Cold is as hot a topic in burning pain as anything right now. Pun intended.
We begin this article with the following reminders:
1) Although Central Pain has had various definitions over the years, the works of S. Weir Mitchell, Dejerine and Roussy, George Riddoch, and David Bowsher have make that they are referring to dysesthetic burning when they referred to pain of central origin.
2) There are other pains which accompany central pain. These include other aspects of superficial sensibilities, including lancinating pains, muscle pains of a cramping, tightening, or burning quality, pins and needles, and in about one third of severe cases gut or bladder burning (over distention sensation) or other pains as well. These additional central pains are not part of the classical definition of central pain. Therefore, they may be referred to as post stroke pains, SCI related pains, MS pains, and the like.
In the more recent literature, ALL of these pains are included as part of the central pains, so we emphasize that the remarks herein about cold allodynia pertain SOLELY to the burning dysesthesia, which for years formed the core definition of what central pain is. Presently, a distinction in CP of spinothalamic tract (ST) pain from lemniscal pain is emerging in much of the literature. Lemniscal central pain usually gives a latency on somatosensory evoked potential testing and tends to respond to treatment and should be addressed aggressively. By contrast, this article deals with a hopeful benefit to ST pain.
3) Dr. David Bowsher was the first to make the “paradoxical” component of cold a definitional part of dysesthetic burning. This paradoxical cold component is now considered part of the standard definition of dysesthetic central pain; however, many patients must be questioned specifically before they themselves realize it is present. Without reflection, the pain feels unitary, and only with time can the sufferer thread out some of the indiviudal parts of the mix.
It is after all the MIX of sensations which is behind our calling the burning dysesthetic. It is the “cold” mixed in which makes the pain burn not capturable by ordinary vocabulary. We are not used to mixed sensations. The term “cenesthetic” has now been coined to denote mixed sensations, but this does not make things clearer than calling the pain “dysesthetic”.
Neither the public nor the garden variety neurologist has much idea of the meaning of “dysesthetic”, let alone “cenesthetic”. If one mixes red and blue, the single color purple emerges, but if one mixes burning and metallic, wet cold, what would we call that? We call it “dysesthesia” but this conceals as much as it illuminates. By having a word, the neurologist looks no further. For most, “dysesthesia” means he/she doesn’t have to try to understand it. The same applies to “allodynia”, which means pain from that which is not normally painful. The illusion of a bracketing word can get in the way of curiosity. “Hyperpathia” means a greater than normal degree of pain from something that IS normally painful. There is no end of words to describe the central pains but hardly a beginning of understanding. Even CP patients give up and just use “nerve pain”, which is impossibly vague.
4) MODERATE COOLING helps the sensation of dysesthesia, but more INTENSE cooling is the most ready evoking stimulus for severe, devastating burning. In the surveys, we have found not a single person who has indicated that heat evokes the burning more quickly than cold. The most commonly experienced cold is a blast on the legs from a car air conditioner. Occlusive light touch is approximately equal to cold as an evoker of the burning. Most have spontaneous burning of a lesser degree even when no cold or touch is present.
5) Based on the articles presented below and our interpretation of the surveys, the EVOCATION of burning from cold which appears after a duration of perhaps twenty seconds (essentially the same delay period as for light touch, which is termed “Mitchell’s Delay”) probably occurs as a result of activation of the TRPV-1 and possibly the TRPV-4 receptors in cell membranes. The TRPV-1 receptor allows sodium and calcium currents to flow.
6) The RELIEF from burning which MODERATE cooling provides for dysesthesia occurs because TRPM8 channels are activated. The TRPM8 channel is a newcomer to the literature, but a knowledge of it allows CP patients to be comfortable in speaking of what goes on in their body, without fear of being accused of making things up.
We owe our awareness of the analgesic effects of TRPM8 in moderate cooling to the absolutely outstanding research by Sue Fleetwood-Walker, an associate of Clare Proudfoot in the U.K. That these fine researchers are aware of the seriousness of the problem is shown by a quote from a recent article “…pain, especially that following nerve injury, is difficult to treat and represents a largely unmet therapeutic need. ” We couldn’t have said it better. This is almost verbatim what the NIH has said, as well.
We are also most grateful to the estimable researchers at the Univ. of Texas Medical Branch, who continue to wow us with their solid advancement on nerve injury pain. We absolutely did not see coming the discovery of cold as an activator of the TRPV-1 channel, which is the “main man” of C fiber induced hypersensitization. U.K. authors
September 27th, 2006 at 4:21 am
Ahhh yes and I believe that this hypersensativity to heat and cold is caused by “sympathetic sprouting” case in point. Sympathetic sprouting was observed in reflex sympathetic dystrophy a disease which is very similar to central pain, but RSD is also almost identical to Erythromelalgia, except for one or two very very small differences. It has very recently been eludicated, by Waxman at Yale Neurology, that EM involves both an overeactive expression of sympathetic neurons in the peripherial and an underactive expression of sympathetic neuons in the central. Both occurring at the same time due to a sodium channel mutation, a channelopathy. Waxman believes EM might serve as a model disease and might yield an end to neuropathic pain, he recently appeared on discovery channel stating it is possible to make a designer drug, and that it might work on the other neuropathic pains i.e. with hyperpolarized extracellular calcium ions. Even more interesting is that EM was first called red neuralgia by the brilliant Sir Mitchell. And as centralpain.org states he made the first observation of a delayed response. Clearly central pain might represent damage to these small fiber nerves as well as damage to the a central area that has been put forth. What a coincidence that these observations have just been validated through genetic research in neurology. How brilliant is Mitchell? Lyrica may work along these lines, certain calcium channel blockers have been known to treat EM, and also cause EM at the same time. Lyrica may work on extracellular depolarized calcium channel ions…there may be a link?
Focusing mainly on the overexpression of neurons in the sensory, we now possibly see it eludicated as the molecular mechanism causing what Waxman has just discovered here in this abstract:
Sympathetic sprouting and changes in nociceptive sensory innervation in the glabrous skin of the rat hind paw following partial peripheral nerve injury.
* Yen LD,
* Bennett GJ,
* Ribeiro-da-Silva A.
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Previous studies have suggested that sympathetic sprouting in the periphery may contribute to the development and persistence of sympathetically maintained pain in animal models of neuropathic pain. In the present study, we examined changes in the cutaneous innervation in rats with a chronic constriction injury to the sciatic nerve. At several periods postinjury, hind paw skin was harvested and processed by using a monoclonal antibody against dopamine-beta-hydroxylase to detect sympathetic fibers and a polyclonal antibody against calcitonin gene-related peptide to identify peptidergic sensory fibers. We observed migration and branching of sympathetic fibers into the upper dermis of the hind paw skin, where they were normally absent. This migration was first detected at 2 weeks, peaked at 4-6 weeks, and lasted for at least 20 weeks postlesion. At 8 weeks postlesion, there was a dramatic increase in the density of peptidergic fibers in the upper dermis. Quantification revealed that densities of peptidergic fibers 8 weeks postlesion were significantly above levels in sham animals. The ectopic sympathetic fibers did not innervate blood vessels but formed a novel association and wrapped around sprouted peptidergic nociceptive fibers. Our data show a long-term sympathetic and sensory innervation change in the rat hind paw skin after the chronic constriction injury. This novel fiber arrangement after nerve lesion may play an important role in the development and persistence of sympathetically maintained neuropathic pain after partial nerve lesions.
PMID: 16506190 [PubMed - indexed for MEDLINE]
Brilliant, then we went one step furthur and asked ourselves what causes this sympathetic sprouting? Well, this 2006 Aug Neuroscience pubmed provides the answer:
Robust increase of cutaneous sensitivity, cytokine production and sympathetic sprouting in rats with localized inflammatory irritation of the spinal ganglia.
* Xie WR,
* Deng H,
* Li H,
* Bowen TL,
* Strong JA,
* Zhang JM.
Department of Anesthesiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, P.O. Box 670531, Cincinnati, OH 45267-0531, USA; Department of Anesthesiology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
We investigated the role and mechanisms of inflammatory responses within the dorsal root ganglion (DRG) in the development of chemogenic pathological pain. DRG inflammation was induced by a single deposit of the immune activator zymosan in incomplete Freund’s adjuvant in the epidural space near the L5 DRG via a small hole drilled through the transverse process. After a single zymosan injection, rats developed bilateral mechanical hyperalgesia and allodynia which began by day 1 after surgery, peaked at days 3-7, and lasted up to 28 days. The number of macrophages in ipsilateral and contralateral DRGs increased significantly, lasting over 14 days. Robust glial activation was observed in inflamed ganglia. Cytokine profile analysis using a multiplexing protein array system showed that, in normal DRG, all but interleukin (IL)-5, IL-10 and granulocyte-macrophage colony stimulating factor (GM-CSF) were detectable with concentrations of up to 180 pg/mg protein. Local inflammatory irritation selectively increased IL-1beta, IL-6, IL-18, monocyte chemoattractant protein-1 (MCP-1), and growth-related oncogene (GRO/KC) up to 17-fold, and decreased IL-2 and IL-12 (p70) up to threefold. Inflaming the DRG also remarkably increased the incidence of spontaneous activity of A- and C-fibers recorded in the dorsal root. Many of the spontaneously active A-fibers exhibited a short-bursting discharge pattern. Changes in cytokines and spontaneous activity correlated with the time course of pain behaviors, especially light stroke-evoked tactile allodynia. Finally, local inflammation induced extensive sprouting of sympathetic fibers, extending from vascular processes within the inflamed DRG. These results demonstrate the feasibility of inducing chronic localized inflammatory responses in the DRG in the absence of traumatic nerve damage, and highlight the possible contribution of several inflammatory cytokines/chemokines to the generation of spontaneous activity and development and persistence of chemogenic pathologic pain.
PMID: 16887276 [PubMed - as supplied by publisher]
So it is possible that EM, RSD and Central Pain are neuroimmune small fiber neuropathic pain syndromes (neuroinflmmatory)due to reperfusion injury
http://en.wikipedia.org/wiki/Reperfusion_injury