The future of medicine seems to be headed toward an understanding of channels and receptors. Nowhere is this more important than in central pain.
Pain has now acquired strange bedfellows. Virtually any disease associated with inflammation is now adding to our knowledge of neuroinflammation, which with MS, Stroke, or SCI, is called central pain.
Riluzole is used in amyotrophic lateral sclerosis, or Lou Gehrig’s Disease. It reportedly delays necessity for ventilator assisted breathing by TWO MONTHS! Is this a miracle drug? It cannot rightly be said to be a cure. It now is being mentioned for neuropathic pain because it blocks high voltage calcium channels and NMDA/glutamate receptors and sodium channels.
According to Wikipedia, “Riluzole preferentially blocks TTX-S sodium channels, which are associated with damaged neurons. This reduces influx of calcium ions and indirectly prevents stimulation of glutamate receptors. Together with direct glutamate receptor blockade, the effect of the neurotransmitter glutamate on motor neurons is greatly reduced.”
TTXs means “tetrodotoxin sensitive”–tetrodoxin comes from the pufferfish and blocks the fast variety of voltage gated sodium ion channels; slow sodium channels are TTX resistant. TTX-S sodium channels are also where conotoxins and saxotoxins bind, the site being right at the opening of the channel pore on the membrane surface of the cell.
And so, the story of riluzole in neuropathic pain is about to be written, but first we must digress about stress and stress hormones.
The story has a complex plot. We have until recently assumed that the “butler did it”, but now the clues are heading the other way. Nowhere is this more obvious than in the area of anti-inflammatory hormones related to cortisol. Glucocorticoids cause a change in sugar and insulin handling and they also help deal with stress. Like all good chemicals, steroids require a receptor, almost always located on the cell membrane to initiate an action. The cell membrane is where it is happening. It is true that the proteins which wind up on the cell surface are made by DNA in the nucleus but the rubber hits the road on the cell membrane, or should we say in the channels which penetrate that membrane and allow what is OUTSIDE to influence what is INSIDE.
It used to be simple. Pain causes a lot of stress. The body released glucocorticoids to help deal with stress and “relieve” inflammation. It was all so logical and no one but a fool would have questioned it. The problem is that this idea is not working out well in the lab right now, not well at all. The surveys however, are still intact.
The conundrum is illustrated by such articles as the one by Wang, et al from Mass. General (associated with Harvard), writing in Pain. 2007 Jan 25; “Central glucocorticoid receptors regulate the upregulation of spinal cannabinoid-1 receptors after peripheral nerve injury in rats”. The cannabinoid 1 receptor is essentially our old friend the TRPV-1 receptor, which is the main conduit for the flow of pain causing ion currents in chronic pain. For all practical purposes TRPV1 and Cannabinoid 1 may be thought of as equivalent for purposes of discussing ion flows in central pain.
Now, as the title revesls, there is something wrong. Wang et al are saying that this stress hormone, which is supposed to help us past stress, is itself upregulating the expression of cannabinoid receptors. This is a square peg in a round hole. CR1 sure enough is a place where, if blocked, relief from pain may be had. However, why would we want to upregulate what we are then going to have to downregulate or block if we wnat to get rid of pain. Apparently, we did not have things right in our understanding.
Peripheral nerve injury models show upregulated glucocorticoid receptors (GR) AND upregulated cannabinoid receptors (CB1R) in the dorsal horn of the cord (the sensory area). However, we have now run into “which comes first, the chicken or the egg” problems. It was always assumed that glucocorticoid transporters and receptors would be up in pain SECONDARY to the stress involved. However, spinal GRs have been shown to upregulate CB1R’s????? Shouldn’t this be in reverse. It should, unless we have been wrong about steroids and the “benefits” they confer in stressful times. However, there was no denying Wang’s findings after this was backchecked with inhibitors of GRs which stopped the upregulation of CB1Rs. The agents used for this verification were both GR antagonist RU38486 and a GR antisense oligonucleotide (antisense oligonucleotides are counterfeits, or modified molecules, which gum up the works and thereby block the action of the original, properly sequenced chemical).
As the authors state, “Furthermore, the upregulation of spinal CB1R after nerve injury was prevented in adrenalectomized [the adrenals make glucocorticoids] rats, which was at least partially restored with the intrathecal administration of an exogenous GR agonist dexamethasone…Since the development of neuropathic pain behaviors in CCI [PNI neuropathic pain model] rats was attenuated by either RU38486 or a GR antisense oligonucleotide, these results suggest that CB1R is a downstream target for spinal GR actions contributory to the mechanisms of neuropathic pain. “Downstream” would mean that stress hormones are encouraging the production of cannabinoid receptors.
This is about as backwards as you can get, but unfortunately, for those of us who assumed glucocorticoids were our friends in times of stress, their upregulation of CB1R is true enough. Theory must be revised. It would be nice if rats could talk. Humans with CP have always let us know that stress made central pain very difficult. Nearly all of the subjects responding to the survey have indicated that their central pain is much harder to deal with during times of stress, when distinguishing distractions from stress. When all else fails, fall back on the surveys. (Note: There is already a prior article on adrenal medulla, enkephalins, and stress related pain at this site)
Let’s face it. For those of us with CHRONIC pain, stress is just not our friend. Distraction may help, but stress does not, and neither do its hormones. Antiinflammatory stress hormones do not appear to help neuroinflammation. We are back to the NIH statement that since there is no satisfactory treatment for central pain, the best approach is to reduce stress in life to the greatest degree possible.
And so, we must pay close attention to behavior at the synapse, which is related to steroid function. The obvious place to look is at glutamate, main pain exciter of the CNS, which requires calcium, which activates NMDA, which leads to chronic pain. Sung et al, also from Massachusetts General Hospital, writing in J Neurosci. 2003 Apr 1;23(7):2899-910 describes the transporter of glutamate.
It does get complex. Things need not only a receptor, but a transporter to take them TO the receptor, as well. Remember now, Sung is speaking about the TRANSPORTER of glutamate.
The article is entitled, “Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats.”We feel more or less like rats so we are not going to get picky about the species here.
Sung writes, “The central glutamatergic system has been implicated in the pathogenesis of neuropathic pain, and a highly active central glutamate transporter (GT) system regulates the uptake of endogenous glutamate.” (This is a repetition of information from prior articles here and you should already know it.)
Then, the MGH researchers inform us, “Here we demonstrate that both the expression and uptake activity of spinal GTs changed after chronic constriction nerve injury (CCI) and contributed to neuropathic pain behaviors.. in rats. Intrathecal administration of the tyrosine kinase receptor inhibitor K252a and the mitogen-activated protein kinase inhibitor PD98059… reduced and nearly abolished the initial GT upregulation…Prevention of the CCI-induced GT upregulation by PD98059 resulted in exacerbated thermal hyperalgesia and mechanical allodynia reversible by the noncompetitive NMDA receptor antagonist MK-801, indicating that the initial GT upregulation hampered the development of neuropathic pain behaviors.”
Here we go again. The world is upside down. Yet, we must accept it.
Glutamate has a bad reputation in pain, the very worst, in fact. Yet, here is Sung telling us that INHIBTION of upregulation of Glutamate Transporter (ie. holding down the glutamate) leads to thermal hyperalgesia and mechanical allodynia!!!
How is a sslf respecting pain scientist supposed to explain that the big bad enemy, glutamate, needs to be allowed a little room to move around at first, or else neuropathic pain will result.
In a prior article here on these matters, we speculated that researchers had failed to do sufficient timing analysis. What is bad at one time may be good at another and vice versa. These articles do not require that we throw everything we have learned into the trash bin. They do require that we NOT regard the synapse as static. There is an evolutionary sequence in the development of central pain and it is high time that we understood it. If we fail to do this, we may wind up giving the wrong medicine at the wrong time.
Finally, there was the coup de gras to everything held to be true to this point in time:
“Moreover, CCI (ie. nerve injury in rats) significantly reduced glutamate uptake activity of spinal GTs when examined on postoperative day 5, which was prevented by riluzole (a positive GT activity regulator) given intrathecally twice a day for postoperative days 1-4. Consistently, riluzole attenuated and gradually reversed neuropathic pain behaviors when the 4 d riluzole treatment was given for postoperative days 1-4 and 5-8, respectively. These results indicate that changes in the expression and glutamate uptake activity of spinal GTs may play a critical role in both the induction and maintenance of neuropathic pain after nerve injury via the regulation of regional glutamate homeostasis, a new mechanism relevant to the pathogenesis of neuropathic pain.”
It is always possible of course that some very early response to nerve injury knocks down glutamate, only to be overriden later, but the sequence of these events is simply not known.
Yet, a drug which blocks the glutamate sequence apparently HELPS neuropathic pain. It would be hard to overstate how contradictory the whole thing is, unless we are simply looking at timing problems, changes in chemical behavior over time.
A drug which treats ALS may be attempted in neuropathic pain!!! It appears that inflammation is certainly making the rounds. From the above description of riluzole, you know that it is already on the market and available. It would not be surprising to see some clinician attempt to use this for neuropathic pain in humans. We can only hope he/she gets the timing right.
In the meantime, pardon us while we humbly retreat for a moment to consider what it all means. At least we don’t have to take back our statement on how important receptors and channels are. We just have to admit that we don’t yet understand what glutamate is up to.
Isn’t science great! The only cure for science we cannot make sense of is more science. May the day be hastened. And as always, AVOID STRESS.