Is it possible the third world has something to offer the pain sufferer?
Kalanchoe, also known as Crassula, has been tested for inhibition of pain. Its primary action seems to be as an anticonvulsant, actually protecting animals given strychnine from death in 20% of the cases. Glycine is the main inhibitor of pain in the brain and is blocked by strychnine, but its role in CORD inflammation is quite different. Possibly nature envisioned the need for balance in its action. The other inhibitor is GABA(A) which is blocked by bicuculline.
For some time it has been a question whether opiates actually inhibit pain or whether they merely excite the inhibitory interneurons of the cord. Recently, Chen et al. publishing in J Pharmacol Exp Ther. 2005 Nov;315(2):696-703 reported that morphine has no effect when GABA(A) is blocked by bicuculline in NORMAL rats, but that morphine did allow GABA(A) to reduce activity in rats with nerve injury, ie in a neuropathic pain model. By comparison, strychnine reduced morphine activity in BOTH the normal and nerve injured rats. This model was of peripheral nerve injury, NOT central pain. This information increases our interest in drugs relating to glycine (which is, again, blocked by strychnine).
Glycine has an alpha 3 subunit which is very sensitive to strychnine. See eg. Racz et al Neuroreport. 2005 Dec 19;16(18):2025-8. Glycine alpha 3 subunit is also a powerful modulator of Prostaglandin E2 pain and inflammation in the cord. (see The Brain is Actually Inflammed in Central Pain, at this site). Inflammation involves increased blood flow which creates a redness (rubor) when near the skin to go along with the pain (dolor). Calor and tumor ie heat and swelling presumably could also be measured if devices were applied Rubor, Dolor, Calor, and Tumor are the four signs of inflammation which every medical student since antiquity has had to memorize. How many of these four are related to GABA is not known, but quite possibly all four are, and most likely they are secondary to glycine changes as well. Inflammation is having a field day currently in medicine ever since it was discovered that inflammation of the large vessels was a prerequisite for deposition of fatty plaques in the arteries. Pain research hopes to benefit from the very large amount of money available for heart attack research. so far, heat shock proteins seems to be involved in forming atherosclerosis and these are manufactured by cells under stress, including pain. What is odd is that certain cells which lack conscious pain nerves behave as if they are in pain when they are injured, ie. they release inflammatory proteins. Must pain be perceived to be real? Probably not.
IF a tree falls in the forest and no one is there to hear, is there sound? If inflammation occurs in the large vessels and no pain fibers capable of sending a conscious pain message to the brain fire up, does unconscious pain count? The answer is probably yes. Many aspects of the unconscious or autonomic nervous system behave identically to the way conscious pain channels and reacts. So brain inflammation also counts, but unfortunately, in CP it does not remain unconscious because the chemicals present activate the TRPV-1 channel. It is not so easy to get anti inflammatory drugs across the blood braijn barrier, but it may be that with time opiates themselves may be revealed to be nothing more than a specizalized type of anti inflammatory chemical.
We are asked whether the brain becomes reddened with the inflammaion of central pain. Functional MRI and PET scans measure in different ways the blood flow or oxygen consumption to areas of the brain. Since they confirma increased blood flow to the insular cortex, one supposes that if a highly sensitive densitometer were used to view the insular cortex, it would indeed appear reddened or at least pinkish. This still does not explain the links between inflammation and pain. BDNF blocks GABA(A) but how GABA (A) links to changes in blood flow is not well worked out. Mice who are genetically engineered to lack the alpha 3 subunit lack the PGE block of glycine in the CORD, and recover faster from acid induced hyperalgesia. This will confuse those who do not distinguish between how exciters and inhibitors act in the cord vs. in the brain (The effect can be opposite).
It is also important to remember that the study by Racz et al did NOT deal with neuropathic pain, where the prostaglandin effect seems to CONTRIBUTE TO, not relieve pain. It is also important to note that the mice lacking the alpha 3 subunit of glycine showed NO benefit in formalin induced pain, but only to pain induced by acetic acid. Some sort of competitive block is possible.
This information about knockout mice is mentioned only because we are looking here at a drug which seems to oppose strychnine. It is also interesting because it suggests that prostagladin may have different effects, opposite effects, over the short term, vs. long term. This may be very important in understanding how inflammation develops. If one thinks of sunburn, it is not hard to realize that TIME can change the impact of a stimulus.
The active ingredient in Kalanchoe appears to be methylene chloride CH(2)Cl(2) and when mixed with methanol is able to oppose powerful seizure inducing drugs. The optimal dose, given orally, was 300 mg/kg. See Nguelefack et al, J. Ethnopharmacology 2006 Jan 16.
This herbal plant is already used by ethnic peoples for headache, earache, inflammation and seizures. It appears to live up to its reputation. The authors claim reduction in the first phase of pain (acute) and elimination of the second phase (sensitization) of pain entirely. If you touch a stove, the first sensation is first pain, the flare as you draw your hand away is second pain, a much more generalized nonlocalized pain. Although this study comes from Cameroon, and did not use a model of neuropathic pain, and has not been corroborated, it demonstrates that patients everywhere are very concerned with pain and hope for a remedy.
It also demonstrates how important it is when speaking of pain remedies to distinguish between first and second pain, cord and brain, the pain model studied, and whether there was time for neuropathy to develop. Central Pain is, incidentally, thought to be most related to second pain. In the past it was even considered synonymous with the second pain phase of pain, since it is poorly localized.
However, we now recognize that there are differences, as well as similarities. Both CP and second pain relate to C fibers, but C fibers are tricky customers with varying actions and can play a surprising number or differing roles. As stated in a prior article, C fibers go to Rexed Layer II or Lamina II in the cord. Yet, the fibers in the marginal Layer I are still considered to be specialized C fibers.
If for some reason it is important to know the precise location of a pain source, you must rely on your A delta pain fibers for speed and precision, since C fibers are poorly localized and slow. C fibers are small, uninsulated neurons, with no specialized nerve endings. Resiniferatoxin kills C fibers specifically and instantly, leaving the other cells intact. Silver bullets against pain are rare, so we are very interested of course in the work at the National Institutes of Health on resiniferatoxin, also known as RTX (see elsewhere at this site). Look for RTX to make its first appearance in the dental office, where its preinjection reduces the inflammation and pain which follows wisdom tooth extraction. It is also sure to find a use in medicine. It is already being infused into the bladder for spastic bladder pain. It is amazing stuff. It works by causing immediate flooding of the cell with calcium, which essentially fractures the delicate membranes of C fibers.
Pain Inhibitors of the CNS
GABA(A) which is blocked by bicuculine and appears to be the real force behind morphine effects in the cord of normal rats.
Glycine, which is blocked by strychnine and appears to be involved in morphine action in the cord in rats with peripheral nerve injury.
Kalanchoe crenata, is a species of Crassula, used as an herbal remedy for pain in Africa. It’s component methylene chloride also acts as an anticonvulsant and protects against the effects of strychnine.
Resiniferatoxin, an extract of the Euphorbia cactus, found in Morocco. It destroys C fibers, which contain the TRPV-1 channel.