Not Reeking with Happiness?

There are many things about central pain which appear disgusting to observers: apparent mental weakness; failure to acknowledge God’s supposed direct dispensation of the pain in response to your transgressions; unusual and abbreviated clothing; exhaustion; avoidance of movement; and pervasive severe depression. All this stuff pretty much makes you “uncool” to the public and annoying to your doctor.


How rude can you be to complain about your pain all the time. Even my grandmother with arthritis doesn’t do that. You say central pain is a “pain beyond pain”? How can that be? Why are you so depressed?

While it is fashionable to speak of “brain chemistry”, it is much harder to actually pin things down. At least for CP depression, the scientists are doing just that.

Brain chemistry, ah how fashionable and knowing the mere mention of it appears. We find “neuroscientists” in nearly all fields of science, including the behavioral ones. Although mired for years in serotonin and dopamine, the neuroscientists have now moved on to their target, receptors, and into the whole science of amino acid and peptide genetics, which is again about the manufacture of receptors. It isn’t the gasoline, it’s the machine it is put into. Receptors are machines which open and close to allow charged ions to move through, generating the electric currents which drive human life. Your heart cannot beat a single beat without the receptors opening channels to allow charged ions to pass. You cannot have any pain, (nor any other sensation), unless receptors create it.

That is what has happened to serotonin and dopamine. They are largely uninteresting and unsophisticated now, relegated to undergraduate biology courses, since the field of neuroscience has moved on to specifics. What we want to know now is “What is the target receptor for the neurotransmitter?” We also want to know what alters the receptor’s sensitivity for the signaling molecules. Power over receptors is power to recreate the human organism. Receptors are the moving parts of human beings–all the rest is just details.

Even more interesting, humans being prototypes for genetic variation, since medicine has removed much “natural selection” (eg. in 1900 only 5% of the population had diabetes, now nearly fifty percent will eventually develop diabetes), many of the diseases floating around are now being traced to a problem with a receptor. The brain is full of receptors, and they are basically the story of the new medicine. Receptors are everything that is important in new research in any area of biology. Receptors are micromachines, made of proteins that MOVE.

What is interesting is that more and more reasons are being found to forgive people their behavior, oddity, and maladjustment. The reason is their receptors. Being made of protein, receptors are no better than their sequence of amino acids, the building blocks of proteins. Take, for example, Attention Deficit Disorder and ADDH, the data are pretty well established that the casein/lactalbumin ratio (the proteins that carry amino acids into the infant’s diet) in cow’s milk is the reverse of humans and that exposure to the alteration in amino acids is linked to ADH and ADDH, which is very, very rare in those who are breastfed.

Then, of course, we have the work of Peter Kramer, who has been a correspondent of one of the authors at painonline. Dr. Kramer, a psychiatrist at Brown, has attempted to describe state of the art research on the role of the hippocampus in depression. (see review of his book elsewhere at this site, using SEARCH).

“Neurogenesis” refers to the growth of NEW nerve cells. Birds do it almost throughout the entire brain, but in humans, it is rare. Basically, the hippocampus is one of the few parts of the brain that actually produces new cells. The hippocampus is part of the limbic system, which is the name given to the circuit of brain parts (the Papez Circuit) which handles emotion. It turns out that the fine tuning work of the hippocampus is delicate, sensitive and subject to injury if too much current and too much trafficking occurs for it to handle. The sensors of our emotional sensibilities in humans are rather fragile, a consequence of the fact that emotions matter a great deal to our species and they elaborate thin nuances requiring sensitive handling. The hippocampus used to be called the Rolodex of the brain, back before we learned that it does so much more than that.

The hippocampus is more or less the indexing center for the brain, helping organize cortico-cortical connections and transmissions. It can be thought of as a stronghold of the contained self, a castle of identity and order around which are erected barriers of specialized cells, with specialized receptors, as needed to protect the hippocampus. The function of the receptors in cells surrounding the hippocampus is largely protective, to dampen any surge of emotion, to prevent a breakdown in the system, to keep the finger in the dike, so that brain functions and thought can proceed as they should, ie. safely.

The problem, or Achilles heel, as it were of the hippocampus is stress, more especially chronic pain. Cortisol, released to allow humans to deal with stress, temporarily stops neurogenesis of protective cells around the hippocampus. Locations that should be part of the protective wall, have voids and gaps (fewer cells) if during development terrible stress occurs. These potential weak spots appear to persist throughout life. A large stress in childhood makes one more prone to depression, and perhaps more prone even to central pain.

Children exposed to chronic pain never fully recover. The wall or protective barrier, as measured in the number of surrounding cells which protect and stabilize the hippocampus, are deficient once a prolonged period of stress or chronic pain is experienced. The debate on nature vs. nurture is not valid here, for external stress/shock/pain has overridden the genetic intentions, truncated the genetic possibilities. This is the price humans pay for FEELINGS.

Adults probably follow the same pattern. Although cortisol helps the body cope with stress, it plays havoc on the cells around the hippocampus, turning a solid citizen into a frightened, depressed mess. We remember the amazement of S. Weir Mitchell, a Civil War neurologist, at the fact that even his bravest officers developed the “temperament of the most nervous girl” if they contracted central pain.

It is worth mentioning that Weir Mitchell was no pushover for those with complaints. If anyone knew how to prosper with placebos, it was he. Mitchell made a good living by recommending the therapeutic effect of mineral baths in Rockbridge County Virginia for any number of maladies, but when it came to nerve injury, he was smart enough to realize he was dealing with something entirely different. Some of today’s “pain is psychological” nuts still haven’t yet realized what Weir Mitchell knew in 1876 about burning pain from injury to the central nervous system. Dr. Mitchell didn’t know anything about the hippocampus, but now we do.

Yes, we all realize that certain psychological events, such as band-aids for children, can make pain worse or better, but having admitted that, we expect the other side to get serious about learning the chemistry of pain that is NOT psychological, the kind of pain you get when you inject capsaicin subcutaneously. Psychology is a miniscule factor in that kind of pain, which activates the same channel as is active in central pain (the TRPV-1 channel). Knowledgeable psychologists such as Ron Melzack at McGill would be the first to second this principle.

Another example of psychologists taking the trouble to understand pain chemistry is Ron Yezierski. See eg. Yezierski RP. Spinal cord injury: a model of central neuropathic pain. Neurosignals. 2005;14(4):182-93. There is in fact a whole slew of good people at UFla in this area.

While behavioral scientists drag their feet and claim pain sufferers just have a bad attitude, pharmacologists at places such as UCSD (Tony Yaksh) and Salk Institute (Francis Crick) have been moving rapidly toward understanding what neuroinflammation and pain are all about. Unfortunately, a large percentage of older trained psychologists who pretend knowledge of pain and its psychological causes should be out selling vacuum cleaners door to door rather than “counseling” patients.

This is somewhat analogous to the old ideas about a woman’s infertility being due to nerves. Sterile women were encouraged to control their “nerves”. Now that we actually know how to cure infertility of course, it is all endocrinologic and there is no more place for a lengthy series of visits to the psychologist. Of course, there was never the slightest evidence that they helped anyone conceive, but the notion conformed to an urban myth.

Pain is in that position today. Supposedly, a psychologist/behaviorist can talk you out of your pain. We will believe this when the behaviorists can talk THEMSELVES out of THEIR OWN pain from capsacin injection, since after all, central pain burning consists of peri-synaptic production of chemicals which mimic capsaicin effect on the TRPV-1 receptor.

Good psychologists with neuroscience training disdain this kind of ignorant arrogance. Most states do not require any kind of license to become a “counselor”. The consequence is that nearly EVERYONE believes themselves qualified to be a counselor, worth perhaps $120.00 per hour. Clue: If the psychologist cannot tell you what MAPK and BDNF do to the dorsal root ganglion, he/she is probably not going to believe your central pain is real, (more real actually than ordinary pain).

Neurokinin-1 and Brain Derived Neurotrophic Factor are chemicals which stimulate nerve repair. Nowhere is neurogenesis really successful except in the prefrontal cortex and the hippocampus, and not there either without NK-1 and BDNF. Since most with severe CP fall squarely into the category of fear and depression, it is not too surprising to learn that neurokinin-1 and BDNF are markedly deficient in those exposed to chronic pain, with a negative result on hippocampal solidarity, and changes in pain handling.

In short, Central Pain subjects suffer from depression, often severe. Chronic pain is depressing. This shouldn’t surprise anyone. The magnitude of it is surprising. It is something like the tendency of cancer patients to lose weight. Everyone knows it happens, but no one is sure why. It is NOT the cancer consuming healthy cells. There is simply some unknown process. The same is true of depression after hippocampal stress. A weakness occurs, and depression follows, but the details have yet to be worked out.

Severe Central Pain patients are virtually always depressed. They nearly never get any attention for the depression. Almost none of them have had the benefit of psychiatric help. Few psychologists receive technical training in the chemistry of pain and so they too tend not to look too closely at the depression of chronic pain. Antidepressants seem to help central pain, but just what is being helped is not known. Is it the depression or is it the actual pain?

Two researchers doing solid work in the area are Duric V, McCarson KE at the University of Kansas Medical Center in Kansas City, Kansas. They recently published on hippocampal malfunction in chronic pain in J Pain. 2006 Aug;7(8):544-55. The title of this article was
“Persistent Pain Produces Stress-like Alterations in Hippocampal Neurogenesis and Gene Expression” These two have also contributed to knowledge in the area with pieces in Brain Res. 2006 Jan 12;1068(1):109-17, and in Neuroscience. 2005;133(4):999-1006

Here are some quotes:

“Clinical observations have shown that patients with chronic pain are often depressed, suggesting the importance of the affective or emotional component of pain and its impact on cognition.”

“molecular and cellular events that may underlie the comorbidity of chronic pain and depression”.

“..pain can alter hippocampal morphology and gene expression”.

“…neurogenesis in the hippocampal dentate gyrus was significantly reduced after long-term inflammatory nociception”,

[Similar to previous observations after various stress models],
“Important activators of nociception-induced spinal central sensitization, the neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF), have also been intimately associated with depressive processes in the limbic system.” In situ hybridization assay results demonstrated that either

“…pain or stress (acute or chronic treatments) reduced the levels of both NK-1 receptor and BDNF mRNAs in the cornu ammonis 1-3 sublayers of the hippocampus, suggesting a possible role of these neuromediators in processing of pain in higher brain centers.”

You get the idea. When we say brain chemistry is behind the profound depression of severe central pain, now you will know we are not just whistling “Dixie”. There are REAL reasons, and we know some of them. So don’t ignore this problem. Severe depression can cost lives. You DESERVE proper care and treatment by a medical professional.

As always, as the NIH pain center says in its brochure on Central Pain, it is absolutely essential to AVOID STRESS if you are to minimize central pain. There is really no other known treatment for the severe burning dysesthesia. Got that? Avoid stress!!!! Your hippocampus cannot stand it.