Gamma Aminio Butyric Acid is at the center of pain inhibition, but which form of GABA?
We are still trying to react to Jeffrey Coull’s discovery that in nerve injury, apparently microglial release of BDNF, a repair factor, continues indefinitely, leading to a reversal of the effect of GABA. Since GABA, ordinarily a pain blocker, is only a slight modification of the pain stimulator, glutamate, perhaps some torquing of GABA back to the Dark Side shouldn’t be so surprising. In the case of BDNF, it is the GABA(A) receptor which is blocked.
What really happens is “anion reversal”, which means that the chloride current which helps modify action potentials in pain nerves, is changed from inhibitory to excitatory. “Exciter toxicity” is another word for this phenomenon in central pain. Because these pain exciters increase perineural acidosis, pain exciters are sometimes referred to as perineural acidifiers. These chemicals include thing such as cytokines, interleukins, growth factors, fatty acids and the like. The body is quite stable normally, and even small changes in the pH can make quite a difference in the configuration of pain proteins. The changes in Central Pain are huge and so are the pain results.
As is discussed elsewhere at this site, anticonvulsants are very commonly used for neuropathic pain. We are very suspicious that the benefit is generalized and neither universal nor specific for pain. Anecdotal endorsements sometimes just express a great appreciation of any perception of pain relief. Despite the positive material on gabapentin (Neurontin), it remains to be seen how these drugs really work. A general quieting of the Central Nervous System could be expected to damp pain signals, but at a price, of course, of general sedation. This raises the question whether the pain benefit is, after all, merely due to sedation, as the chemicals of “non-sedation” or stress mostly feed into the pain system to make sensitization worse. Thus, if an anticonvulsant helps your central pain, we also might expect you to be drowsy, etc.
At any rate, it would appear that anticonvulsants work on the GABA(B) receptor, but there are a number of these. They seem in part to increase in number by portions of the receptor becoming dimers and splitting. This has been thought of as one way GABA is upregulated. It was natural then for McCarson et al to study this in Brain Res. 2005 Dec 17.
What they found is that anticonvulsants appear to act most consistently on the GABA(B)(1a) receptor while having uneven or unpredictable effects on the other GABA(B) receptors, such as GABA(B)(1b) or the GABA(B)(2) receptors. Remember that neurotransmitters and neuroactive chemicals ordinarily act as drivers, but the end result is almost entirely dependent on the receptor, which is often a small part of a larger protein. Changes may result from alteration in shapes of the protein due to altered folding at the active receptor site.
And so we must continue to look at the GABA(B)(1a) receptor and determine whether it is really anti-hyperalgesic or merely acting as a sedative. The same may be said of opiates or nearly any other medication used in central pain since there really is no specific blocker of the cascade of pain chemicals which are known to combine to cause varying degrees of central pain, in varying parts of the body. Muscle and lightning (lancinating) pains, thought to be carried in the back of the cord have traditionally been treatable, while the dysesthetic burning which is carried in the front of the cord (spinothalamic pain) traditionally has been VERY hard, if not impossible to treat. Benzodiazepines have been reported in the surveys to dull spinothalamic pain, but even here it has to be wondered if what is going on is mere sedation, since the benzodiazepines are known as “hypnotics”, in other words sleep inducing drugs, which is close enough to sedative to BE sedative.
Research is becoming more specific, but there is still a way to go before we really can shut off the hyperalgesia which occurs because of the outpouring of chemicals in the dorsal root ganglia** and dorsal horn of the spinal cord. There is also an apparent mirroring of these pain exciters in chemical production in the thalamus. Fatty acids and other acidifying agents appear to multiply and the channels and receptors to respond to them also increase. So far central pain seems to be a direct failure of the damping apparatus, as well as a wildly overactive increase in the excitatory chemicals of pain. Our defenders, GABA and glycine are somehow chemically overriden. If Coull has the whole story, GABA is overridden by BDNF, which prevents GABA from binding to the trk receptor.
Logically it would seem that in cord injury, nature would have made it so that the default result of loss of sensation would be loss of pain, but the opposite is true. Nature seems determined not to cut s off from our environment and information about it, no matter what the cost. Burning pain is a high price to pay for the feeble and misleading information cord injured subjects get via CP pain, but Nature abhors a vacuum and if pain fibers must be recruited to have SOME slight bit of information about what is going on around us, Nature does not appear reluctant to make it happen.
On the other hand, Nature apparently did not expect us to be stupid or indifferent to pain, and anticipated we would devote the necessary research to learn how to cure this disease (Central Pain) along with many others. Cancer OUGHT to be easily curable. Pain also OUGHT to be easily stopped, but it would appear that we need more information on shutting off genes than we currently have to suppress the unbelievable outpouring of pain exciters in the dorsal horn, to the point where a puff of air, or the light touch of a tshirt would make life miserable. In some, no stimulus at all is required, so sensitized the dorsal root ganglia have become. This spontaneous dysesthesia seems one of Nature’s brutalities. Nature makes few accidents that it does not also provide a way to remedy so we continue to hope that the scientists linked to the National Institutes of Health will find the secret door to the control room where they can reach in and shut off the pain alarm that is driving us insane.
Prayer cannot hurt, but we must continue to press elected legislators to fully fund pain research. Given the one hundred billion currently approved to begin another trip to the moon, the four million dollar budget for pain research at NIH seems too small to indicate any kind of commmitment. We had better become a squeaky door to get some grease, a VERY squeaky door. Show up at a politician’s speech and ask if they favor funding for pain research, and since your pain is invisible, you will probably get a stare of disbelief, but repetition brings conviction. If you can do nothing more than publicize Central Pain by writing letters to the editor, please continue to do so.
When Harold Varmus was head of NIH, a national letter writing campaign actually led to the setting up a pain center at NINDS. Now we have to get the politicians to fund this thing well enough to encourage bright young minds to pursue pain research as a career. In the meantime, if you are taking anticonvulsants for CP, you are probably feeling any effects through your GABA(B)(1a) receptor, so watch for any other medications which might block or diminish that particular receptor. You can usually find this information in the Physicians Desk Reference, (PDR) which is available at any library, or at your doctor’s office.
**Sensory neurons usually have long axons or cell processes and locate their cell bodies in a group or ganglion, right outside the cord. This area is known as the DRG or dorsal root ganglia. This is where pain exciters really increase in nerve injury. The neurons enter the cord and immediately are influenced by other neurons, known as interneurons, which can increase or decrease strength of the signal. Interestingly, the small slow C fiber can act in this area of the cord (known as the dorsal horn) to cause the big heavy pain fibers, the A deltas, to become sensitized as well. Capsaicin injected under the skin, for example, sensitizes C fibers which then travel to the dorsal horn where they sensitize the A deltas, which then cause the sensitized area to spread well beyond the area of skin which was injected.