More on Calcium and Pain

For this article, the word “Calcium” will be understood to mean the Ca2+ ion. This is soluble calcium, as opposed to the insoluble calcium in bones. Also, for brevity’s sake, neuroinflammation and hyperacidity will be used interchangeably, although the real picture is actually more complicated than that.


Calcium is a substance which is quite rare in the cell compared to the extracellular space, EXCEPT in the membranes INSIDE the cell, such as the endoplasmic reticulum, where Calcium is high.

Ion channels are protein arrangements, or assemblies of protein domains performed by genetic operations, that have the characteristic of opening and closing. The term, “micromachine” has been applied to them. They are rather complicated so as to select for the particular ion to which they are dedicated. A channel may make several passes back and forth across the membrane until it finally passes the ion inward. However, the ion moves with remarkable speed.

The flow of a charged ion is a significant electrical event. Because there may be tens of thousands of ion channels in a membrane, considerable current can be created, given the very small size. One particular set of ion channels, transient receptor potential voltage gated ion channel #1, or TRPV-1 has been identified as sitting in the center of action so far as pain is concerned. Calcium and its binding protein, calmodulin, more or less control the TRPV-1.

If calcium moves into a pain neuron and then moves within the cell, you are certain to experience pain. The propogation of the pain signal toward the brain is performed by other ions, such as sodium. It is a very complex arrangement, and the details of a pain action potential, or firing, are still being worked out. In general, largeer diameter pain nerve fibers propagate a pain signal much faster and more powerfully. However, tiny pain nerve fibers (C fibers) have the ability to recruit and sensitize the larger ones, so the tail wags the dog, in a manner of speaking.

Latorre et al in Cell Calcium. 2007 May 11, point out that “Ion channels activate by sensing stimuli such as membrane voltage, ligand binding or temperature and transduce this information into conformational changes that open the channel pore.” They then address the question of how sensors, ie. protein domains involved in sensing stimuli communicate with the protein domains involved in opening the gates (pore) of the channels.

The gate opening of ion channels in a pain nerve can be via:

1) voltage change,

2) a tying ligand, that is, a G protein binding ligand (of which metabotropic glutamate receptor number 1, or mGluR-1, is considered to be the receptor responsible for pain),

3) or, it can be opened by temperature.

We have already written about how acidity influences the TRPV-1 channel when reviewing the book by Annika Malmberg and Bley. Acidity increases the likelihood of ion channels opening, and in hypersensitization, body heat alone is enough to open some of the channels–the presumed mechanism of spontaneous burning dysesthesia in central pain.

Let us repeat that:
Because temperature alone can cause opening of channels, if those channels are sufficiently hypersensitized, by the presence of acid, they will open at body temperature, more or less the same as if a flame were present. This creates a chronic pain state. All it takes is resetting the level at which the ion channel opens, which we call hypersensitization. Sometimes we call it neuroinflammation.

No matter how many channels are open, there are always more channels to open, since more channels are made all the time by the relevant genes and the rate can be greatly accelerated. The chronic pain state, already sufficient to keep too many chahnels open and thereby accomplishing hypersensitization, can be exacerbated further or “evoked” by a stimulus, not necessarily a noxious stimulus. Light touch is sufficient, just as it is in a sunburn. In sunburn, however, it is presumably the PERIPHERAL neurons which have hypersensitized. Healing occurs and the pain stops. In the central nervous system, the body lacks the ability to heal itself and so the pain generally continues. Central pain begins at a level and generally over time reaches a plateau. There may be remissions and exacerbations**.

Under the influence of growth factors, channels are actually being manufactured inside the cell protein factories, and then carried to the cell membrane. In central pain, NEW channels, known as the Nav1.3, which are FETAL channels, are manufactured because of the massive genetic alterations in glia which surround injured neurons in the CNS.

So, the question is how the sensor proteins which precede the transient receptor potential (TRP) channels combine a variety of physical and chemical stimuli and then signal to the channel openers. See eg A. Dhaka et al , TRP ion channels and temperature sensation, Annu. Rev. Neurosci. 29 (2006) 135-161; and I.S. Ramsey, et al, An introduction to TRP channels, Annu. Rev. Physiol. 68 (2006) 619-647.

Articles cited by Latorre, include:

M.J. Caterina, et al, The capsaicin receptor: a heat-activated ion channel in the pain pathway, Nature 389 (1997) 816-824 ; G.M. Story, et al, ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures, Cell 112 (2003) 819-829; S. Jordt, D. Julius, Molecular basis for species-specific sensitivity to “hot” chilli peppers, Cell 108 (2002) 421-430]

The integration of the various stimuli elicits pain. See M. Tominaga, M.J. et al, The cloned capsaicin receptor integrates multiple pain-producing stimuli, Neuron 21 (1998) 531-543; M. Bandell, et al, High-throughput random mutagenesis screen reveals TRPM8 residues specifically required for activation by menthol, Nat. Neurosci. 9 (2006) 466-468; S. Zurborg et al, Direct activation of the ion channel TRPA1 by Ca(2+), Nat. Neurosci. 10 (2007) 277-279].

These combined references show that the signaling includes such stimulus sequellae as voltage, pH, agonist (activator) binding, and temperature.

Each of these modalities has its own channels, eg.:

1)voltage gated sodium channels,
2) acid sensing ion channels,
3) mGluR1 related channels which open when bound to a G protein ligand,
4) temperature gated ion channels.

The flow of charged ions, whether it be sodium, calcium, or whatever represents an electrical CURRENT, with an electric potential (voltage), also known as the generator potential, which leads to the initiation of an action potential, which IS the nerve firing signal. More rapid firing equals more pain.

Basically, the assassin in the nerve injury pain “murder mystery” is the TRPV-1 channel, which confers thermosensitivity on the pain pathways. The accomplice is acidity, and the weapon is calcium. Calcium and calmodulin regulate the TRPV-1 channel, while the cannabinoid 1 receptor CB1 has a regulatory effect on how much intracellular calcium can be released for action.

TRPV-1 is on the cell surface but Hangenacker et al (see Cell Calcium. 2007 Jul 26) theorizes a “possible interference of TRPV-1 induced [Ca(2+)](intracellular) modulations to the function of other membrane receptors and channels, like voltage gated calcium, sodium or potassium channels, or co-expressed CB1-receptors.” In other words, jamming in of calcium at the TRPV-1 causes a backup inside, and prevents normal clearing of calcium inside the cell at the endoplasmic reticulum (ER). The ER is a series of narrow conduits surrounded by membranes which conduct molecules within the cytoplasm. Ribosomes surrounding the endoplasmic reticulum turn out peptides and protein structures.

This idea would make calcium the main player in deciding how channels for other ions might tend to open, and thus create a pain signal which can be sent to the brain. Presumably, under this mechanism, TRPV-1 asserts itself when, via calcium, stimuli are tranduced and cause a pore opening. Too much of this has a backup effect on the calcium moving along at the endoplasmic reticulum, which is inside the cell. Calcium excess may lead to sythesis of protein structures designed to process calcium, many of which are pain chemicals. This cannot be a complete explanation, but evidence does exist that TRPV-1 overactivity somehow leads to overactivity in the endoplasmic reticulum. (See Hangenecker above cit)

Latorre points out that “thermoTRP channel-forming proteins are modular in the sense that certain structure or structures (modules) confer temperature-dependent regulation, whereas others confer voltage-dependent regulation.” Acidity can make either channel mechanism, temperature or voltage, more pain intensive. Hyperacidity and hypersensitization are close to the same thing.

We are getting near understanding why burning dysesthesia is the predominant feature of central pain. Acidity, or pH, is active at every step of the interactions described above, and the overabundance of resulting pain signal could be expected to be interpreted as communicating the presence of acid to the brain, which is a real or accurate perception, and may well morph other sensations into an acid like feeling. If light touch floods the synapses with acid, then what is felt is acid, rather than light touch, under this perspective. Temperature change would act similarly.

The number one verbal descriptor of central pain, with nothing else even close, is the sensation of “acid just under my skin”.* The acid is actually there, in the synapses, and derives from the fatty acids and acids such as arachidonic acid, which form from the eicosanoids (20 unit structures) which are found in body tissue. Please see the review of Malmberg’s book at this site (or better yet,the book itself) for better understanding of the importance of acidity. Please see the article here on eicosanoids for better understanding of arachidonic acid. There are also articles on fatty acid amylase at this site, which briefly cover fatty acids.

The ion channels of pain begin to fire (open) automatically when the pH becomes low enough, which it has been shown to do when a central neuropathic state exists. The acidity is due to an overproduction of inflammatory chemicals in hypersensitized injured neurons. Acidity is the primary mechanism by which inflammation is expressed. The nerves are inflammed because there has been injury, similar to the way skin turns red when burned.

The hypersensitization traces back to overproduction of growth factors by glia surrounding injured neurons. The firing in pain nerves accurately conveys the acidic environment in the synapses and perineural space and even overwhelms other types of sensation by making them seem to be acidic in origin, which in a hypersensized nerve, they in fact are. Touchy, high strung pain nerves also carry increased quantities of other pain (as in allodynia or hyperpathia). Morphable (malleable) sensations include light touch and temperature change. Note from Story’s article, cited above, that cold can cause burning via TRP receptors. The surveys at painonline indicate in fact that cold is a more rapid and punishing evoker of burning pain than is heat.

Is it possible to create chemicals which impact calcium flow or channel opening? Of course!. Nature does it all the time with toxins. This is true of many land and sea creatures. Inside the human, our toxin is the acid which forms to fight off invaders, but sometimes the inflammation can hurt the subject. Money and researchers are needed to come up with something, probably already existing in nature, to change the CP picture, so that those with central pain can finally achieve some relief.
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*Nearly all CP sufferers have other distinct pains, some of them VERY intense, such as the lancinating pains. An ordinary person suffering a jolt of lancinating pain would almost surely cry out. However, for pure suffering, burning dysesthesia reigns supreme. Lancinating pain is comparatively minor to the all pervasive, soul destroying burning.

**Adrenaline, the stress hormone, or anything linked to its big brother, angiotensin II, will greatly worsen central pain, so stress MUST be avoided in order to keep CP at bay. Since the patient has loss of working memory, decisions are laborious and it is common for CP patients to rely on rituals or single minded focus to avoid the difficult mental operations necessary for ordinary life. Therefore, when we say stress must be avoided, we are including very small stresses.

Only in this way, can the mind proceed. Loss of working memory means the subject has trouble doing, thinking, or reacting to two things at once. The available consciousness is compromised. Whether this is from the pain or primary in itself, is not known. However, loss of working memory has been too much neglected in the clinical evaluation and rehabilitation for central pain, which is practically nonexistent anyway. For some reason, physical medicine departments focus exclusively on MOTOR impairment, with virtually no counseling on how to arrange life to be lived with loss of working memory.

In central pain, it is the neurons of the CENTRAL nervous system which are hypersensitized. There is an additional mechanism in CP regarding stimuli which are SUPPOSED to hurt, such as the poke of a needle, but this is termed “hyperpathia”. Much nonsense has been handed to patients over the years because an examiner asks “Can you feel this?”, rather than, “Can you feel this painfully”. We are aware of an individual with severe kinesthetic dysesthesia and burning dysesthesia who consulted a neurosurgeon, whose records make no mention of pain testing whatsoever.