I am going to describe an array of fascinating, mostly new findings about the chemical substances in the body called neuropeptides. Based on these findings, I am going to suggest that neuropeptides and their receptors form an information network within the body. Perhaps this suggestion sounds fairly innocuous, but its implications are far reaching.
I believe that neuropeptides and their receptors are a key to understanding how mind and body are interconnected and how emotions are manifested throughout the body. Indeed, the more we know about neuropeptides, the harder it is to think in the traditional terms of a mind and a body. It makes more and more sense to speak of a single integrated entity, a body- mind."
Most of what I will describe are laboratory findings, hard science. But it is important to remember that the scientific study of psychology traditionally focuses on animal learning and cognition. This means that if you look in the index of recent textbooks on psychology, you are not likely to find a listing for "consciousness," "mind," or even "emotions." These subjects are basically not in the realm of traditional psychology, which primarily studies "behavior"because it can be seen and measure.
THE SPECIFICITY OF RECEPTOR SITES
There is one field in psychology where mind -- at least consciousness -- has been objectively studied for perhaps twenty years. This is in the field of psychopharmacology wherein researchers have developed highly rigorous ways to measure the effects of drugs and altered states of consciousness.
Research in this field evolved from an assumption that no drug acts unless it is "fixed" -- that is, somehow gets attache to the brain. And so researchers initially imagined hypothetical tissue constituents to which a drug might bind -- much the way a key fits a lock -- and they called these "receptors." In this way, the notion of specific brain receptors for drugs became a central theory in psychopharmacology. It is a very old idea.
In the past several years, a critical development has been the invention of new technologies for actually binding drugs to these receptor molecules and for studying both their distribution in the brain and body and their actual molecular structure.
My initial work in this area was in the laboratory of Soloman Snyder at Johns Hopkins University, where we focused our attention on opium, a drug that obviously alters consciousness and that also is used medicinally to alleviate pain. I worked long and hard, over many months of steady failure, to develop a technical system for measuring the material in the brain with which opium interacts to produce it effects. To make a long (and technical) story short, we used radioactive drug molecules, and with this technology were actually able to identify the receptor element for opium in the brain. You can imagine, therefore, a molecule of opium attaching itself to a receptor -- and then from this small connection, large changes follow.
It next turned out that the whole class of drugs to which opium belongs -- they are called opiates and they include morphine, codeine, and heroin, as well as opium -- attach to the "same" receptors. Further, we discovered that the receptors were scattered throughout not only the brain but also the body.
After finding the receptor for the external opiates, our thinking took another step. If the brain and the other parts of the body have a receptor for something taken from "outside"the body it makes sense to suppose that something produced "inside"the body also fits the receptor. Otherwise, why would the receptor be there?
This perspective ultimately led to the identification of one of the brain's own forms of opiates, a chemical substance called beta endorphin. Beta endorphin is created in the brain's own nerve cells and consists of peptides -- this is is a neuropeptide. Furthermore peptides grow directly off the DNA which stores the information to make our brains and bodies.
If you picture an ordinary never cell, you can visualize the general mechanism. In the center (as in any cell) is the DNA, and a direct printout of the DNA leas to the production of a neuropeptide, which then travels down the axons of the nerve cell to be stored in little balls at the end waiting for the right electrophysical events that will release it. The DNA also leads to the production of receptors, which are made out of the same peptide material but are much large.
What has been added to this picture is that fact that 50 to 60 neuropeptides have been identified, each of them as specific as the beta endorphin neuropeptide. We have here an enormously complex system.
Until quite recently, it had been thought that the information of the nervous system was distributed across the gap between two nerve cells, called the synapse. This meant that the proximity of the nerve cells determined what could be communicated.
But now we know that the largest portion of information coming from the brain is kept straight not by the close physical juxtaposition of the nerve cells, but by the specificity of the receptors. What was thought of as a highly linear system appears to be one with far more complex patterns of distribution.
Thus when a nerve cell squirts out opiate peptides, the peptides can act "miles" away at other nerve cells. The same is true for all neuropeptides. At any given moment, many neuropeptides may be be floating along within the body, and what enables them to attach to correct receptor molecules is, to repeat, the specificity of the receptors. Thus, the receptors serve as the mechanism that sorts out information exchange in the body.
THE BIOCHEMISTRY OF THE EMOTIONS
What is this leading to? To something very intriguing -- the notion that the receptors for the neuropeptides are in fact the keys to the biochemistry of the emotion. In the last two years, the workers in my lab have formalized this idea in a number of theoretical papers, and I am going to review briefly the evidence to support it.
I should say that some scientists might describe this idea as outrageous. It is not, in other words, part of the established wisdom. Indeed, coming from a tradition where the textbooks do not even contain the word "emotions" in the index, it was not without a little trepidation that we dared to start talking about the biochemical substrate of emotions.
I will begin by noting a fact that neuroscientists have agreed on for a long time; the emotions are mediated by the limbic system of the brain. The limbic system refers to a section ofneuroanatomical parts of the brain which include the hypothalamus (which controls the homeostatic mechanism of the body and is sometimes called the "brain" of the brain), the pituitary gland (which regulates the hormones in the body), and the amygdala. We are talking mostly about the hypothalamus and amygdala.
The experiments showing the connection between emotions and the limbic system were first done by Wilder Penfield and other neurologists who worked with conscious, awake individuals. The neurologists found that when they used electrodes to stimulate the cortex over the amygdala they could evoke a whole gamut of emotional displays -- powerful reactions of grief, of pain, of pleasure associated with profound memories, and also the total somatic accompaniment of emotional states. The limbic system was first identified, then, by psychological experiments.
Now when we began to map the location of opiate receptors in the brain we found that the limbic system was highly enriched with opiate receptors (and with other receptors too, we eventually learned). The amygdala and the hypothalamus, both classically considered to be the main components of the limbic system, are in fact blazing with opiate receptors -- 40-fold higher than in other areas of the brain.
These "hot spots" correspond to very specific nuclei or cellular groups that physiological psychologists have identified as mediating such processes as sexual behavior, appetite, and water balance in the body. The main point is that our receptor-mapping confirmed and expanded in important ways the psychological experiments that defined the limbic system.
Now let me bring in some other neuropeptides. I have already noted that 50 to 60 substances are now considered to be neuropeptides. Where do they come from? Many of them are the natural analogs of psychoactive drugs. But another main source -- very unexpected -- is hormones. Hormones historically have been conceived of as being produced in glands -- in other words, not by nerve cells. A hormone presumably was stored in one place in the body, then traveled over to its receptors in other parts of the body. The prime hormone is insulin, which is secreted by the pancreas. But, now, it turns out that insulin is not just a hormone. In fact, insulin is a neuropeptide, made and stored in the brain, and there are insulin receptors in the brain. When we map insulin, we again find hot spots in the amygdala and hypothalamus. In short, it has become increasingly clear that the limbic system, the seat of emotions in the brain, is also the focal point for receptors of neuropeptides.
Another critical point. As we have studied the distribution of these receptors, we have found that the limbic system is not just in the forebrain, in the classical locations of the amygdala and the hypothalamus. It appears that the body has other places in which many different neuropeptides are located -- places where there is a lot of chemical action. We call these spots "nodal points", and they are anatomically located at places that receive a lot of emotional modulation.
One nodal point is the dorsal (back) horn of the spinal cord, which is the spot that sensory information comes in. This is the first synapse within the brain where touch-sensory information is processed. We have found that for virtually all the senses for which we know the entry area, the spot is always a nodal area for neuropeptide receptors.
I believe these findings have amazing implications for understanding and appreciating what emotions do and what they are about. Consider the chemical substance angiotensin, another classical hormone which is also a peptide and how shown to be a neuropeptide. When we map for angiotensin receptors in the brain, we again find little hot spots in the amygdala. It has long been known that angiotensin mediates thirst, so if one implants a tube in the area of a rat's brain that is rich with angiotensin receptors and drops a little angiotensin down that tube, within ten seconds the rat will start of drink water, even if it is totally sated with water. So, chemically speaking, angiotensin translates as an altered state of consciousness, a state that makes animals (and humans) say, "I want water." In other words, neuropeptides bring us to a state of consciousness and to alterations in those states.
Equally important is the fact that neuropeptide receptors are not just in the brain, they are also in the body. We have mapped and shown biochemically that there are angiotensin receptors in the kidney identical to those in the brain and na way that is not quite understood, the kidney-located receptors conserve water. The point is that the release of neuropeptide angiotensin leads both to the behavior of drinking and to the internal conservation of water.
Here is an example of how a neuropeptide -- which perhaps corresponds to a mood state -- can integrate what happens in the body and what happens in the brain. (A further important point that I only mention here is that overall integration of behavior seems to be consistent with survival.)
My basic speculation here is that neuropeptides provide the physiological basis for the emotions. As my colleagues and I argued in a recent paper in the "Journal of Immunology:"The striking pattern of neuropeptide receptor distribution in mood-regulating areas of the brain, as well as their role in mediating communication through the whole organism, makes neuropeptides the obvious candidates for the biochemical mediation of emotion. It may be that each neuropeptide biases information processing uniquely when occupying receptors at nodal points with the brain and body. If so, then each neuropeptide may evoke a unique "tone" that is equivalent to a mood state.
In the beginning of my work, I matter-of-factly presumed that emotions were in the head or the brain. Now I would say they are really in the body as well. They are expressed in the body and are part of the body. I can no longer make a strong distinction between the brain and the body.
COMMUNICATING WITH THE IMMUNE SYSTEM
I now want to bring the immune system into this picture. I have already explained that the hormone system, which historically has been studied as being separate from the brain, is conceptually the same thing as the nervous system. Packets of juices are released and diffuse very far away, acting via the specificity of receptors at sites far from where the juices are stored. So, endocrinology and neuroscience are two aspects of the same process. Now I am going to maintain that immunology is also part of this conceptual system and should not be considered a separate discipline.
A key property of the immune system is that is cells move. They are otherwise identical to the stable brain cells, with their nuclei, cell membranes and all of the receptors. Monocytes, for example, which ingest foreign organisms, start life in your bone marrow, and they then diffuse out and travel along through your veins and arteries, and decide where to go by following chemical clues. A monocyte travels along in the blood and at some point comes within "scenting" distance of a neuropeptide, and because a monocyte has receptors for the neuropeptide on its cell surface, it begins literally to chemotax, or crawl, toward that chemical. This is very well documented, and there are excellent ways of studying it in the laboratory.
Now, monocytes are responsible not for just recognizing and digesting foreign bodies but also for wound healing and tissue- repair mechanisms. What we are talking about, then, are cells with viable, health-sustaining functions.
The new discovery I want to emphasize here is that "every" neuropeptide receptor we have looked for (using and elegant and precise system developed by my colleague, Michael Ruff) is also on human monocytes. Human monocytes have receptors for opiates, for PCP, and for another peptide called bombasin, and so on. These emotion-affecting biochemicals actually appear to control the routing and migration of monocytes, which are so pivotal in the immune system. They communicate with B-cells and T-cells, interact with the whole system to fight disease and to distinguish between self and non-self, deciding, say, which part of the body is a tumor cell to be killed by natural killer cells, and which parts need to be restored. I hope this picture is clear to you.
A monocyte is circulating -- this health-sustaining element of the immune system is traveling in the blood -- and the presence of an opiate pulls it over, and it can connect with the neuropeptide because it has the receptor to do so. It has, in fact, many different receptors for different neuropeptides.
In turns out, moreover, that the cells of the immune system not only have receptors for these various neuropeptides; as is becoming clear, they also make the neuropeptides themselves. There are subsets of immune cells that make beta endorphins, for example, and the other opiate peptides. In other words, these immune cells are making the same chemicals that we conceive of as controlling mood in the brain. They control the tissue integrity of the body, and they also make chemicals that control mood. Once again, brain and body.
THE UNITY OF VARIETY
The next point I am going to make about neuropeptides is an astounding one, I think.
As we have seen, neuropeptides are signaling molecules. They send messages all over the body (including the brain). Of course, to have such a communications network, you need components that can talk to each other and listen to each other. In the situation we are discussing here, the components that "talk" are the neuropeptides, and that components that "hear" are the neuropeptide receptors. How can this be? How can 50 to 60 neuropeptides be produced, float around and talk to 50 to 60 types of listening receptors which are on a variety of cells? Why does order rather than chaos reign?
The finding I am about to discuss is not totally accepted, but our experiments show that it is true. I think it is only a matter of time before everybody can confirm these observations.
There are thousands of scientists studying the opiate receptors and the opiate peptides, and they see great heterogeneity in the receptors. They have given a series of Greek names to the apparent heterogeneity. However, all the evidence from our lab suggests that in fact "there is only one type of molecule in the opiate receptors, one long polypeptide chain whose formula you can write.
This molecule is quite capable of changing its conformation within its membrane so that it can assume a number of shapes. I note in passing that this interconversion can occur at a very rapid pace -- so rapid that it is hard to tell whether it is one state or another at a given moment in time. In other words, receptors have both a wavelike and particulate characters, and it is important to note that information can be stored in the form of time spent in different states.
As I said, the molecular unity of the receptors is quite amazing. Consider the tetrahymena, a protozoa that is one of the simplest organisms. Despite its simplicity, the tetrahymena can do almost everything we can do -- it can eat, have sex, and of course it makes the same neuropeptide components that I have been talking about.
The tetrahymena makes insulin. It makes beta endorphins. We have taken tetrahymena membranes and in particular studied the opiate receptor molecules on them; and we have studied the opiate receptor in rat brains and on human monocytes.
We believe that we have shown that the molecular substance of "all"opiate receptors is the same. The actual molecule of the human-brain opiate receptor is identical to the opiate receptor components in that simplest of animals the tetrahymena. I hope the force of this is clear. The opiate receptor in my brain and in your brain is, at root, made of the same molecular substance as that of the tetrahymena.
This finding gets to the simplicity and the unity of life. It is comparable to the four DNA-based pairs that code the production of all proteins, which are the physical substrates of life. We now know that in this physical substrate there are only 60 or so signal molecules, the neuropeptides, that account for the physiological manifestation of emotions -- for enlivening emotions, if you will, or perhaps better yet, for flowing energy. The protozoa form of the tetrahymena indicates that the receptor molecules do not become more complex as the organism becomes more complex. The identical molecular components for information flow are conserved throughout evolution. The whole system is simple, elegant, and it may very well be complete.
IS THE MIND IN THE BRAIN?
We have been talking about the mind, and the question arises: Where is it? In our own work, consciousness has come up in the context of studying pain and the role of opiate receptors and endorphins in modulating pain. A lot of labs are measuring pain, and we would all agree that the area called periaqueductal gray, located around the third ventricle of the brain, is filled with opiate receptors, making it a kind of control center for pain. We have found that the periaqueductal gray is loaded with receptors for virtually all the neuropeptides that have been studied.
Now, everyone know that there are yogis who can train themselves so that they do or do not perceive pain, depending on how they structure their experience. Women in labor do the same thing. What seems to be going on is that these sorts of people are able to plug into their periaqueductal gray. Somehow they gain access to it -- with their consciousness, I believe -- and set pain thresholds.
Note what is going on here. In these situations, a person has an experience that brings with it pain, but a part of the person consciously does something so that the pain is not felt. Where is this consciousness coming from -- this conscious I -- that somehow plugs into the periaqueductal gray so that he or she does not feel a thing?
I want to go back to the idea of a network. A network is different from a hierarchical structure which has one top place. You theoretically can plug into a network at any point and get to any other point. A concept like this seems to me valuable in thinking about the processes by which a consciousness can manage to reach the periaqueductal gray and use it to control pain.
The yogi and the laboring woman both use a similar technique to control pain -- breathing. Athletes use it, too. Breathing is very powerful. I suggest there is a physical substrate for these phenomena, the brain stem nuclei. I would say that we now must include the brain stem nuclei in the limbic system because they are nodal points, thickly encrusted with neuropeptide receptors and neuropeptides.
The idea, then, goes like this: breathing has a physical substrate which is also a nodal point, this nodal point is part of an information network in which each point leads to all other parts, and so on, from the nodal point of the brain stem nuclei, the consciousness can, among other things, plug into the periaqueductal gray. I think it is now possible to conceive of mind and consciousness as an emanation of emotional information processing, and, as such, mind and consciousness would appear to be independent of brain and body.
CAN MIND SURVIVE PHYSICAL DEATH?
One last speculation, an outrageous one perhaps, but on the theme I was asked to consider for this symposium on "Survival and Consciousness." Can the mind survive the death of the physical brain? Perhaps here we have to recall how mathematics suggests that physical entities can suddenly collapse or infinitely expand. I think it is important to realize that information is stored in the brain, and it is conceivable to me that this information could transform itself into some other realm. The DNA molecules surely have the information that makes the brain and body, and the bodymind seems to share the information molecules that enliven the organism.
Where does the information go after the destruction of the molecules (the mass) that compose it? Matter can neither be created nor destroyed, and perhaps biological information flow cannot just disappear at death and must be transformed into another realm. Who can rationally say "impossible"? No one has mathematically unified gravitational field theory with matter and energy. The mathematics of consciousness have not even been applied. The nature of the hypothetical "other realm" is currently in the religious or mystical dimension, where Western science is clearly forbidden to tread.