetic background different from person to person, the EXPRESSION of those genes varies. It matters not if you have the gene for a certain sequence if that gene never gets expressed. Although some gene alterations are critical, the vast majority in humans just impart variation. (We all look different because our genes are different, or at least different genes are expressed).

For example, women feel pain differently from men. That does not mean the pain apparatus is found solely on the X chromosome. It means that gene expression varies due to many factors. The way genes may be turned on or off in a given chromosome is called plasticity, and there is a great deal of plasticity going on all the time. Plasticity just means a potential to be changed. Gene expression is “plastic”.

At or near the core of central pain appears to be, among other things, excessive production of Nerve Growth Factor. NGF is released in an attempt to repair injured nerve, which leads to spreading plasticity in things like how much mitogen activated protein kinase is made (see prior article on AC1) and how cyclic AMP gets the pain ball rolling. The composition and amounts of acid to afflict the perineural spaces are also impacted by genetics. How we digest fats, to make fatty acids to acidify pain nerves is also genetic.

The clinical response of CP patients to pain drugs, plus what we know about chemical pain cascades leads the scientists at painonline to conclude that humans, like the snails, have a bag of pain tricks. We have not just one possible pain pathway. We have many places of input, each of which varies from person to person.

At any rate, it is too late in the day to think pain is simple. That was for Descartes’ day (which may be the era your doctor lives in). Now, we know better. Human pain pathways are varied, multifocal, and complex.

Could a snail figure us out and block all pain while it kills us. Yes, without doubt. Now, all we have to do is to become as smart as the snail, block our pain, and NOT kill ourselves in the process. We will leave out the coup de gras toxin which actually does the killing.

So the next time your doctor gets after you for not responding to anything he has tried, perhaps you could say, “Well,they just haven’t figured out the medicine that works in me, yet.

Almost no one with central pain responds to opiates beyond the ability which opiates have to confer some sedation. Not responding to opiates can make a doctor really mad. It may even lead to the conclusion you want more of that awful stuff that will make you puke and give you a headache.

Another problem is confusing CP with mechanical pain which is being routed through a confused and damaged and pain system. Examples of this would be pain from Harrington rods, or from damaged cervical facets at the backside of spinal vertebrae.

Normal pain can feel a bit odd when the pain system is messed up and it is common to mistake ordinary mechanical (nociceptive) pain with neuropathic pain. If a doctor has had such a person respond to opiates, he may imagine that true central pain will respond to opiates. Oh, if it were only true.

A recent article claimed seventy five percent of all people with spinal cord injury have central pain syndrome. This was from a major medical center, publshing in a major medical journal. This is clearly incorrect. No more than about one in fifteen SCI patients have severe central pain. Real central pain is NOT intermittent insofar as the dysesthetic burning is concerned, which includes a paradoxical component of “cold”. Real CP usually also has INTERMITTENT lightning pains, also pins and needles, and muscle pain (isometric and/or isotonic kinesthetic dysesthesia). The potential severity of muscle pains is remarkable and may cause total paralysis despite an intact motor unit. In nearly all CP subjects kinesthetic dysesthesia creates severe limitation of movement and a heavy price to pay in pain if the pain signal is ignored. (See work by Aleksandre Beric in Muscle and Nerve)

Atopoesthesia (inability to tell precisely where the surface of the skin is located) and some sensory diminution is always present. Visceral distention pain is also nearly universal but not necessary to make the diagnosis. Dysesthetic burning is the gold standard and it is spontaneous, which is to say more or less constant. The dysesthetic burning is capable of being mightily evoked by light touch or temperature change, especially cold.

Other non-neuropathic pains experienced by SCI sufferers are likely to be mechanical pain, routed through a disordered pain system so that they feel unusual, odd or very severe. THESE pains may well be helped by opiates. They are not central pain in the classic sense. They may, however, be very severe and disabling. The majority of post SCI pain sufferers with CP also have significant mechanical or noxious pain.

The snail knows that we are all different. Our response to medication will be different. This does not, however, make mechanical pain into central pain. Neuropathic pain comes from excess nerve growth factor. Mechanical pain comes from ordinary events. These chemical events move through the spreading pain message which filters up through the nervous system, invariably encountering pathways which are messed up, creating unusual pain sensations. Morphed mechanical pain is NOT central pain, however.

Don’t kill the snails. They need to be cultivated and their venom collected. Eventually, they may deliver us from our agony.


*Very lethal, with death occurring in about five hours in humans.