Gamma amino butyric acid is a pain inhibitor. We have already discussed GABA(B)in the article on CREB. GABA(A) acts like the opposite side of the coin from Purine2 receptors, which are pain exciters, which are part of the nitric oxide (N0) pathway. GABA and P2 entities are normally in balance, but there is evidence of dysfunction between GABA(A) and Purine2(P2) receptors, in nerve injury pain.
SUMMARY OF POINTS IN THIS ARTICLE
i. Glutamate is a general exciter of the nervous system.
II. GABA is a general inhibitor of the nervous system.
III. The Purine receptors oppose the action of GABA in reactions specific to pain. Drugs which block the purine receptors are under investigation.
IV. Interleukin, which leads to acidification of the environment of the pain neuron acts via the Purine receptors.
V. There is a possibility that dysesthetic burning of CP, anterior cord pain, or Spinothalamic Tract pain, which is described as “acid under the skin” is due to interleukin and acidifying chemicals which are related to the prostaglandins. It is NOT verified that these pains respond to opiates, but there seems to be some benefit from GABA active drugs, such as baclofen and klonopin.
VI. Pain thought to be carried in the posterior cord, shooting pains, muscle pain etc. often responds to opiates.
VII. Different chemical mechanisms may be at play in anterior cord pain and posterior cord pain. Medicines should be administered with an eye to the particular symptoms a patient has.
VIII. As to central pain from MULTIPLE SCLEROSIS, a specific purine receptor (P2X-R-7) has now been identified as the possible mechanism of injury which leads to central pain. Further investigation may reveal that this purine receptor is also the or a cause of CP in spinal cord injury.
Because many submitters to the survey have described their burning as “like acid under my skin”, we have devoted space to the actual acids that are part of nerve injury sensitization, and to acidifying pain chemicals such as the interleukins, cytokines and prostaglandins.
Many other survey respondents have used terms related to inflammation or muscle cramps to describe both their burning and also the general “feeling” in the body, so we here devote space to the link between pain and inflammatory chemicals such as the growth factors (see article on CREB, at this site).
It is to be remembered that all these chemicals require ion channels to exert effect, but insufficient knowledge currently exists to classify ion channels according to acidifying pain chemicals and inflammatory pain chemicals, realizing that the two are closely linked. It may not be the case that pain symptoms can be sorted out according to the underlying chemical mechanisms, but it makes a useful background for emphasizing the difference in therapeutic success for posterior cord pain and anterior cord pain (ST pain).
Research in the Wall/McHenry database has focused of late in trying to determine how therapies for Central Pain should be tailored to individual symptoms. Some sense must be made of those who claim considerable benefit from medications and those who claim no benefit at all, beyond that of sedation. It is also unclear just how much pain relief with anticonvulsants is actual pain relief and how much is simply due to quieting of the central nervous system.
It is not scientific for drug manufacturers to lump all central pains together, and allege global effectiveness, if the effectiveness is zero in the anterior cord patients. Lumping can create false ideas of therapeutic benefit. “Ideas must be distinct before reason can act upon them”–Thos. Jefferson. If ST pain is the problem, it may be of no benefit for the treating physician to go on a wild goose chase after meds that affect only posterior cord pain.
The first step has involved attempting to get more and more clinicians to speak of specific central pains and not to lump all together. The database has very strong evidence that pain which has traditionally been relegated to the posterior columns of the spinal cord (cramps, shooting pain, muscle pains) is in fact treatable by morphine, baclofen, and certain other drugs.
It also appears that claims of therapeutic benefit for pains carried in the anterior spinothalamic tracts are unverified, and possibly exaggerated. Nearly all benefit for anterior cord pain may well be due to nothing more than sedation, no matter what drug is utilized to achieve sedation.
Sedation is NOT pain relief. Because of this admitted viewpoint, we have sought to determine if evolving pain theory might provide some insight on WHY our survey respondents do NOT report actual PAIN RELIEF for ST tract pain, but DO report relief for posterior column pain.
A very interesting article by Vale et al in Nov 04 Brit J. Pharm shows some parallels. These researchers found that pentoxiffyline blocks hyperalgesic, hypernociceptive pain from injection of bradykinin, carageenan, and tumor necrosis factor (TNFalpha) but did NOT block pain from injection of interleukin1-beta and prostaglandin E2. This suggests that acidifying chemicals like IL1-beta and PGE2 work via different mechanisms from local irritants and neurotrophic growth factors like TNF.
Pentoxiffyline blockade of interleukin was NOT reversed by blockade of opiates with nalorphan. Interleukins have been found to regulate the Mu opiate receptor, suggesting a link. Morphine has a second effect; namely, it increases phosphorylation of CGRP which acts directly on the VR-1 channel. Thus, it is perfectly acceptable to find a different response between interleukin and morphine. Most CP patients do in fact have BOTH posterior and anterior cord pain, so we expect overlap chemically in most people. This overlap DOES NOT necessarily mean that the same medicine will benefit both posterior and anterior cord pain equally well.
If Vale’s work holds up, this is sn important step in identifying laboratory models for what is observed clinically, or at least seems to be demonstrated clinically from survey results here. Since those with anterior cord pain typically describe the pain as “like acid under my skin”, and the acidifying agents have been shown by Vale to behave differently from certain other pain chemicals, a different mechanism for anterior and posterior cord pain may become evident. At the very least, researchers should be aware of this possibility and consult CP patients for their input on the nature of specific pains, and NOT lump all the central pains together.
Recent studies continue to bear out the chemical link between pain and inflammation. We include now a brief discussion of the purine2 receptors. These are certain to become a topic in the pain literature, since much of the important work on them is coming from drug companies. Because one drug, baclofen, is already touted as a GABA drug, treatments aimed at blocking the purine receptors, which oppose GABA, are virtually certain to appear. Purine receptors generally are abbreviated as P2X or P2Y receptors.
Whiteside et al in Eur J Pharmacol. 2004 Nov, have already shown that
A-317491, a selective P2X receptor antagonist, reverses inflammatory mechanical hyperalgesia.
Other articles at this site have emphasized the role of ATP, with its high energy phosphate bond in energizing the chemicals of pain and also as an agent unto itself, a neurotransmitter. ATP exerts its effect through the P2 receptors. P2Y receptors require ligands (metabotropic) to work, and P2X receptors are activated by ion flow (ionotropic). Remember that a ligand is a chemical which allows a metabotropic gated channel to open. GAbA(A) is such a ligand, and operates on a subunit of the chloride channel (see below).
P2X is pain excitatory and its co-chemical GABA(A) is pain inhibitory.
The inflammatory cytokine, interleukin-1beta (acts as a precursor to acidification) exerts its effect specifically on the P2X(7)R receptor. IL-1b causes pores to develop in the membrane of brain astrocytes, allowing calcium++, a pain exciter, to exert greater effect. (See Narcisse etal in Oct. 2004 Glia) The interleukins also regulate the production of the mu opioid receptor (see elsewhere at this site, using Search).
In the past, it was known that Central Pain occurs in a significant number of those with multiple sclerosis. It was assumed this Central Pain was due to generic pain injury. The discovery of P2X(7)R in the neurons of those with MS now raises the question whether P2X(7)R has a specific action, linked to Calcium metabolism, which causes the Central Pain.
A channel is a physical protein structure which is manufactured by the genes in a cell and embeds in the membrane of a the neuron. The more channels, the more possibility of pain, and the more chemicals which foster channel activity, the greater the likelihood of pain. There are many types of these channels for each of the major ions, sodium (Na), potassium (K), calcium (Ca) and chloride (Cl). Much of pain chemistry relates to processes which create pores or affect their function. Glutamate upregulates pain excitation, and GABA inhibits pain processes.
Masubuchi et al in Sept 04 Brain Res Bull indicated that both GABA(A) and GABA(B) drugs work better on a high salt diet. HOwever, the dangers of salt to the kidney and other organs indicate you must discuss this with your physician.
GABA(A) activates ligand gated chloride- channels. GABA(A) acts extremely rapidly and specifically. GABA(B) increases conductance in potassium channels. GABA(B) receptors are G protein coupled. GABA(B) acts more with repetitive activity and modulate rhythmic firing.
Although not proven, this makes it tempting to look first at GABA(B) drugs, since GABA(B) also tends to block GABA(A) to some extent and should help prevent disinhibition in the brain (Ie. inhibiting an inhibitory tract, leading to paradoxical excitation).
Antidepressants except for Prozac (fluoxetine) tend to increase the effect of GABA(B) drugs.
At high doses of GABA(B) drugs, 5 hydroxytrytamine drugs may cause a paradoxical increase in glutamate release and a reduction in the effective of GABA(B) drugs.
When Estrogen is present, cocaine interferes with G protein function, suggesting females with CP should NOT use cocaine if they are using baclofen or GABA(B) drugs.
See Smith, H. “Drugs for Pain” to which is owed much of the following:
The GABA(A) receptor acts on the chloride- channel (Remember, negative ions are INHIBITORY, and positive ions are EXCITATORY). Nearly 30% of cells in the dorsal horn express GABA AND Glycine, another inhibitory transmitter. Those GABA cells which do not express Glycine, then express Acetylcholine, a neurotransmitter. (Future post on ACh to come)
The chloride channel is modified by barbiturates, benzodiazepines (Klonopin), and propofol. Stimulation of the GABA receptor increases chloride conductance (flow in the chloride channel) and keeps the neuronal membrane hyperpolarizeed (less likely to fire)
By comparison, GABA(B) receptor is a G protein type arrangement which increases potassium (K=) flow. This also hyperpolarizes the membrane, which decreases the opening ability of voltage gated calcium channels, including VR-1, the channel of burning pain.
Loubser showed that intrathecal Baclofen (a GABA-B drug) is effective for muscle pain (such as occurs with pain traveling in the posterior columns) but is ineffective for burning dysesthesia such as is carried in the Spinothalamic tracts. (See J. Pain Symptom Manag 12:241, 1996.)
The antiepileptic drugs gabapentin and topiramate, are said to enhance GABA. Gabapentin (neurontin) does not act on the GABA receptor, but is said to increase the output of GABA. Neurontin enjoys a reputation in diabetric neuropathy, but Pfizer lost a large case on neurontin effectiveness in neuropathic pain. The jury is still out on this. A poorly defined association with firing by sodium (Na+) channels in the dorsal root ganglion (gathering of sensory nerve cells just outside the cord) is postulated. However, only the TTX (tetradotoxin) resistant sodium channels are thought to be associated with pain.
Rowbotham at UCSF has suggested a role for Gabapentin in post-herpetic pain, but noted side effects of swelling and edema, dizziness, drowsiness, and ataxia.
With some similarities to gabapentin, topiramate also may have some blocking action on a glutamate (excitatory) receptor. Some troublesome side effects of topiramate such as tremor, kidney stones, confusion, and weakness, and have limited its use, which has largely centered on diabetic neuropathy.
Divalproex (Depakote) is a fatty acid, which may increase GABA levels by inhibiting two catalytic enzymes, GABA transaminase and succinic semialdehyde dehyrogenase, but enhancing GABA by upregulating synthesis of glutamic acid dehydrogenase (GAD). There are many side effects and Depakote is mainly used for migraine headaches.
Klonopin is a GABA-B agonist. Like other benzodiazepines, there is a problem with sedation at therapeutic levels.
Pregabalin is a GABA analog, but questions over safety have greatly curtailed use.
Tiagabine inhibits the uptake of GABA presynaptically so as to maintain levels of GABA at the synapse. It is associated with GABA-B receptors and increases GABA in the brain. it is an antiepileptic drug which has not had much use in neuropathic pain.
Felbamate enhances GABA receptor influenced chloride channels and is used mainly for trigeminal neuralgia
Lamotrigine is another antiepileptic which has some play. It is currently used on occasion for complex regional pain syndrome. It is noted to have neuroprotective effects. The benefits for pain are not yet verified.