Opiate Receptor Mechanics
last updated 8.25.05

One line of reasoning is that enzymes are not capable of breaking down every miniscule amount of harmful peptides when used as a replacement to the GFCF Diet. It has also been said that giving enzymes with casein and gluten is like giving poison and the antidote. Both of these statements are no doubt intended to invoke a sense of urgency to conform to a rigorous diet. However, they also fail to account for how opiate/receptor mechanisms work, and may therefore be non-applicable to the situation. If we are operating under the assumption that exorphins are interacting with opiate receptors, then we have to go by what is known concerning receptor mechanisms. (The harmful peptides produced in the body are known as exorphins. These are one source of exorphins in the body.)

First, it is impossible to eliminate all opiate-like exorphins in the body, or from the diet for that matter. "100% GFCF" does not necessarily translate into 100% peptide-free", as many other food proteins are potential sources of exorphin peptides, including the blood itself. So, being 100% GFCF rarely, if ever, does removes all harmful peptides to begin with. Since people routinely say they are "immensely" improved at times by just this elimination diet, then this validates that you do not need to get every single molecule to achieve immense improvement. The fact that many people see even better improvement off a GFCF diet with enzymes (at least with the Houston enzymes and perhaps others) validates that the enzymes can do a more thorough job on their own than just eliminating foods.

Next, must one eliminate 100% of all exorphin peptides from the body, whether by diet, enzymes, or diet plus enzymes? Can one molecule of dairy or wheat cause problems in children with autism? In all honesty, the answer is "No". If we base the "problem" on opiate reactions, then we must also look at how those reactions actually work.

If we assume that the problem with opiate-like exorphins is their interaction with opiate receptors in the gut, brain, and elsewhere, then we have the effect of "receptor occupancy" on our side. A ligand is something that binds to a receptor. In this case, the ligand is the exorphin peptide. The ligand, or peptide, must be physically bound to the receptor molecule's binding site. The basis for most modern pharmacology is the recognition that drugs, hormones, and peptides work by binding to receptors on cells and must occupy a certain percentage of those receptors to elicit an effect. It is based on a percentage and not each individual molecule, or even an exact number of molecules. One very well-characterized aspect of these receptors is that a certain number of opiate receptors must be occupied to have a receptor- mediated event occur.

For example, if one is in pain, then morphine may be prescribed. However, one molecule of morphine is not going to cause a decrease in pain, nor is two molecules. You may need 5 mg of morphine before you feel less pain. It took that much morphine to bind to and activate the percentage of opiate receptors needed to produce the effect. Any less was not effective, but it was still in your system. But it wasn't doing anything. Same with exorphins. Pain will not be decreased until a certain amount of morphine is bound to a certain percentage of morphine (an opiate) receptors. The particular percentage will vary depending upon a number of complex factors that are beyond the scope of this discussion. It usually has to do with:

  • individual physiology
  • the nature of the opioid substance
  • the quantity of the substance
  • how often the individual is exposed to the substance
  • how extensively the individual has developed a tolerance to the substance
  • the ability of the individual to eliminate substance, and
  • the actual dose of the substance at any given time

It is a moving target and not a concrete number. The point is this: often, all that is needed is a decrease of exorphin peptides to a certain threshold level to observe demonstrable positive effects. This can be accomplished both with diet and/or appropriate enzymes. Both perform the same action, namely, to lower the exorphin peptide level.

Let's say there are 100 gut opiate receptors available, and all their ligand-binding sites are empty. In this example, we will say it takes 25% occupancy of receptors to trigger a particular reaction – let’s say it is "constipation." Now, 10 exorphin peptides come along which proceed to bind to 10 of the opiate receptors. We now have 10% occupancy of available receptors. At 10% occupancy, no constipation occurs because it is below the
threshhold level of occupied receptors. But then 15 more peptides come along which bind to the receptors. Now we have 25% occupancy and constipation occurs. If even more peptides come in, like about 15, we will have 40% occupancy. However, the event is already in action, so possibly the only additional event to occur is a prolongation of the constipation, because there are more occupied receptors that will have to become "unoccupied" for the receptor event to stop.

There is ALWAYS a critical amount of substance (peptide or ligand) needed to be bound to the receptor population to elicit an effect. That percentage may be 10% or it might be 80%, it is going to vary. But the thing is, you observe less effects with less ligand (exorphins or peptides, in this case) because fewer receptors are binding the ligand. That is why most drugs, working through receptor systems (which the majority do) have dose-response studies attached. The response is dependent on the dose. This response is a well-known, well-characterized system called receptor signal transduction mechanisms. Our bodies produce a certain of opiate substances naturally anyway.

There is an important consideration in the breakdown of casein/gluten as related to 'opioid' peptides (remember that this is still an unproven hypothesis).

Another consideration is that digestive enzymes may not even need to get every single molecule of gluten or casein peptide completely broken down to the essential amino acids to prevent any supposed 'opiate' reaction.

A 'reaction' can be disrupted as along as the pattern of protein breakdown is changed. So if taking enzymes breaks protein bonds in a different pattern, or a different order, then the one configuration of peptide is not produced (or produced in far less quantity needed to produce a reaction) and the unwanted reaction does not happen.

Enzymes break bonds when they come across the appropriate bonds. Breaking a protein bond leaves pieces of protein called peptides. Peptides can consist of any number of size, amino acid makeup, configuration, etc. You can have a peptide made up of any 2 amino acids. Or any pattern of 100 amino acids. The word 'peptide' only means 'piece from a protein'. Of all these possible configurations, only one type of peptide has the proper shape and order of amino acids to fit into the supposed 'opiate' receptor.

When protease enzymes are added in the stomach with the food, this introduces proteases early in the digestive process besides pepsin (protease in the stomach). Eating raw meat would also put added proteases in the stomach, but most people don't do that.

The protease enzymes in the stomach have a longer time to not only disrupt the pattern of protein breakdown; but there are more protease enzymes available to more thoroughly breakdown more peptides altogether. There are very likely many more amino acids available to the small intestine by the time the food mix gets there. So trying to eliminate 'every molecule of a certain protein' anyway misses the point.

Note that even it is not necessary to get every molecule of supposed opiate peptide anyway because opiate receptor triggered reactions do not take place by one molecule....it is the total percentage of molecules and triggered receptors that matters...not any one number.

This may also be why other types of enzymes are effective on some other types of food.


Toxins and Poisons

Almost everything is poisonous in some amount. "The Dose Makes the Poison" is a standard saying in toxicology. This means that the dose is what makes something poison/toxic or not, and NOT the substance itself. One example is table salt. A tablespoon of table salt can kill a child. Okay, so I say salt is poison to my child, and I need to make sure he never gets one single grain or molecule. Well, if I do accomplish that, the child will die, because salt is essential for life. Just as animals instinctively know to go to a salt lick for salt, and producers must ensure salt blocks are available for their livestocks' health. So, salt is essential in one dose, yet toxic in another. Salt has a lot of company in this matter. Although essential for health and life, vitamin D is very toxic if very much at all is consumed. Dishwashing soap is more toxic than most pesticides.

The standard basis for determining toxicity for comparative reasons is called the lethal dose, or LD. The LD standard is based on a benchmark value where 50% of a test population (usually rats or mice) dies from exposure at a given dose. This will be different for each substance, and is known as the LD50 of that substance. The higher the LD50, the less toxic the substance. The lower the number, the more toxic it is. The units on the LD50 are given in weight – the weight of the chemical per the weight of the animal.

For example, the LD50 for Roundup herbicide and Abound fungicide are 5000 mg/kg, while the LD50 of table salt is 3000; therefore these pesticide chemicals have been found in laboratory feeding studies to be less toxic than the regular salt we consume everyday. The LD50 of methyl bromide is 214 mg/kg, which is less toxic than caffeine (LD50 = 192) or nicotine (LD50 = 55). The acute toxicity of caffeine demonstrates that small quantities of a toxic chemical can be ingested in small quantities daily without adverse effects for humans. Strychnine and parathion are both deadly toxins with an oral LD50 of 10. Vitamin D has the same oral toxicity. If vitamin D were not exempt from the standard regulatory safety requirements, you would have to wear a moon suit to take your morning vitamin pill.

Table salt has an LD50 which means that at a certain dose it is toxic. Therefore, we cook and eat "toxins" every single day. Since salt is necessary for life, you can easily see that this "toxin" is necessary for survival. Table salt is a common and necessary part of our daily diet. An adult would have to ingest close to a half cup (400 grams) to receive a fatal dose.

One of the problems with animals studies is that they do not extrapolate to equivalent amounts to humans. Animal studies usually involve high levels of exposure to a substance/toxin for short periods of time. Human exposure usually involves low levels of exposure for long periods of time. Another reason this does not correlate satisfactorily is because animal studies usually look at just one substance at a time. In "real life" with actual humans it is hard to simulate how a certain chemical interacts with the many other every day chemicals. This does not mean that animal studies are not useful, it just means these studies do not represent an exact situation or number, and should be taken as a guide.

Keep in mind that even at these doses, only HALF of the test population is killed, the other half is not killed.

Besides the dose, there is the issue of rate and time. Because of these two factors, we can safely take the vitamins and salt we need, and don't collapse from breathing air or drinking water. If a box of salt contains around 48 lethal doses, and you eventually feed it to your whole family, it is processed normally performing vital functions. 48 people are not killed, nor are even the 4, or so, members of your family killed by the time the box is used up.

How about aspirin? An entire bottle of aspirin may contain one lethal dose, or 100 tablets. If you take it all at once, this is poison, but even if we had 10 bottles that would equal 10 lethal doses, we can distributed them around town, giving each person only one tablet, and not see 10 deaths.


Tolerance and Dependency

Another factor that comes into play, are the mechanics of tolerance and dependency. Many parents have noted variable responses to casein and gluten infractions. Some kids can eat more wheat or dairy with no problem, but others seem to be set off by the tiniest bit. Parents have also reported that after gluten and casein elimination, their child gets a huge reaction from just a tiny amount of casein and gluten. The mechanics behind this are related to those where a person needs more and more of a chemical to get the same response. The body "adapts" to many biochemical changes and this is no different.

In days gone by, one technique of poisoning thy enemy was to intentionally slowly consume arsenic over time and thus you would develop a "tolerance" for arsenic. Then you would have the person you detest over to dinner or for a drink prepared with arsenic. You would have the same food or drink but you would not suffer whereas your foe would keel over.

The point here demonstrates that the threshold limit changes over time and by circumstances or exposure to a particular substance. In addition, the body "compensates" and develops "tolerance" or "dependency" by creating more receptors or less receptors. Going back to our example, there is not a consistent 100 receptors all the time either. 30% of occupied receptors today, is not the same exact number of occupied receptors in a couple of weeks, or a year ago.

So, the situation gets even more complex because the number and activation state of receptors can change. One of the factors that cause this change is the prolonged presence of the ligand for the receptor(exposure to peptides in our example). The affinity for a substance can change over time too. To understand "affinity" think of two people shaking hands. The "grip" of one hand on the other may be loose, medium or tight. The ligand and receptor are binding or shaking hands. Their grip may be looser or tighter over time and this results in a "nerve" response of more or less, just as the recipient of a hand shake will feel the change in pressure. Chronic exposure to some level of the ligand (opiate peptide), can result in "desensitization", where the peptide binds to the receptor but the effect is muted or decreased.

We see this all the time with some medications and with drug abuse, where higher amounts of the drug are needed to get the same effect that originally was seen with smaller doses.

When one goes "cold turkey" or suddenly decreases the amount of ligand available to the receptors, the receptors will revert back to a 'sensitized' state. In some cases, if the level of ligand is extremely low for a long period of time, the receptors may become "super-sensitized" such that a very small amount of ligand causes a receptor-mediated event. This could be why those on the diet for a long time become very sensitive to small amounts of casein/gluten, whereas those not on the diet only see it with larger amounts of wheat/dairy.

"Unfortunately, prolonged opiate use may cause the brain to adapt, so it comes to depend on the presence of the drug just to function normally. Then, if the person stops using the drug, he or she experiences the opposite of pleasure-- anxiety, irritability, and low mood. The immediate, worst symptoms are called withdrawal. Opiate withdrawal has physical symptoms as well as psychological ones; these include nausea, chills, cramps, and sweating. Even long after the person has stopped using opiates, brain abnormalities can persist, causing feelings of discomfort and craving for more of the drug to relieve these feelings." This link shows an animation of with and without opiates: http://www.pbs.org/wnet/closetohome/animation/opi-anim-main.html

There is probably a "base level" of peptide exposure in everyone, and a balance develops between ligand concentration and receptor occupancy. When this balance is disturbed, from use of enzymes for example, the peptide concentration decreases, resulting in more unoccupied receptors. Unoccupied receptors can also have a physiological response on the body. This is where the "withdrawal effect" comes into play. The body had become accustomed to having a certain percentage of opiate receptors occupied with exorphin
peptides. One of these events of occupied opiate receptors is decreased pain sensitivity (analgesia). Suddenly, with diet or enzymes, not as many opiate receptors are occupied by exorphin peptides, and these unoccupied receptors stop signaling to the cell to which they are attached, and the result is increased sensitivity to pain or other sensory input. This is the basis of the "increased awareness" when starting enzymes. It is positive overall but at
the same time, the person needs to get used to the new sensory input. The same receptor can have a different function depending upon what organ or tissue it is a part of.

This link shows a graph of this relationship over time.

This compensatory reaction is part of everyday life. Think of a runner's high, caffeine, or nicotine. Endorphins and dopamine are made naturally in the body and have useful and essential functions. There is even a Pepper High involving a tolerance and "feel good effect" from spicy foods - http://www.thelittlevillage.com/stuff/pepper/high.shtml

It is also interesting that many studies have been done to determine if patients using morphine for real pain, such as with cancer or other painful illnesses,(not for recreation or abusive means) do not become "addicted" to it. Just as salt and vitamins are essential to proper health and enhance health in the proper range, so are casein or gluten or corn or many other substances once the mechanism is functioning well. So, if enzymes contribute to healing a leaky gut, and then break down foods appropriate, the opiate-peptide effect can be eliminated, and the foods resume their proper role in enhancing health and well-being. This may explain why many people see the best results when using enzymes and not on an elimination diet (this has been reported often for Houston enzymes, and may or may not apply to other brands as well).

Bottom line is that enzymes may not have to get every single bit of exorphin peptide. There will be ones produced in "typical healthy" people all the time anyway and for good and useful purposes. All one may need is to lower the threshold of occupied opiate receptors below that necessary to provoke a signaling reaction. However, this threshold limit will be different, and will vary with each individual, and change over time and as conditions change. "Poison" is based on dose response as well. Many times a certain amount is needed for proper health or even life itself, and is only toxic outside a given range.


For those who have a science/technical interest in receptor signal transduction mechanisms, searching for the terms: tolerance, addiction, receptors, and ligands can also bring up a wealth of information. For toxicology, look up: poison, dose response, LD50.


Thanks to Dr. Michael DeFelice for his assistance with toxicology.
copyright April 8, 2002.



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