It is quite common for those providing information to the Wall/McHenry database to indicate that their Central Pain makes the distal part of the extremities or other areas feel inflamed. Other descriptors of dysesthesia include “burning” and “like acid under the skin”. New research from Harvard may explain why.
All researchers agree, it is almost impossible to block out inflammation so you can study pain, and just as impossible to block out pain so you can study inflammation. One researcher went so far as to define pain as “inflammation which just happens to have cut out the immune part.” Of course, it is just as logical to define inflammation as “immunity which just happens to have blocked out the pain part.”
There is some evidence that inflammation would cause even more NORMAL pain than it does if inflammatory cells did not cause release of endogenous opioids when they arrive to initiate a process of acidification of the perineural area, which makes life difficult for invading organisms. Although research has not proven it, there is every reason to believe that in nerve injury the analgesic protective portion of the signaling cascade is defective, probably at several points. Hence, the feeling of “inflammation” or “burning” is present.
The pain world took note recently when scientists at Duke (see Alzate et al Brain Research Molecular Brain Res Sept 2004), using a technique called proteomic two dimensional gel electrophoresis, purified protein from the brainstem of animals with nerve injury pain and found unexpected increases in the alpha chain of T-cell receptors (white cells involved in inflammation), as well an expected increase in interleukin-1*, and fatty acid binding protein-brain or FABP-B
(for better understanding of fatty acids and pain see FAAH elsewhere at this site, and at “Dysesthesia is not bizarre”, using search).
Now, Ji and Strichartz in Sept 2004 Science STKE have shown that in neuropathic pain, there is an increase in the expression of substances mediating inflammation. The increase was particularly noted in the inflammatory kinases. Kinases can be looked at as switches which turn a chemical “ON” Without kinases, chemicals like in the cell like stored firewood, inactive and temporarily irrelevant. Kinases attach high energy phosphate bonds to chemicals to make them active. They must be shaped to fit the particular chemical on which they act, but the end result is the same, to attach a high energy phosphate bond. The level of hypersensitivity (kinases running amok) in nerve injury was observed to cause ectopic (spontaneous, automatic) firing in pain neurons. The sustained firing was found even when NO stimulus was being applied to the injured nerves.
The kinases include protein kinase A and C (which activate NMDA), as well as Calcium/calmoduln-related protein kinase, which is related to CGRP and the VR-1 channel (see “The Smoking Gun”, at this site); but, to an even greater degree Ji and Strichartz found p38, extracellular signal-regulated kinase and C-Jun-N-terminal kinase which are together known as mitogen activated protein kinase or MAPK. These technical names are provided here in case you come across MAPK in the literature. Annika Malmberg has shown that knockout rats lacking protein kinase C cannot be made to develop Central Pain. Once MAPK knockout rats are created, it should be interesting to see if they also are immune to CP.
The pain chemicals lead to a sustained increase in neuron firing due to inflammatory chemicals coming out of spinal microglia. (Glial cells also produce many of the growth factors which increase gene activity and lead to increased transcription and translation of pain chemicals in nerve injury).
The body seems to utilize acidosis profusely in the battle against infection and inflammation. Localized acidity which is recreated at each of the three synapses pain neurons make on the way to the brain, and also in the thalamux, also causes pain, which in CP, can feel exactly like an acid burn. This is what clinicians call burning dysesthesia. (See Dysesthesia is not bizarre, it is just acidic, at this site).
The mechanism of nerve injury hypersensitization by inflammatory chemicals is well known by now, but the clinical disease of Central Pain is still not commonly understood by doctors. This continues to make the very predictable and expected symptoms of perineural acidosis (burning pain) seem odd to doctors who do not understand the underlying mechanism. Puzzling over the description can make the doctor skeptical and interfere with treatment. The patient should not have to exhaust the time of the visit trying to convince the doctor that they are telling the truth. Resort to a pain clinic is generally necessary to find someone who understands CP.
Links between pain and other functions can be seen in CIPA, congenital insenstivity to pain with anhydross, the name for children born without the ability to feel pain. They also do not sweat from heat because the body links the subtle “pain” of too much heat with sweating. Many with CP feel as if they are hot enough to sweat. Because they feel as if they ARE hot enough to sweat, and are not sweating, they sometimes answer the survey that they have decreased sweating.
NMDA is N-Methyl-d-ASPARTATE, a facilitator of chronic pain. Aspartate and Glutamate are the two principal excitatory proteins of pain. They are both ACIDIC amino acids (see “Dysesthesia is not Bizarre, it is just acidic”, at this site)
*Transcriptional Regulation of the Human micro-Opioid Receptor Gene is done by interleukin-6, which putatively inhibits pain. See Borner et al Molecular Pharmacology Sept 2004. This matter is not straghtforward, however, since Wang et al in Sept 2004 J. Neuroscience showed that antisera to IL-6 and antagonists to brain glucocorticoids actually reduced neuropathic pain to mechanical touch and thermal allodyia. This is reminiscent of the work in 1975 by Kenneth McHenry wherein certain injectable steroids quieted the CNS in shock lung and reduced the neurogenic constriction of the postcapillary venules in the lung, which causes both shock lung and premature lung disease.
Put together, these findngs suggest that the central action of steriods appears to be a type of disinhibition, wherein inhibition of inhibitory pathways in the brain actually causes excitation, thus creating an opposite behavior than that observed in the cord. Steroids at cord level decrease both inflammation and pain. It is also possible that only certain receptors have a given effect, since Borner showed that delta opioid receptors do not display the same behavior as micro-Opioid receptors in the brain.
Feb. 2–5 update from National Lib of Medicine Abstracts:
Curr Opin Investig Drugs. 2005 Jan;6(1):65-75. Related Articles, Links
Purines and pain mechanisms: recent developments.
Liu XJ, Salter MW.
University of Toronto Centre for the Study of Pain, Programmes in Brain and Behaviour and Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Purines, such as adenosine and ATP, are endogenous ligands involved in modulating pain transmission and pain hypersensitivity by acting on P1 and P2 purinoceptors, respectively, at sites both in peripheral tissues and in the central nervous system. For P1 (adenosine) receptors, clinical studies in humans, as well as experimental animal studies, have demonstrated that activation of the A1 subtype reduces both inflammatory and neuropathic types of chronic pain. For P2 receptors, there is a growing body of evidence indicating that multiple receptor subtypes are differentially involved in pain processing. The most well-known of the P2 receptors is the P2X3 subtype, which is found in primary sensory neurons. Inhibition of P2X3 receptors is effective in reducing pain behaviors in animal models of chronic inflammatory and neuropathic pain. Recently, the P2X, subtype has been implicated in nerve-injury-induced pain hypersensitivity. There is also emerging evidence for roles for P2Y, and P2Y2 receptors, subtypes of G protein-coupled P2 receptors, in pain hypersensitivity. Thus, multiple subtypes of purinoceptors are potential molecular targets for development of new pharmacological agents for the treatment of pain.