Vibration. Pain, and Aldose Reductase

There is very good reason for neurologists to ask “Can you feel this vibrating?” rather than “Can you feel this?”. “Feeling” is not the same thing as detecting vibrations.

They may have to refine the test for vibration to “Can you feel this vibrating strongly or weakly?” They may even have to trot out the old analog scale and let patients rate the strength of vibration from 1-10, if Hotta’s work on vibration proves out.Sometimes small things turn out to have meaning. Loss of vibratory sense is one of these things.

Vibration is a test which simply MUST be performed correctly, or not at all. The author well remembers watching a neurologist test a central pain patient by holding a 64 Hz tuning fork on the feet and asking, “Can you feel this”. The patient, who had already been examined by a neurosurgeon and had marked loss of vibratory sense, nevertheless could feel “something” as the tuning fork was pushed into the foot and answered “yes” and that was how the neurologist recorded the exam, NORMAL. This process is why IME’s are often hapless and hopeless. Insufficient time, and certainly not enough expertise. Lives are ruined, and families forced into poverty without benefit of state help, because medicine has neglected to make pain science a part of every medical education.

It was discouraging to watch nearly the entire neurological exam go the same way. The piece of cotton touched on the skin was not occlusive and was left on a second or two, much less time than needed to demonstrate Mitchell’s delay, which would have brought out pain. And so it went. The patient, who had marked hyperpathia, was poked with a safety pin and asked if it felt sharp. Sadly, the patient was already well past the threshold for hyperpathia and so of course felt the pin. However, with more subtle testing, a needle could be inserted a certain distance into the flesh with no awareness at all, until the THRESHOLD was reached, when there was a wild sense of sharpness.

This is the famous “delay with overshoot” which for years has been said to be characteristic of spinothalamic tract damage, which this patient had, although motor paralysis was more subtle. If you are going to get central pain, best to also become quadriplegic, or else no one will pay the slightest attention to you. If you are going to have damage to the spinothalamic tract, you just as well have the entire cord severed, or no neuroradiologist is going to be particularly impressed. The ST tract, being smaller than the level of MRI resolution, does not exist for the neuroradiologist, who NEVER sees it. Only the pathologist will see ST damage, and for that, you will have to be dead and undergoing an autopsy. By the way, unless specifically requested, pathologists do not look for ST damage either.

It has been said that neurologists are withdrawing from treating pain patients. This is unfortunate, since all that is necessary is to modify the neurological exam to look for what is present in central pain.

One of the things which is typically not present in CP after spinal cord injury is normal vibratory sense. Up until Hotta and his group looked into this further did we realize, that vibration is strongly linked to many of the sensory abnormalities.

Hotta et al Clin Drug Investig. 2004;24(11):671-80 were studying Fiderastat which inhibits aldose reductase. Diabetics often suffer loss of vision. Aldose reductase (AR) is an enzyme which limits the conversion of glucose to sorbitol in the polyol pathway in the eye. AR inhibitors favor conversion of glucose, which lowers the level, which is good for diabetics and maintaining eyesight.

From the perspective of one who focuses on pain, these are basically pain chemicals which are destroying eyesight.

If you read the prior sentence again, you will come to the obvious conclusion. The body could not be set up that way. What is true instead is that they are INFLAMMATORY chemicals causing damage to vision, which if stimulated in the area of nerves, cause pain.

This brings us back to neuroinflammation. Why would the body be designed to create chemicals so toxic (ROS, or reactive oxgygen species as described in prior articles here) which actually hurt the host. The host, by the way, is us.

The answer must be that it is a real war going on at the microscopic level between microorganisms which wish to use us for food as against our own struggle for survival. In a sense, we pay a price for our survival; namely, our own death, for the processes leading to the end of life largely reflect the accumulated side effects of the ROS war against invading microorganisms.

In this sense, we are like a Nature show in Africa, one life form fighting the battle to emerge victorious as a successful species, but taking heavy casualties along the way.

The war for human life is not over. The chemicals which cause central pain are part of that war. Our pain systems are a casualty, or rather the tissues damaged by our pain cascades, are a casualty.

To treat the injury to nerve without hurting other nerves, mankind must find a way to stop the acidification of sensory nerve endings in the pain apparatus. The human body manufactures VERY toxic materials in order to kill invaders. Many of these killer chemicals are stored in lysosomes in white cells, but even more important is the production of inflammatory chemicals in the gene factories, which churn them out, sometimes at inhuman levels. The maximum sustained level of gene overproduction of acidifiers is called “severe Central Pain”.

Whether it is the newfound field of inflammation in cardiac muscle or the even new area of acidifying reactive oxygen species in the retina, it is clear that there is this HUGE system in the body to pretty much destroy everything in its path. It is linked with the regrowth apparatus. it is as if the body knew that in the process of kllling microbes, NEW cells of our self would need to be regenerated.

Even as the inflammatory chemicals pour out to coat everything with acid from the ROS, the growth and repair factors begin to pour out of the gene factories. These two systems, inflammation and repair are so closely linked that chemically it is often impossible to separate them.

ERK is a general promoter of transcription. And so, although the MAPK/ERK system is undoubtedly behind central pain, it is also behind inflammation generally.

Since pain is always given short shrift, with virtually no funds (about six hundred million annually including ALL clinical research, which is the lion’s share) pain struggles on all fours to make headway. In the meantime, heart attack, mental illness, and other areas receive large amounts of funding.

Inasmuch as researchers in these other fields are coming up against MAPK/ERK in their respective areas, we can only wait until they solve it there, and THEN, we will finally have a hope for a cure against central pain. This ought not to be the case, since pain is the number ONE thing for which people seek medical care. However, pain is invisible, and until the imaging scientists find a way to make it seen, we will have to wait in the shadows while other branches of medicine shed some light on neuroinflammation, by extension and extrapolation.

In this article, we show how glucose can be changed into toxic substances, via the action of aldose reductase. The medium is via the reactive oxygen species (ROS), a familiar feature of inflammation because ROS are so toxic. By considering how this is harmful to the eye, which is nothing but the part of the central nervous system which reads the sensation of light perception, we can expand our understanding of how similar chemical pathways are relevant in another type of sensation, TOUCH.

However, when admnisistering FIderastat, these careful investigators stumbled on the fact that Federastat has other neurologic benefits. Another problem for diabetics is painful neuropathy, occasioned it is surmised by inability to oxygenate nerves properly due to thickened blood vessels, swollen with sugar.

As Hotta and the other authors stated:

“Vibration perception threshold at baseline was negatively correlated with the severity of the following subjective symptoms: numbness in the upper limbs, and numbness, coldness and hot flushes, smarting pain causing difficulty walking and hypoaesthesia in the lower limbs. During treatment with fidarestat, vibration perception threshold increased significantly in the upper (p = 0.0017) and lower (p = 0.0001) limbs. The following symptoms were also significantly improved: severity of numbness in the lower limbs, heaviness in the foot, coldness and hot flushes in the lower limbs, smarting pain causing difficulty walking, sensation as if walking on sand, sensation as if walking on an uneven road, spontaneous pain in the lower limbs, and dizziness.”

This makes it no so surprising that a large number of those in the survey have diminished vibratory sense. After all, they are in pain. It would raise the question if improving vibratory sense might somehow benefit CENTRAL pain as well as diabetic neuropathy. Perhaps a clinical trial of Fiderastat will follow.

The authors also found that “The C64 quantitative tuning fork analysis is useful in the diagnosis of diabetic polyneuropathy, and as a measure of the severity of the neuropathological symptoms of this condition.” Reading this reminded this author of the way loss of vibratory sense has been taken for granted. Who ever would have even considered it as a marker of pain severity. Interesting thing, the human nervous system. It should be fun watching the anatomists try to figure this one out.

We suspect the chemists will have better luck, because as discussed at the iHOP site, (that’s information hyperlinked over proteins, NOT international house of pancakes) discusses, Aldose reductase regulates TNF-alpha-induced cell signaling.

Furhermore, iHOP reviews report that ” Nitric oxide (NO), generated by the endothelial NO synthase (NOS) and acting via the formation of reactive oxygen species, activates the epsilon isoform of protein kinase C (PKC), which activates the Src family of protein tyrosine kinases (Src and Lck) and transcription factors (nuclear factor-kappaB, and possibly others), with resultant upregulation of the inducible NOS (iNOS) gene and protein expression. iNOS, …In raised glucose conditions, activity of the ERK/MAPK pathway, PI3K pathway, and PKCbet aII were all sensitive to aldose reductase inhibition.”

Since these are all part of the pain cascade, including the free radicals which result in acidifaction, aldose reductase will bear some more investigation in pain matters.

There appears to be some sort of glucose deprivation induced cell death. “Inhibition or ablation of AR…also prevented the LPS-induced apoptosis, cell cycle arrest, activation of caspase-3, p38-MAPK, JNK, and NF-kappaB, Once again, we are right back in the pain cascade. Hydrogem peroxide, a generator of free radical reactive oxygen species (ROS) CAUSES induction of aldose reductase.

It is quite novel to think of injured neurons unable to receive enough glucose to conduct proper metabolism, but this all makes Fiderastat more interesting to the group here at`If you look around for experts in sugar metabolism in central pain, you won’t find any, but one suspects, there will soon be such a group.

There are some technical terms in this article, which might seem imposing to the first time viewer. However, be assured that ALL chemicals mentioned here have been reviewed in prior articles, which can be located by using the SEARCH function on the home page. The nature of painonline is that it builds line upon line, illuminating current discoveries, but it is sometimes necessary to review the old discoveries first, to understand.