Admittedly, botanopharmacology reflects desperation to find a pain cure, but given the natural origin of most effective drugs, it is nevertheless a respectable approach.
Certain Brazilian natives have used extract of a plant related to Junipers, known scientifically as Humirianthera ampla Miers, for the treatment of the pain and swelling of snake bites.
Humirianthera amplis is already known for its production of humirianthol, acrenol, and annonalide. Clicking on the map at http://www.discoverlife.org/mp/20m?kind=Icacinaceae
illustrates the global zone at which these plants grow. Brazil features as the leading area. A photo of the plant can be found at http://fm1.fieldmuseum.org/vrrc/?page=view&id=26340 (note, it is the roots, however, which are used for antinociception).
Humirianthera is one of the Icacinacaeae, and the active chemicals are considered to be di and tri terpenoids, which are also known as isoprenoids, because they are derived from five carbon isoprene units. In chemistry, the suffix, “oid” means “similar to”. The groupings are chemically similar to isoprene groupings.
The interesting thing is that these compounds are LIPIDS. Lipids are naturally occurring fat soluble molecules. Properly, fats are triglycerides or similar compounds. Triglycerides are usually three fatty acids linked to a glycerol. Glycerol (C3H8O3) is a triatomic alcohol, and an alcohol has one or more hydroxyl (OH) groups attached to a carbon (C) atom, in such a fashion as to replace what would typically be hydrogen (H). Fatty acids usually have even numbers of carbon atoms and generally follow the formula CnH2n+1COOH. The COOH group at the end, attached to the lipid, is known as carboxylic acid (COOH).
Coincidentally, fatty acids are one of the substances most responsible for the images generated in MRI. So it is no wonder that the brain and spinal cord light up so well in MRI–nervous tissue is full of fatty acids.
As you know, the local acidity leading to nerve injury pain has been linked at painonline to fatty acid amide hydrolase (FAAH) abnormalities and the downstream formation of fatty acids from altered lipid metabolism in nerve injury pain and neuroinflammation.
Painonline has consistently attempted to detail the cascade of lipid derived acid structures, primarily because those with burning dysesthesia consistently describe nerve injury pain as “like acid under my skin” which in actuality, it is. We desire the medical profession to accept such symptoms as normal expressions of an abnormal situation, not the invention of fevered minds. Fortunately, the science has come our way in recent years, and few question that the acidity is a real sensory phenomenon.
We have spoken in terms of actual acidity to try to avoid the stigma of calling nerve injury pain “bizarre” burning. Use of the term “bizarre”, when simple “chemical burn” would do, makes it seem unreal and not worthy of treatment. It is true dysesthesia MIXES sensations, but only in that sense is it bizarre. “Novel” or “unfamiliar” are better terms. The creepy, sick aspect of the burning is also real, but simply sitting hard on the tailbone or being struck in the gonads can cause “sickening” pain, and these pains are not dismissed as “bizarre”. It is too easy for the uneducated to decide that bizarre pain is something had by bizarre people. This would be like saying when we create animal models of central pain that we are making the little rats “bizarre” rather than giving them a pain state.
The terpenoids (isoprenoids), common in plants, are a very large class of chemicals and are often aromatic. Interestingly this feature is demonstrated in the eucalyptus, and in the aromatic flavor of cinnamon, ginger, and cloves. Also interesting is the fact that the cannabinoids in the Cannabis plant are terpenoids, and are also aromatic. It is not known if cannabis benefits nerve injury pain.
Passing on the addictive potential, which is always a concern, cannabinoids are not generally regarded as potent against Central Pain, but research continues. Nevertheless, cannabinoids, which are vanilloids, do have activity at the Vanilloid-1 receptor (aka TRPV1), which is also the capsaicin receptor, which is capable of reproducing PART of the dysesthetic burning of Central Pain.
Gunthrope et al in March 38 2007 Journal of Pharmacology And Experimental Therapeutics DOI: 10.1124/jpet.106.116657, reported on a new drug, SB-705498. This drug is now in clinical trials. Signficantly, it blocks opening of the TRPV1 channel in response to capsaicin, heat, and ACIDITY as low as pH 5.3, which is more acid than is thought usually to occur in central pain. The binding/blockade is rapid and reversible.
By comparison, resiniferatoxin blocks TRPV1 permanently.
Johnson and Johnson are studying another TRPV1 blocker, JNJ17203212, to prevent cough. See Battacharya J Pharm Exp Ther Aug 9, 2007.
Gavva et al at Amgen have reported that two more TRPV 1 blockers, AMG 517 and AMG8163, also act against heat, acid, and capsaicin pain. Amgen has already contributed articles to painonline.
Luiz, et al, reporting in J Ethnopharmacol. 2007 Dec 3;114(3):355-63 examined the antinociceptive effects of Humirianthera ampla Miers. The findings were most interesting. The extract did have an action against chemical pain but not thermal pain. That is to say, ORAL extract “dose-dependently inhibited glutamate-, capsaicin- and formalin-induced licking”. It did not benefit the tail flick response to radiant heat.
In nerve injury pain, we are concerned with neuropathic pain, ie. chemical pain. Nociceptive pain, such as normal pain from excess heat is different. Therefore, failure of Humirianthera against normal or nociceptive pain does not necessarily indicate it would not have some benefit for nerve injury (neuropathic) pain.
If you review the lists of plant extracts against pain, the natural question is why more has not been done to pursue these leads. The answer of course is money. Of particular frustration has been the slow progress with resiniferatoxin, an extract of a Moroccan cactus, which is known and proven to destroy the TRPV-1 channel. It continues to be a disappointment that no scientist has injected resiniferatoxin locally in the vertical lineup of dorsal root ganglia, or even the dorsal root entry zone, in order to destroy the TRPV-1 channels which are central to the hypersensitization which characterizes central pain. We have wtitten to a number, with the request, but there have been no willing respondents.
Perhaps the lab work on resiniferatoxin is being done by PhD’s who do not feel competent to perform clinical work. The M.D.s, on the other hand, may not feel competent in the biochemistry of resiniferatoxin. Perhaps the undesirable sequelae associated with laminectomy is being transferred onto the simpler maneuver of merely injecting the DRG without removing bone. We have not even seen resiniferatoxin for “at-level of injury” pain.
It is surprising this has not been tried in animal models. The market for peripheral nerve injury pain is much greater, but the need for help is even larger in central pain (which is to say that elimination of pain in a body part is less daunting than eliminating pain in the entire body, potentially). No one who has watched someone in agony from shingles, with pain in a single spinal nerve can doubt that they merit any help possible; but what about a patient who has identical pain in all spinal and most cranial roots bilaterally?
It is clear that a funding shortage continues. Since the topic is severe pain, it seems that irrespective of scientific interest, humanitarian motives would drive more money into the field. We thank the companies which are studying pain. CP subjects await a cure.
Ironically, pain medicines are the most profitable of all pharmaceuticals, so it seems that nonparticipating drug companies are shortsighted in not aggressively pursuing the leads. Our thanks again to Kory McHenry for his information on resiniferatoxin, to date.