Purines, ATP, and pain

We have already published several articles on purine receptors but they continue to gain prominence.

You have read here extensively about glial cells and their role in hypersensitization of neurons. In the brain, “glia” means astrocytes, oligodendrocytes, and microglia. They surround the neurons, which are “true” nerve cells. Very little work has differentiated how these three types differ in their response to nerve injury. It has been assumed that the microglia are linked most tightly to pain events, but this is speculation.

Think of the purine receptors as mobilizing intracellular Ca2+ stores, and also facilitating movement of Ca2+ across the cellular membrane. Somehow, this movement attracts or coexists with “ATP leak” (our term). ATP then becomes a neurotransmitter, rather than an energy supplier. As always, with neurotransmitters, they are merely keys to turn on the machine. It is the RECEPTORS which decide what the end effect will be.

It is distressing to read the populist press which is still hung up on “neurotransmitters” and reports with breathtaking vaguensss that this or that neurotransmitter, generally dopamine or serotonin, has been discovered to be responsible for this or that brain function. This concept verges on kindergarten neuroscience. The RECEPTOR is where the main science is, and is also where we will defeat pain. Drug companies can be just as bad, or worse, when they attempt to explain HOW their medicine acts. Not uncommonly, the manufacturer will say it acts through dopamine, acetyl choline, or serotonin pathways. This miniscule bit of window dressing information, although better than nothing, is not particularly helpful, and may actually be a cover for the researcher’s failure to really study in depth what is happening at the receptor level.

Dopamine, supposedly the “molecule of love” can do little on its own unless it is acting on a receptor. Ditto for serotonin, norepinephrine, acetyl choline, or whatever. Even hormones are in neutral until a suitable receptor comes along. For example, if the receptor for testosterone is defective, a genetically male child will develop to look perfectly like female, better even, because they have NO testosterone binding in the blood vessels, whereas normal females have a little, which gives them more bodily hair. In central pain, the pain related receptors are not working correctly–they refuse to shut down, and that is where the need for research is greatest.

What does seem correct is that purine receptors are “chemical introverts”, ie normally quiet, which come on like social lions in the membranes of neurons when excess ATP (the mainly intracellular supplier of high energy phosphate bonds) is around. So the question emerges, where does all that excess extracellular ATP come from?

The answer appears to be the glia, but which type is anybody’s guess. P2X receptors are ionotropic (powered by electric current created by the flow of charged ions) while the P2Y receptors are metabotropic, ie. they require a ligand in order to function (open or bind). Both types are capable of pore formation, so that is why we use “bind” and “open” more or less interchangeably.

In the normal human nervous system, it is tough to show much dominating action by the purine reeptors. They are more for fine tuning than for any bigtime operations. However, when ATP comes rolling in, the purine receptors become bigtime players. ATP normally lives at home inside the cell where it torques intracellular membranes to do their job, such as the endoplasmic reticulum. ATP is a neurotransmitter when it gets out on its own, and it doesn’t mess around. It dramatically empowers the purine receptors.

Painonline has long tried to emphasize the role of perineural acidity in pain. When this idea was first presented in 1994, it seemed novel. However, time has borne out our early convictions. Everything about nerve injury pain is about acid.

It just so happens that ATP itself becomes incredibly more powerful when there is arachidonic acid around (linked to the prostaglandins). See James and Butt, Eur J Pharmacol. 2002 Jul 5;447(2-3):247-60.

One has to wonder why the cell is willing to give up its ATP to the extracellular space when there is injury to neurons. This mechanism has not been elucidated, but we prefer to think of it as “ATP leak”. The leak is in the glia, and this leak is an important part of the response to injury and resulting neuroinflammation.

Purine Y receptors and Inositol-3-phosphate (IP3) play a primary role in release of Ca2+ from intracellular stores. How IP3 and ATP signal or affect each other needs to be further studied. This signalling is important.

James and Butt found that “high concentrations of ATP activated a significant P2X component that did not desensitise or saturate and was dependent on extracellular Ca(2+)”. The statement “did not saturate” means it can keep on climbing. There is no “lid” on ATP induced pain. This may be why central pain can be so severe.

There are of course inhibitory mechanisms in the brain, but as we have already seen, growth factors, such as BDNF, cripple some of the inhibitory factors, such as blocking GABA(A). This behavior is a characteristic of the P2X(7) receptor and so the assumption has been made that P2X(7) may be a real pain culprit. It is surprising that specific blockers for this receptor have not been forthcoming as possible therapeutic and pharmaceutical treatments for neuropathic central pain.

James and Butt blame purine receptors for
1)triggering reactive changes in glial cells, including expression of immediate early genes (such as c-fos),
2)induction of extracellular signal regulated kinase (ERK)
3) induction of cyclooxygenase-2, (remember the link to reactive oxygen species (ROS) or free radicals.
4)synthesis of phospholipase A(2), (read elsewhere here using SEARCH)
5)release of arachidonic acid,
6)production of prostaglandins and
6)release of interleukins. (acidifiers which have a complex relation to opioids)

This is like a laundry list of pain related aspects of neuroinflammation. The above six events are linked to nearly every other important step in pain hypersensitization, and of course are related to the production of acid in the synapses and perineural space.

The important point is that pain changes everything, or in other words, acid changes everything. Acid cranks up the power of ATP, which in turn makes purine receptors thugs of the central nervous system.

Cell signaling as it relates to purine receptors is bound to increase in importance. Please see the prior article here for discussion of what a purine is. Hint: The double ringed structures adenine, guanine, and uracil, are core components of DNA/RNA and are purines. Structures related to these aforementioned chemicals, such as caffeine (coffee) and theobromine (tea), are also purines, but they do not normally play a role in endogenous bodily functions or DNA formation. Some purines, such as colchicine, can immediately arrest cell development. It is not too much to conclude then, that purine RECEPTORS have the power, if motivated by ATP, to really mess up the works.