Neuropeptides and Psychoneuroimmunology (PNI): How Our Emotions Impact The Immune System

Neuropeptides and Psychoneuroimmunology (PNI): How Our Emotions Impact The Immune System

Written:  November 17, 2000

“Peptides are the sheet music containing the notes, phrases, and rhythms that allow the orchestra—your body—to play as an integrated entity.  And the music that results is the tone or feeling that you experience subjectively as your emotions” (Pert, p.148)

The above statement by Dr. Candace Pert in her book The Molecules of Emotion (Pert, 1999) has led me on a quest to discover exactly what neuropeptides are, in the microcosm, and what psychoneuroimmunology is, in the macrocosm.  Charles Darwin wrote about the emotions in his Expression of the Emotions in Man and Animals.  He observed similar facial expressions for emotions across species, and noted that they have been preserved over time; so, emotions must be key to the survival of the fittest (Pert, 1999, video).  We all know intuitively that the way we are feeling emotionally will affect our health; but the questions are, how can we explain this logically, and what is happening on the molecular level, and where is this taking place in the body?  What is going on at the molecular level with emotions to make such profound changes in the state of our health from wellness to disease?  Which starts first, anyway, the emotion then the disease, or the disease then the emotion?   In this article I will attempt to describe neuropeptides, a kind of informational substance, and the receptors that they bind to, as well as the process of binding.  Then, I will attempt to expand the view of the neuropeptides into the affect they have on the rest of the body’s systems, specifically on the emotional tone of the body, and the outcome of that emotion, whether helpful, or deleterious.

Main components of emotions in the body are the endorphin/opiate receptor function; out of all the peptides this combination has the greatest affect on the emotions, or the pleasure/pain continuum.  These small molecules have a very big job, and one of the main responsibilities is “bonding”, as with mother-child, between lovers/spouses, or bonding with one’s community in order to stay safe and out of danger’s way; certainly these bonds are necessary for survival.  This research has been no small feat, as science does not like to talk about such “non-things” as emotions, or the soul (Pert, p.21).  There is a new field of science that has formed over the last forty years called “Psychoneuroimmunology”, which has it’s basis in the belief that the central nervous system, and especially the brain (neurons and the informational substances secreted), endocrine (the hormones secreted), and the immune systems (particularly the macrophages and lymphocytes) are all linked together, and more importantly, that they communicate (Rabin, 1999).  Just as this new field has begun to prove the communication between the body’s different systems, it has also acted as a bridge between the people of “left brain thinking”, and people of “right brain thinking”, or logic vs. intuition.  On with the science…

First let’s take a look specifically at peptides, and the receptors that they choose to bind with, or that chose to bind with them.  In the beginning of this research, when “neuro”-peptides were discovered, they were thought to be only produced in the brain, until it was discovered that peptides are secreted from all different parts of the body  (Pert, p. 70).  What is a “peptide”?  It is a specific kind of ligand, or a kind of protein/sequence of amino acids; basically, one form of the body’s drugs.  When two molecules bind together, the second molecule is called a ligand.  In order for these ligands to interact with other protein molecules, there must be weak bonds between them, so that the fit onto the surface of the cell is tight and secure (Zigmond, 1999, p. 220).  The term “ligand” is the broad generalization for many kinds of substances that bind.  There are many kinds of ligands:  neurotransmitters, such as GABA, glycine, histamine, acetylcholine, etc.; steroids (a kind of hormone made from modified cholesterol), such as testosterone, estrogen, progesterone, etc.; and then the subject of our query, peptides, such as oxytocin, the endorphins, cholecystokinin (CCK), bradykinin, angiotensin II, and several more (Pert, p.25 and p.67).  Peptides make up the largest group of the ligands by far.  There is a new term coined by Francis Schmitt of MIT in 1984 for these ligands; he calls them “informational substances”, and said where chemical information substances travel the extracellular fluids circulating throughout the body to reach their specific target-cell receptors, alongside the well known synaptic circuitry there is a para-synaptic, or parallel system.  This new work suggests there are almost infinite pathways for the conscious mind to access—and modify—the unconscious mind and the body (Pert p. 139-41).

Where do the peptides bond?  They bond to receptors. They are a “single molecule, perhaps the most elegant, rare, and complicated kind of molecule there is” (Pert p. 21) Fundamentally and reproductively speaking, the ligand is the masculine of the molecules, and the receptors are the females.  Receptors have a molecular weight of 50,000 units, and so therefore when they start to hum, shimmy, and vibrate on the surface membrane of a cell, they do not tear apart, as other molecules would, such as water that has a molecular weight of only 18.  Rather, they float on the surface membrane, “snaking back and forth…much like lily pad floating on the surface of a lake” (Pert p.22) waiting to send information deep inside the interior of the cell.

Then, how do the ligands and receptors mix?  It is very similar to the process that enzymes, a catalyst inducing protein, undertake with their substrates.  It is a process called binding, and it is very specific, and very selective; only opiates such as endorphins can fit into opiate receptors, or Valium-like peptides can only fit with Valium receptors; however, some ligands are so much like others, such as aldosterone and estrogen, that the receptor is fooled and binds with either of them.  A key fitting into a lock is the standard image that is used to describe the process of binding.   The receptor is the part that the ligand binds to, but the region of a protein is called the binding site (Zagmond, 1999).  The ligand, or informational substance, will bump into the receptor, slip off, bump on again, etc; the bumping on is the binding.  However, a better visualization might be “two voices—ligand and receptor—striking the same note and producing a vibration that rings a doorbell to open the doorway to the cell.” (Pert, p.24).  After the message is received, the cell transmits the message deep into the cell’s interior, where the message changes the state of the cell dramatically.  The life of the cell is dependent on these ligands; they are the directors of the cell’s activity, ranging from anything from protein manufacturing, to opening or closing ion channels, to name just a few.

So, what makes peptides so special?  What differentiates them from other kinds of ligands, such as neurotransmitters, and hormones?  It is the mode of transportation, the communication!  Neurotransmitters need a synapse to cross the cleft between cells to get to their receptor site, hormones need the plasma in blood to travel to their receptor site, and peptides need the extracellular space, such as blood and cerebrospinal fluid, to get to their receptors!  It is this very extracellular fluid that can allow a peptide to travel such long distances in the body, if it is not manufactured near the receptor site (Pert, p.26-27).  Since they are essentially made from the same stuff, amino acids/protein molecules, it is their mode of communication that differentiates them from one another.

Now that we understand the fundamentals of peptides at the cellular level, let’s look specifically at what Dr. Pert calls the “molecules of emotion”, the opiates, and where the receptors are located in the body.  As stated above, peptides were once thought to be mainly manufactured in the neurons, and secreted throughout the body.  While many most certainly do originate in the brain, they are also found elsewhere, such as the gut (peptide Y), and also in small-cell lung cancer cells (bombesin) (Koob, 1984, p.350).  New peptides are being discovered everyday through purifying them in bioassays and determining their amino acid sequence, and we are just beginning to grasp their manufacture site; because of their presence in the entire body, it is a challenging task.  Some of the questions that are asked to see if a peptide is a neuropeptide are: are they localized to neurons?; what are their actions on neurons?; are they released from neurons?; and is there any synaptic mimicry? (Koob, p.350).

These above questions help determine whether the site of manufacture for the peptides is in the brain or not, but where exactly in the brain are neuropeptides specifically manufactured, and where are the greatest concentrations of receptors?  The classic seat of the emotions in the brain is the limbic system, a beautiful butterfly-looking coil consisting of the amygdala, the hippocampus, and the limbic cortex.  While this system definitely contains many opiate receptors, emotions are surely not only contained or controlled here.  It is located in the forebrain, and the amygdala, the two almond-shaped lobes at the front of the coils, are about an inch or two in from your ears (Pert, p.133).  “Neuroanatomic and functional data have provided the basis for an interesting hypothesis that neuroanatomical substrates for the reinforcing actions of drugs may involve neural circuitry that forms a separate entity within the basal forebrain, termed the extended amygdala.” (Alberts, 1994, p.1270).  Another area of the brain known to have a profound effect on emotional behavior is the neocortex, and just happens to be a major producer of peptides (Koob, p. 349).  The “darling” of the peptide discoveries, and one of the first, is oxytocin, which is produced in the pituitary gland, and is responsible for parental bonding in male and females, as well as primarily other female reproductive functions, although it has other functions in males, too.    We must not also forget about the thalamus-to-cortex pathway of neurons for pain; these opioids followed the same pathways in a mapping research done by Dr. Pert, Miles Herkenham, and Remi Quirion with the art of receptor autoradiography in 1977 at the National Institute of Health (Pert, p.123).

So, the question now is, if the emotions aren’t just produced by the neuropeptides in these “emotional” parts of the brain, where are they produced, held and released?  What is this mysterious “mind/body connection”?  We know that these peptides can travel through the extracellular fluids to all parts of the body.  Could it be possible that these peptides are getting stuck in various bodily organs, and producing “dis-ease”?  The followers of Psychoneuroimmunology, or PNI, seem to think so; not only do they think this, but also that the other bodily systems of the endocrine and immune communicate with the brain in regulating peptides, and hence emotions.

But first let’s take a look at two schools of thought on the mind/body connection:  that of physiologist William James and his student Walter Cannon.  James had the idea that emotions “trickle up” from the body to the brain, and then we make judgments about them.  For instance, another car while driving almost hits us, and immediately our sympathetic nervous system kicks in; our heart beat increases, our gut contracts, we start perspiring, etc., and then we think “Ahhhh!!!”  We don’t have time to think first or put an emotional judgment on the situation, our body reacts without our mind thinking, much like in a muscular reflex arc.  Well, Cannon thought that James’s theory was wrong.  He thought that emotions “trickled down” from the brain by the peptides secreted from the pituitary gland to the hypothalamus through its connections in the neuronal pathways to the brainstem, producing various responses in the body; in this theory, the “cause” of the emotion would originate in the above mentioned emotional areas of the brain.  Actually, knowing now what we know about peptides, both theories are correct (Pert, 1999, video).

The scientific discipline of Psychoneuroimmunology is the study of how “(1) psychological factors that an individual experiences and that activate neurons in the brain (2) modify the production and release of neuropeptides and endocrine hormones that (3) alter the function of the immune system, which then (4) increases the susceptibility of an individual to diseases that are normally prevented by a healthy functioning immune system” (Rabin, p.4).

Emotions have a profound effect on our immune system.  We have shown the molecular basis for emotions, but now we are going to take a brief look at how these peptides interact with the immune system to break it down, and bring on disease.  An immunologist named Ed Blalock discovered rather by accident that some immune cells known as lymphocytes were secreting endorphins, the mood-altering peptide we’ve been discussing thus far, but also that the receptors for these peptides were also on the lymphocytes (Pert, p.161).  Basically, this makes the immune system rather a floating endocrine system in this function.  These cells “chemotax”, or pick up the scent of peptides in the extracellular fluid, and latch them onto their receptors. Virtually every peptide produced in the brain has a receptor on the immune cell surface!  Not only that, but peptides produced by immune cells, such as interleukin-1, which induces sleep and aids the body in healing, also have receptors in the hypothalamus, the cortex, glial cells, and the tough membranes around the brain (Pert, p164).  Since the systems of the endocrine, brain, and immune exchange this molecular information, this proves that there is communication between them.

Stress greatly alters the function of the brain, endocrine, and immune systems.  Sleep, and eating patterns change, usually having something to do with the lack of hormonal discharge (Rabin, p.5).  It is known that when our “defenses” are down, we get sick.  Knowing what we know about the connection between neuropeptides and the immune system, it is clear that emotional stress can also tear down our immune defenses, and allow disease to disrupt our homeostatic balance.  The psychophysiology of anxiety is a good way to look at the impact stress has on the mind/body connection.  The parameters that were used in the lab were:  electromyography, finger pulse volume, skin resistance, gastric motility, respiration rate, eye blink, plasma amino acid concentration, plasma free fatty acids, growth hormone, palmar sweating, and forearm plethysmography.  Also noted for changes were heart rate, respiration rate, blood pressure, plasma corticosteriod concentration, urinary steroid and catecholamine excretion (Brambilla, p. 487-88).  To note precisely how all of these factors changed with anxiety would be too lengthy, so suffice to say that stress turns on the sympathetic nervous system; heart rate increases, gastric motility ceases, blood vessels dilate, respiration increases, etc.  Adrenalin is known to be a hormone released during stress; it aids in the “flight or fight” response.  Also, cortisol, a hormone released from adrenal cortex, inhibits the activity of the immune system.  The best way to tone down the effects of these anxiety-ridden states and turn off the sympathetic nervous system is obviously to calm ones self so that the parasympathetic nervous system can resume its job.

One area of life that is particularly affected by psychological stress is in the field of education, and learning.  Neuro-physiologist Carla Hannaford has written a book, Smart Moves, in which she has studied movement and its crucial link to learning (Pert, 1999, video).  Her findings in Denmark where there is much more profound scientific research have shown some interesting parameters:  there is 100% literacy in two languages, but they do not read before the age of 8; there are not tests until the age of 18, however there is no grade given for the tests, so that the child is encouraged to learn (the tests are used as a means to show the weaknesses that need to be worked on); and lastly, but not leastly, there is a safe environment for the child to learn in, so that there is no psychological stresses inhibiting the process.   I know from my own experience as a dancer how my own ability to learn is greatly increased when I can “act” something out.  Studying human anatomy in the lab did absolutely no good for me until I could “see” what I was learning on my own body; pure memorization did nothing for me.  At the time I was taking introductory yoga where we had to do an anatomy coloring book, and I’m lucky and grateful that I took the two classes together, because my learning and ability to absorb the information would have been greatly diminished had I not.

It is important to recognize at this point that PNI is a science in progress.  Much research has been done on the negative effects of psychological states on homeostasis, but not much on the positive effects of psychological states.  It is just possible that neural-immune signaling in the form of laughter, strong personal and social support, determination, and the will to overcome adversity can help a patient to overcome an immune-mediated disease, and keep it from reoccurring (Felton, 1991, p.1117-18).  What I have included in this paper are just some of the fundamentals at the molecular level of how these various systems of the body communicate, and influence each other’s functions in reference to the body’s homeostatic balance.  We can say with certainty, however, that psychological stress has physiological consequences, particularly with the immune system and it’s ability to fight off foreign antigens, even if these “antigens” are from the own body, as in the case of autoimmune diseases when the body starts to attack itself.  Rather than taking outside drugs to facilitate healing, I hope I have shown that our body produces some of the best mood-altering drugs in the form of endorphins.  Learning how to tap into the body’s rich resources by changing our behaviors can not only bring us emotional well-being, but hopefully also a more disease-free life, and increase our longevity.

Sources Cited:

Alberts, Bray, Lewis, Raff, Roberts and Watson. (1994).  Molecular Biology of the Cell.  New York, NY.  Garland Publishing, Inc.

Brambilla, Bridges, Endroczi, and Heuser.  (1978).  Perspectives in Endocrine Psychobiology.  Budapest, Hungary.  Akademiai Kiado.

Felton, David B. (1991).   “A Personal Perspective in Psychoneuroimmunology” in Psychoneuroimmunology, 2nd Ed. New York, NY.  Academic Press, Inc.

Koob, LeMoal, and Bloom.  (1984). “The Role of Endorphins in Neurobiology, Behavior, and Psychiatric Disorders” in Peptides, Hormones, and Behavior.  New York, NY.  Spectrum Publications, Inc.

Pert, Candace B.  (1999).  “Emotion:  The Gatekeeper to Performance—the Mind/Body Connection” (audio-visual)  Port Chester, NY.  National Professional Resources.

Pert, Candace B. (1997).  Molecules of Emotion:  The Science Behind Mind-Body Medicine.  New York, NY.  Touchstone Publishers, Simon and Schuster.

Rabin, Bruce S.  (1999)  Stress, Immune Function, and Health:  the Connection.  New York, NY.  John Wiley & Sons, Inc.