New results suggest caution in long term use of ketamine. It also raises the question of whether ketamine might be exploited to suppress sprouts at the cut ends of interrupted nerve fibers, which sprouts promote hypersensitization.
It’s just one article, but the Swiss are very good scientists. Vutskits et al in Toxicology. 2007 Mar 12 have published some very troubling data on the effects of ketamine on cultured neurons. Their dendrites atrophy. This is not what you want in the brain.
Ketamine has been a mystery drug almost since its use began in the late 1960′s. There has been no trouble showing an effect, but to be absolutely certain of the mechanism of action has been less easy. Now, a potentially ugly aspect may have been revealed. We hope this does not prove out, since ketamine is a very useful drug, avoiding many of the dangers of inhaled anesthetics.
When ketamine first hit, it wss revolutionary. Anesthesiologists were delighted to have a drug where it was not necessary to worry about breathing for the patient, nor the typical reactions to anesthesia such as low blood pressure, cardiovascular collapse, etc. Then, came a bizarre era where female patients swore they had been sexually assaulted by their surgeons while under ketamine anesthesia. Many of these suits were successful, with millions paid out to silence females who would otherwise have destroyed the careers of vulnerable surgeons. Lucky the malpractice lawyer who could attract such a client. It was a slam dunk case. Ketamine use came to a screeching halt.
Slowly, however, medical circumstances were identified where it was just so clearly to the patient’s advantage NOT to have a general anesthetic, that limited use of ketamine resumed.
During this era of resurgence, it was learned that hallucinations of all sorts, including sexual ones, were very typical of ketamine. Dosage adjustment and continual chaperonage by female nurses protected doctors. Patients were warned that such hallucinations might occur and when they did, they were reassured by testimony from females in attendance that no inappropriate action had occurred.
Ketamine was back on the team. Various delivery methods are now in use, including a gel, which does not work by local effect, but by slow absorption into the blood stream where it exerts a generalized effect on the body. One of the main uses for ketamine gel is for chronic, severe pain.
Now, something even more alarming has turned up. Vitskuts et al found that the dendrites of GABA ergic (pain inhibitory) neurons atrophy when ketamine is applied to those cells in tissue culture. It is always possible that some ameliorating effect is present in the body to avoid the neuronal atrophy, but this will certainly impact the decision to give ketamine. GABA ergic neurons are very important in the body’s own attemtpts to suppress pain.
One of the astounding discoveries of late has been the revelation that the mechanisms of cells include a very specific and important system for causing cell death. This is called the apoptotic cycle. Apoptosis is cell death. Many very elaborate and sophisticated methods exist fot the body to cause certain cell death. Some are automatic and clearly programmed into the body by nature. This appears to be a defense against certain things such as cancer, or as a sacrifice of cells which must die in order that cells bearing invading microbes be killed.
Apoptosis is every bit as sophisticated as any other cell signalling operation. The vast majority of cells which would otherwise turn cancerous are killed before this can occur. Cancer represents a failure of apoptosis. It is thought that the potential for AIDS infection involves a block by the AIDS virus of inflammatory cascades which would otherwise intrude to kill the cell before the virus can spread.
Now with ketamine, we have something peculiar, a sort of semi-apoptosis (axonal atrophy) in the least expected place, the very cells which are designed to fight pain. The meaning of this is uncertain, but what is clear is that clinicians will be taking a very careful look at things before agreeing to long term ketamine usage.
This makes efforts to block pain in other ways more important, primarily the new cell signalling drugs.
Blockers of NF Kappa B, TNF, BDNF, and certain other of the inflammatory chemicals may be one path for pain relief, although cessation of inflammation might make us more vulnerable to cancer or infection.
Another promising route involves cell signalling molecules known as transduction regulators, which could directly shut off the genes which make pain chemicals. Blockage of certain forms of MAPK or ERK, or use of ROS scavenging chemicals, as well as Raf kinase blockage all need to be tried to determine how we can begin to implement cell signalling chemistry into the control of pain.
Also promising are calcium channel 2.2 blockers of the neuronal calcium receptors, as well as agonists of nACHR (ACV1, manufactured by Metabolic Pharmaceuticals), which could become very useful. Ziconotide has not proven a role for iteself in central pain but a slight modification of the molecule may very well make it active centrally. Other cone toxins are also under study.
Articles on these topics are already at this site.
Romero-Sandoval also reports in this months “Anesthesiology” that activation of the Cannabinoid Type II receptor can block glial proliferation after nerve injury, (glial proliferation is behind hypersensitization at the dorsal horn of the cord.)
We anticipate that the near future will see some radical new classes of pain drugs.
Regarding ketamine, remember that Vutskits study was on GABA producing cells. It is curious that he would choose a culture of those cells since they are known to be pain inhibitory. It is not intuitive to think ketamine would be affecting pain inhibitors, since ketamine itself is a pain inhibitor. This raises our curiosity as to the effect of ketamine on glutamate ergic cells. Glutamatergic cells activate NMDA, which is behind the development of central pain. The hypersensitization of the dorsal horn requires NMDA to maintain hypersensitization.
This raises the possibility that if ketamines effect on dendrites also extends to glutamatergic cells, it would qutie possible suppress the sprouts which produce the chemicals which cause glial proliferation and maintain the process of ongoing neuroinflammation. Thus, it is worth watching ketamine. It might possibly prove to have a use in spinal cord injured patients to prevent the development of sprouts, or even to suppress them once they are present. It is now known that sprouts arise not only from the cut end nearest the brain, but also the far end of the neuronal axon which is coming up from the skin or body. Proper testing with ketamine may reveal which of these two groups of sprouts has the most impact on hypersensitization.