Is the word "Brain" obsolete? Opiate receptors studied.

Languages have their conventions. The meaning behind words can become obscured by convention. New studies suggest a wedding of the thalamus and cord which forces a revision in thinking about what makes something a brain structure vs. a brain visitor. One day we may describe the body in terms of interactive chemical processes. When a boy tells a girl he loves her, he may have to use three or four paragraphs of chemical reactions, before she knows if his intentions are really sincere. Long before that, we hope to have found at least one way to stop central pain. There are many.

Think of flying over a canyon in the Rockies. If a cartographic mapping venture is undertaken, it may begin around highlights, such as the ridge here, the plateau there, and the dry river bed running low in the canyon. What is hidden is the vast aquifer underground in this desert and the huge slab of uranium bearing rock which runs through most of the state which are really much more relevant to what lies below us on the ground. What is the anatomy of this canyon? If we really want an answer, we must account for more than just surface features. Brain description is the same way. Not only do we have to get down to cell type, we have to zero in on cell chemistry composition and production to be sure we know what we are talking about and can group things as they should be grouped.

For so many years, anatomy was the most “cut and dried” science. (Pun intended). “Anatomy” comes from the Greek, to “cut apart”. We simply LOOKED and if we looked carefully enough, it was possible to give names to locations, often colorful Latin names. Parts of the bodies reminded the early anatomists of cul de sacs. openings, etc. Sometimes they weren’t very original and gave different parts the same name, because, after all, they looked the same.

We can do a little better now, but brain function is, well, sacred, and you can be labelled “crazy” for even suggesting that the brain works differently than expected. The brain is what is inside the skull, because that is the way it is. Of course, we know this is not true because the eyeballs which extend outside the skull are really extensions of the brain. It gets worse, as you will read below.

Pain is the same way. Supposedly, I don’t need to bother to think what pain is because I feel it vividly. Pain is not simply a matter of routing, it is a matter of chemistry. The problem is that “pain” is all over the map, so we have to be prepared for complicated chemical pathways and that is exactly what the body gives us. Pain, the most clearly perceived sensation in the body, is also the most complicated in its composition. It should be easier to foul up a complicated system than to make it work correctly, but Nature had other ideas. If the nerve cell is still partially alive, the pain neuron is rigged to set off a pain signal of unreal proportions. We call this “central pain”.

Anatomy is subjective and not self-obvious. Take for example, the “arm”. Everyone knows what an arm is, right? The problem is that cultures see the body differently. The Navajo begin the arm from the elbow down. The upper arm in that language is part of the shoulder. The point is that there is no inherent way to split the body up, to dissect it into divisible parts, to make it modular. Naming is somewhat arbitrary. Naming is sight-weighted, but the eyes can deceive a person. What really matters is where parts fit in to chemical cascades, which are the real components of life. This is especially true of the nervous system, the brain and cord having little to offer structurally, being about the consistency of pudding.

Embryology is really confusing now also, with genes turning on and off like crazy in embryonic life, making life miserable for anyone who claims to know something about fetal biochemistry. Things during fetal life change at the speed of life, which turns out to be amazingly fast, with genes replicating and stopping, and beginning again in an orchestrated sequence of protein assembly, with complicated unfoldings and combinations absolutely unmatched by anything else in the universe.

The fetal genes turn out complicated and changing versions and revisions of altered substances like a postal machine sorting mail, faster almost than can be comprehended. What is odd is that every step turns out to have a purpose. Pity the poor embryological biochemist who is asked to make sense of it. Nothing stands still. We are going to be a long time understanding how life happens. Despite the billions being sent into space to allegedly “determine how life began in the universe” the answers are going to have to come here on earth, and it will not be easy.

The orientation assemblage is also a problem in the brain. Anatomists speak of “tracts” as if there are discrete railroad tracks in the central nervous system. This is fine as a help, to get started, but when more careful examination is done, it often turns out that a minority of cells in that “tract” actually PERFORM the function ascribed to that tract.

For example in the brain, thirty percent performance is considered perfectly acceptable for naming a tract after a function. No matter that seventy percent of the neurons in that tract do something entirely different or are merely passing through.

Lacking a better term, anatomists divide neurons in a tract into “computational” ie. performing whatever is done by the tract, such as vision, and “metabolic” meaning “other functions”, thought in the past to be almost entirely nutritional. What has become embarassingly apparent is that the cells performing “other functions” are absolutely essential to what the computational cells are doing. Growth and repair factors, immune and inflammatory behavior, as well as nutrition, are controlled by the supposedly nonperforming cells, which it would now appear are both regulators and switches for the computational neurons. So the question arises, is the neuron the boss, or is it merely a tool utilized by surrounding cells, which are really the ones which are “wired”.

Bear in mind that when we speak of cells, we are really talking about bags of chemicals, which have their own pathways, which interconnect with chemical reactions in other cells, many of which have incredibly complicated synthesis algorhythms. Most of the chemical processes performed by living organisms cannot be performed anywhere else. No lab in the world can perform the most routine and fundamental behaviors at the nerve synapse.

This knowledge is intimidating. Mixed with the exhilaration of discovery is the bewilderment of unfolding questions which suggest arrangments at almost unlimited levels of sophistication. The structure of the body is nothing more than interconnected chemical processes, operating to maintain life. The more patterns we learn, the more patterns we learn which exist. Fortunately, it is not necessary to know everything before attacking a particular chemical process. It is harder to make things work than to foul them up. It is actually surprising that we have not blocked the pain pathway already. It has so many vulnerable points, but they turn out to be surprisingly durable, because there are so many of them. Pain has backup systems and so we have to get a little smarter to seal up the “ship” which is leaking pain proteins and spilling toxic waste (fatty acids and pain kinases) all over our nervous system.

The skin is an organ, yet we speak of differing body parts, each with its own skin. Similarly, pain is a process, but there are many contributors. Pain neurons contain chemicals which no other cells do, resulting in protein structures which no other cells possess. Exploiting this uniqueness will soon allow us to selectively kill pain cells. Resiniferatoxin can already do this in the peripheral nervous system, and RTX, or something close to it chemically, appears capable of doing the same in the CNS if we handle if correctly. The central nervous system has qualities unique from the peripheral nervous system.

The brain supposedly controls this, but the thalamus is supposed to be brain yet it chemically matches the cord as to opiate receptor composition. Whether resiniferatoxin could be injected curatively into the VPL or VPM of the thalamus is unknown. Currently, there are few places skilled enough to locate precise nuclei of the thalamus, but it is possible.

The thalamus appears to control what the “higher center”, the cortex, does. Flip flop. Where is the brain? It is wherever we say it is, but our saying it will not alter how the nervous system actually operates. It is said that NO motor signal coming out of the brain may actually pass through unless the anterior nucleus of the thalamus says it can. Control functions formerly assumed to be entirely brain in origin are now being discovered at C1, the first segment of the spinal cord. C2 is coming under suspicion. It is possible we have more “brains” than one, as it were, and that we may have to shift how we name our internal structures. The best candidate for brain number two, if we choose to make divisions, is the thalamus.

The fact is that the central nervous system is integrated on a scale that is almost impossible to comprehend, even in this age of the supercomputer. Things are placed close to other things, to facilitate the integration and for reasons which we do not yet glimpse.

To help bring order, the discipline of “chemoarchitecture” began about forty years ago. The idea was that if two cells had the same or nearly the same chemistry, that could define a structure in the brain. This approach turned out to be much more orderly than merely peering under a microscope at cells which did or did not take up a certain stain.

What has spoiled this approach is that the brain’s genealogy is ever so much more complicated than we suspected. This problem makes one choose anatomical terms in a way that contains a lie, a deception, a misleading LUMPING of parts which are really only chemical cousins, or even in opposition to another which is named with it.

It is not surprising that such conflicts have now begun to arise in the pain tracts. The area under discussion is the thalamus, classically and even presently described as part of the brain. It would be heresy to suggest otherwise. However, if it is part of the brain, would we expect it to match the brain chemically. The problem is that it does not. The most recent example is a study by Lawson and Traynor.

Although we are concerned with opioids and pain, it should be pointed out that opioid receptors have other functions than pain alone. It has been discovered, for example, that individuals with Tourette’s are deficient in certain opiate receptors in the globus pallidus. Opiates have more than one face. This should be obvious. They are commercially extracted from the poppy flower, where they obviously perform some function other than moderating pain.

The accepted theory that opiates act by inhibiting the cord pain has been turned upside down by studies (see prior article at this site) which more or less prove that opiates are excitatory. What we call pain suppression is due to the EXCITATION of GABAergic cells (GABA-A) cells in the cord. It is the GABA which is the inhibitor, NOT the opioid. Opium is the exciter. We can get used to this with a little readjustment in thinking. However, the problem does not stop there, with the neuromodulation.

We have repeatedly emphasized that the neurotransmitter, or neuromodulator, if you will, is NOT the real issue. The thing which requires most study is the function of the receptor. Now, what is a receptor. Commonly, a receptor is part of a protein. As the binding angles of molecules in the protein are altered by chemical processes the protein changes shape. In this sense, proteins are micromachines. The change in shape may cause a physical event, such as the “opening” of an ion channel. The change may instead reveal to the outside some inner “gut” area of the protein which has been concealed, which then becomes free to interact with some other product of amino acid composition. The portion of the protein which underlies a change is called a receptor. There are other types of receptors, but they signify a change in shape, which signifies a change in chemistry, which signifies a result.

The term opioid means ANY compound which interacts with opiate receptors to cause an effect which resembles that of opiates. Opiate receptors, sometimes called “opioid” receptors, are named with Greek letters. The ones most studied are delta, kappa, and mu. The opioids differ markedly in their ability to bind a receptor. Most opioid receptors require a ligand or tying agent to effect the binding. This is not uncommon in the chemistry of the body. The ligand latches the other two entities together, speaking figuratively.

Now the thalamus, being as we are assured by ALL current textbooks, a proper part of the brain, is the seat of all sensory messages which come up from the cord. This includes pain signal, which is routed to the VPL and VPM nuclei at the lower sides of the thalamic half which is on either side of the midline of the brain. Pain also routes to some of the nuclei in the midline septum (intralaminar)) of the thalamus and even to the subthalamic nucleus. (See discussions of these matters in prior articles at this site).

The cortex of the brain, or gray matter, more or less coats the outside. It is about 1/4 inch thick, not very much gray matter to do all the work of cognition. If there is brain, the cortex is it. You don’t get any higher. The problem is that in recent studies, the gray matter does not behave as expected. Its function more resembles a mechanical processing unit, the number cruncher par excellence of the human being. So where is the individual? More and more, our unique natures seem to be found in the matter BENEATH the grey matter. The thalamus itself is a rather good candidate as the “seat of the soul” and has in fact been so named by many a brain theorist. There is no proof of course. Even the limbic system, a group of related structures which are said to handle emotion, also known as the Papez circuit (which includes things like the amygdala, prefrontal cortex, the hippocampus, etc) appears to be more part of our humanity than the cortex.

Thus, we are forced to have two views of the brain, making the brain scientist sound schizophrenic. He must speak of the grey matter as what makes us uniquely human, while he speaks of the rest of the brain as what makes it uniquely the brain. Is RAM memory your computer, or is the CPU the computer. Where is the heart, the guts, the real essence of the computer. Who writes software for the brain anyway. Again, the thalamus seems to write the software and does it on the fly, attaching software of its own making to EACH signal, EACH impulse, EACH message. Things get very hard to pin down. Will the real individual PLEASE stand up? And if central pain is in the thalamus, where are we? If our heart and soul have been commandeered by pain chemicals which control the thalamus, can we any longer be human. These are not real questions, but they are not idle conversation either.

People continually advise or scold those with CP that they MUST take control of their own lives, be inspirational, reach for the stars etc. The problem is that the pain chemicals seem more or less in control of the thalamus and it is not entirely clear that we retain the equipment to be real people, if we make as a requirement for being authentic, the capacity to exert thought and urge our thalamus in the right direction. We retain agency, but certain feelings and attitudes are no more accessible to us than movement is to the quadriplegic. Since many here have quadriplegia, they will understand best that when something is gone, it is gone, not subject to really determined will power.

If you were a betting man, you would assume that the cortex and the thalamus, dancing an intimate dance of sensation there in the “brain”, operate according to similar chemistry. For example, if a particular opiate receptor was one favored by the cortex, it would surely be the same one favored by the thalamus. The problem is that it does not work this way. Lawson and Traynor, reporting in Brain Res. 2006 Jan 26 have shown that the cortex favors kappa opioid receptors, while the THALAMUS AND THE CORD both favor mu receptors. Chemically, the thalamus and cord are much more closely related to each other than either is to the cortex. Now you see why we don’t want to give too much meaning to the term, “brain”.

The receptor present is important since if we are trying opioid therapy, we would like to choose the one which has most effect on the receptor which is present in the area of interest. The authors tested some common opioids and four relatively well studied receptors, which include the kappa, delta, mu and the OPL(1) receptor. Orphan proteins are ones discovered as the human genome project began for whom no function was known. OPL-1 is actually orphaninFQ/nociceptin. The OPL stands for opioid receptor-like receptor. (We will not go into the background on how it was named at this time–just think of it as another opioid receptor.)

Lester and Traynor, studying dogs in a peripheral nerve injury model and what is called the [(35)S]GTPgammaS binding assay, which utilizes ligand binding, reported that the frequency and power of opioid receptors in frontal cortex is the virtual reverse of what is found in the cord and thalamus. In the cortex, “kappa > ORL(1) > delta > mu in cortical homogenates, compared with mu > ORL(1) > kappa > delta in thalamic and spinal cord.” In other words, in the cortex, kappa is the primo opioid receptor, while in the thalamus, it is the mu receptor. Anyone who was trained in classic anatomy will find this unbelievable and may actually grow angry. Do these researchers not know the difference between brain and cord? The thalamus is brain. How can they possibly have the nerve to report such findings. That is how science goes. It isn’t like religion. Revisions and revolutions happen almost every day. No one gets too smug, even in the terms they use, which they must use, but they realize all conclusions are transitory and even terms are loaded with unproven presumptions. Newton had his Einstein. Now Galen has his Lester and Traynor.

What does this have to do with central pain? The problem is the identity of the structures we are trying to supress when we attempt to choose an opioid for therapy. Most pain tracts in the brain inhibit pain. In the cord it is the opposite. The cord dishes out the pain signal and the brain usually tries to quiet it. No matter what you have heard, ALL pain neurons fire ALL THE TIME.

Fortunately they do not fire at a frequency which causes the brain to construct a pain message. Unfortunately, in central pain, the hypersensitivity is so great that the frequency of spontaneous firing is upregulated to a degree that the brain DOES construct and perceive a pain message. This is called spontaneous pain, and includes burning, lightnihg pains, pins and needles, muscle pain,etc.

Beyond this some kinds of innocuous events (such as light touch or temperatue change) which do manage to push signal through a damaged system wind up making the situation worse by evoking considerably more pain. Severe evoked CP pain is true, authentic, unbearable, agonizing torture. The highly sensitized pain apparatus is a real demon.

Returning to opiates, by quieting inhibition, they may increase certain kinds of pain (disinhibition). That bears repeating. The number one pain relieving drugs paradoxically increase pain if it originates in the brain. There is also, as mentioned, a difference in spontaneous and evoked pain. Evoked pain requires some sort of input. We may be fighting ourselves if we treat evoked pain. We may inhibit cord and stimulate brain, causing opiates to backfire. It becomes important to know which opiates operate at which part of the nervous system.

Thus, it is no wonder that the record of opiate therapy for central pain is disappointing, if not shameful. Opioids seem to help pains carried up in the posterior columns, but their record for pain carried in the anterior cord (spinothalamic tracts) is dismal.

These two pharmacologists also did us the favor of identifying which opioid worked best on which receptor. They found “efficacy decreased in the order etorphine >> morphine > fentanyl = oxymorphine > butorphanol = oxycodone = nalbuphine. ” This makes oxycodone, with the reputation of being highly addictive no more effective than nalbuphine, both of them being relatively WEAK.

We mention nalbuphine because at least one author, Dr. James S. Howard, III, writing in the American Journal of Pain Management January 2006 feels nalbuphine has fewer side effects than oxycontin. Nalbuphine has been around a very long time and is most commonly called “Nubain”. (Nubain is favored by some anesthesiologists because a dose of it prevents the elevation in heart rate and blood pressure which otherwise occurs when a surgical patient is intubated, (the time of laryngostomy tube insertion). Dr. Howard was NOT studying nerve injury pain, but common chronic pain, which is called “Nociceptive” pain as opposed to “Neuropathic” or nerve injury pain.

One more opiate studied, buprenorphine, is a mu-opioid AGONIST (agonist is the biochemist’s word for promoter) but is a kappa-, delta-opioid receptor ANTAGONIST (antagonist is the biochemist’s word for opposer). This makes life interesting because one could apparently stimulate mu activity while blocking kappa, delta, and OPL(1) activity. We don’t know what effect this would have on the various flavors of central pain, but we would very much like to know. We should also become aware of these variables in deciding which opioid to place in implanted pumps in the spinal fluid.

It seems a little late in the day for such studies to be performed, given the almost knee jerk presciption for morphine for pain. Shouldn’t we have done this work a very long time ago? If there is anything we have learned at the Wall/McHenry database, it is that central pain patients DIFFER. It seems highly likely that therapies should differ. Unless physicians will begin to take the time to indicate WHICH of the central pains the patient has (eg. burning dysesthesia, muscle pain, pins and needles, lancinating pain, etc.) it will not be possible to make rational decisions about therapy. All of these pains are not going to be handled the same. The record of opiates on posterior column pain is pretty good. It reeks when treating spinothalamic tract pain. Even the NIH concedes that for severe dysesthetic burning, the best that can be done is to try to quiet the CNS by keeping stress out of the patient’s life. Note that this is the mirror opposite of the “you can do it if you try” mantra of the motivational crowd.

If physicians could act like scientists and not managed care lackeys and take the time for a careful history to figure out WHICH of the central pains the patient has, and then give careful reported follow up on WHICH therapy was beneficial to WHICH of the central pains, if any, we could act more like scientists, and less like amateurs playing a guessing game. The wild goose chase could at least be narrowed a little if we could just take the time to be more precise in describing symptoms, terms, area of the body covered etc. In other words, by including a decent medical history along with the imposing reports of brain surgery and other invasional attempts at eliminating central pain.

It is time to STOP speaking of “Neuropain” as if it were a homogenous entity. and start being precise about what we are talking about. Burning dysesthesia shares NO characteristics with lancinating pain. NONE WHATSOEVER. They may both be found in the same patient, but that is like saying the heart must be the same as the testicles/ovaries since both are found in the same body.

What is needed is precise information. We are doing the best we can to gather this information and appreciate the time so many have taken to complete the survey at this site on the home page. It is presently the largest database in the world on central pain symptoms. We cannot really complete our objectives unless doctors and nurses will respond by learning to be specific in taking histories and matching those histories with therapeutic results. We do not care to hear about “neuropathic pain”. We want to know WHAT KIND of neuropathic pain, its duration, its evocation, and the area of the body it localizes to. This sort of information is essential before wildly jumping from one medication to another without first asking WHAT SYMPTOM, and WHAT KIND OF PAIN, we are treating and what is the location of the CNS injury. Shooting from the hip is not fair to the patient. It leaves them feeling incompetent in seeking and obtaining care.

Special thanks to Lawson and Traynor. We are glad to know more about the receptors, where they are located, and which opioid reaches them best.