This article informs us how membrane activity relates to the VR-1 rceptor. One offshoot of this research is the realization that blocking of mechanically induced pain does not necessarily block thermal hyperalgesic pain. This would explain the fact that thermal pain and touch pain are not necessarily linked in the responses to surveys in the wall/McHenry databsee.
This is a technical article of interest to the scientists who visit here. However, we have tried to include enough information for the layperson to benefit from this information.
We have already emphasized the sensitivity of protein configuration to pH and speculated on what folding studies might show on the various receptors, such as the NMDA receptor. Previously, the Stsnford folding lab found this receptor too large for present computing studies which must calculate endless bonding angles in or doer to derive shape. The physical shape of ion channels and receptors is very important in function. A channel shaped to permit a certain chemical to pass may cease to function if acidity alters shape.
With our earlier emphasis on the importance of nerve acidosis, we are interested in acids of any kind associated with pain. We have already published on arachidonic acid and the related prostaglandins as acidifying agents on the perineural area.
We are familiar with endorphins and enkephalins, but there is growing evidence that some receptors made naturally by the body bind to cannabinoids as well, and perhaps with equal impact on pain. Cannabinoids have bad press because of their association with cannabis sativa, but any neuroactive drug is worth understanding, even if it is one assoiated with illicit use.
In June Pain, Lichtman et al review acids which form from fatty acids. Of particular interest are those fatty acids which attach to an amide (chemical group with nitrogen). These fatty acid amides are metabolized (processed and broken down) by a common enzyme, fatty acid amide hydrolase (FAAH).
The recent literature has been full of reports on anandamide (aka. N-arachidonoyl ethanolamine, a cousin of the above mentioned arachidonic acid).
Of the fatty acid amides most have their specific receptors for nerve signalling. Only anandamide binds generally to the endocannainoid receptors. Lichtman’s article examines the peripheral receptor for cannabinoids, the CB2 receptor. However CB1 presumably acts similarly in the central nervous system, on the CB2 receptor.
Lichtman and associates have studied “knockout” mice who lack the gene to manufacture fatty acid amide hydrolase. They also demonstrate analgesia to certain noxious stimuli. This raise a question whether blockers of yet another acidifying chemical in the pain cascade might help chronic pain.
The article by Todorovic in June Pain alerts us to the fact reducing agents tend to increase thermal hyperalgesia in nerve injury. He suggested the novel approach of using oxidative agents to “ameliorate neuropathic pain”. A very simplified way of looking at reduction is as an increase in the number of electrons. Oxidation refers to the complimentary compound which gives up electrons. The hydrogen ion found in acids is a good receiver of electrons, so it is a good reducing agent. It is capable of reducing the number of electrons in something else by drawing them to iteself. If acid reducing affect is important in pain, Todorovic is suggesting we look at oxidating agents to reverse the reducing processes, such as the impact of the hydrogen ion in acids. Hence the awareness of fatty acid amide hydrolase.
We are on record as emphasizing the possibility the dysesthetic “acid burn” sensation of CP may exist because of underlying acidosis around the neuron. Most receptors which effect pain are proteins and so should be affected by acids.
The large impact of pH on protein configuration raises an interesting question as to the SHAPE of receptors. Shape is very important in channels. This raises the question as to whether that is the common denominator of many pain chemicals, the production of acid somewhere in the pain system, which alters receptors.
We had speculated on what folding studies might show on the various receptors, such as the NMDA receptor, which the Stsnford folding lab found too large for present computing studies. Although some algorhythm or sequence may yet be found which integrates the large number of pain chemicals, it is not impossible that pain may have as much to do with the number and shape of channels and receptors as chemical composition of the various neuropeptides and neurotransmitters.
If so, we do not have a ready explanation for the varying “phenotypes” of central pain sensations, the varying pain qualities in similarly injured individuals, other than the possibility that we may inherit receptors more or less susceptible to acidity. Of course, discrete tract injury is likely to influence this, but it is hard to find two CP patients who are exactly alike.
The surveys here at the Wall/McHenry databsae have shown a population of central pain subjects who do NOT have hyperalgesia to thermal stimuli, and others who are hyperpathic to thermal changes. When Dejerine and Roussy described the thalamic syndrome, apparently ALL of their patients did show thermal hyperalgesia since abnormal pain in the superfical sensibilities was universal.
However, some of the documented cases of Central Pain here indicate that heat alone is not part of the evoking stimuli for their central pains. The majority who have pain to light touch do have thermal hyperalgesia, but not all.
We cannot give actual percentages, since we are still attempting to understand which pains are neuropathic and which are not. Some with Central Pain also have injuries to spinal nerves, which are considered to be in the peripheral nervous syttem. PNI pain must be separated out as well as nociceptive pains.
In addition, it is not easy, and perhaps not possible to differentiate nondysesthetic central pains from nociception originating from accompanying injuries.
Pains in the anterior cord or spinothalmic tracts are apparently all dysesthetic. However, pains carried in the posterior cord, so called lemniscal pains, may not be dysesthetic, and may localize sufficiently well to confuse them with nociception.
Nociceptive pains are rather common in CP inasmuch as many SCI central pain subjects from cervical cord injury have nociceptive pain from such things as arthrosis of the facet joints, or injury to other neural and mechanical structurs.
Since Substance P is found normally in facet joints, chronic pain should occur there with or without neuropathy. The literature are simply not sufficient to make definite statements about how to differentiate pains. The clinical assumptions are likely to come from accompanying neuropathic symptoms, such as bizarre pain in other areas, presumably originating from nerve injury. For example, the CP patient with a high cord injury and heacaches, should always be considered suspicious for neuorpathy in the somatic afferents accompanying vessels in the dura.
It is known that 5 hydroxytrypamine 3 is a facilitator of pain in peripheral nerve injury. Perriperhal neuropathy is not the same thing as CP, but being accessible it is the best model for study of neuropathic chemical events. Blockers of 5HT3 in a model of peripheral nerve injury have shown reduction in hyperalgesia to von Frey filaments (punctate mechaninical pain) but NO reduction in the hyperalgesia to thermal stimuli. This important work by Suzuki et al in September Brain Research confirms our clinical evaluation of the data. A subset of CP subject with touch hyperalgesia are NOT hyperpathic in such tracts as carry thermal pain.
The mechanisms by which NMDA causes pain are constantly of interest and have some place in a disccussion of pain. (You must read the article at this site on oxidation/reduction to understand this best.) In September 2004 Pain, Muscoli et al show that N-Methyl-D-Aspartate blocks SOD, the enzyme which keeps the radical superoxide (O2-) at normal levels. The highly reactive and hence destructive radical superoxide is always dangerous because it can inactivate ribonucleotide reductase (RR), imparing DNA sythesis.
To consider this, think of a five sided pentagon with oxygen and hydrogen at the C2 position (count the C positions by going clockwise from the top). RR spins off the oxygen as the radical superoxide, but in the process produces deoxyribose, which is necessary for the production of DNA. Anything which would impair SOD (superoxide dismutase), will also impair DNA synthesis because the superoxide radical can inactivate RR.
Muscoli’s important work reveals that NMDA activity blocks SOD, thereby imparing DNA production. This causes rats to have THERMAL hyperalgesia. AT last we have a mechanism linking NMDA release through the pain mechanism with thermal hyperalgesia. We do not know which impaired DNA production is causing the thermal hyperalgesia, but we anticipate that it either causes the Nav1.3 channel to come into production, or impairs the production of inhibitory compounds or their carriers, such as KCC2.
The discreet nature of pain, and the complexity of its components makes collection and publication of clinical data important for researchers who are fleshing out the various components of Central Pain. Completion of the survey here is appreciated for its contributions to pain research. We can presume touch hyperalgesia and thermal hyperalgesia are carried in different tracts, but we would like to know WHICH tracts, and whether the difference comes from the distinct genetic makeup of individuals, or from the difference in injuries causing CP.
Nociception=normal pain carried by normal nerves
Neuropathy=pain carried or originating from injured nerves
Central Pain=nerve injury pain in the central nervous system
PNI=peripheral nerve injury, ie. outside the CNS
SCI=spinal cord injury
Dysesthetic=bizarre pain, generally a mix of pains which includes burning, which is poorly localized.
Cannabinoids=derivatives of cannabis sativa
Fatty Acid Amides=Fatty acids joined to an amide, a close chemical to amino acids.
Endorphins=pain reducing agents in the cord, which reach the same receptor as derivatives of opium. Opiates are inhibitory in the cord.
Enkephalins=pain reducing agents in the brain. Opiates may be stimulatory in the brain by inhibiting inhibitory tracts there (disinhibition).