Standing in the Gap: Activated Glia and Neuropathic Pain

graphic from Principles & Practice of Palliative Care
 & Supportive Oncology, 3rd Edition

Difficult Pain Syndromes: Bone Pain, Visceral Pain, Neuropathic Pain

The good folks at the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA) recently hosted a discussion about research on the role of activated glia in the context of neuropathic pain. Experts in neuroimmunology, neuropharmacology, neuroimaging, neurophysiology, and pain medicine gathered in early October 2010 for an international workshop.  Thanks, as always, to Jim Broatch for keeping everyone apprised of the goings-on...

Activated Glia: Targets for the Treatment of Neuropathic Pain

Summary of the Workshop Proceedings

The role of activated glia in the neuronal mechanisms of chronic pain was the focus of the workshop, Activated Glia: Targets for the Treatment of Neuropathic Pain, held October 8-9, 2010 and sponsored by the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA). Goals for this workshop included approaching neuropathic pain disorders, complex regional pain syndrome (CRPS), and other chronic pain conditions from a new perspective; bringing together experts in glial cell biology and function, imaging, patient advocacy organizations, clinicians, and industry representatives to challenge current concepts of chronic pain; and, ultimately, developing a knowledge consortium to further the work of this workshop.


Presentations focused on the biology of glia, imaging of activated glia, new ways to attenuate the deleterious actions of glia. Donald Manning, MD, PhD, set the stage with an overview of glial activation and its implications in neuropathic pain disorders. Glia, which until recently were thought to be passive support cells for the neurons, now are considered an important link between the immune and nervous systems in inflammation and trauma. Therapies directed at activated glia hold promise for a new approach to intractable pain. To expedite the goal of developing new diagnostic tools and new therapies for intractable pain, it is important to allow the cross-fertilization of ideas to occur between preclinical and clinical researchers in venues such as this workshop. Dr. Manning cautioned, however, that any new developments in the treatment of chronic pain must also begin and end with the patient. If animal models do not hold up to patients’ experiences, their value in furthering clinical development is questionable.


Joyce DeLeo, PhD, described the evolving model of the synapse, the junction across which a nerve impulse, such as a pain signal, travels from one nerve cell to another nerve cell, muscle, or gland. Glial cells, including microglia, astrocytes, and oligodendrocytes, constitute more than 70% of the total cell population in the brain and spinal cord. Microglia are the macrophages of the brain and are the first responders to central nervous system (CNS) injury, but exactly which signal triggers microglial reactivity is not fully understood. The activating signals may include changes in neuronal transmission, or the appearance of nitric oxide or proinflammatory cytokines.


Glial Activation and Modulation
In neuropathic pain, damage to the peripheral nerves shifts the glia to an activated state within the spinal cord. This occurs as a consequence of signals released by stressed and damaged neurons, including factors that activate the “endogenous danger signal” receptor, toll-like receptor 4 (TLR4). Once activated, the microglia release proinflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF); later, anti-inflammatory cytokines are generated to help dampen the injury response.


Several pharmacologic targets have been proposed that modulate specific glial function and the immune response, including inhibition of glial proliferation and migration, modulation of astrocyte components, and interference with proinflammatory interactions between glial cells and immune cells. Moreover, glial cells block the analgesia induced by morphine, as opioids induce glia to increase the release of IL-1. If we can block the action of glia, we can increase the efficacy of opioids.


Opioids and Chronic Pain
The use of opioids in chronic pain is often limited by hyperalgesia and tolerance. Glia play a key role in the formation and maintenance of morphine tolerance, as chronic morphine treatment has been shown to increase microglial reactivity. Studies by Dr. DeLeo and others in animal models have shown that minocycline, an antibiotic in the tetracycline class, and propentofylline, a glial modulator that decreases mechanical allodynia (an enhanced pain response to touch), can inhibit spinal microglial reactivity and attenuate the development of morphine tolerance. In vitro studies have confirmed that these agents can attenuate microglial migration. Dr. DeLeo and her group hypothesize that morphine enhances microglial reactivity by inducing the release of proinflammatory cytokines and chemokines, as well as through direct signaling between microglia and nociceptive neurons.


Potential Therapies Under Development
Several therapeutic approaches to target the negative consequences of glial activation are currently under investigation. Kirk Johnson, PhD, Chief Scientific Officer at MediciNova, described research on ibudilast, a nonselective phosphodiesterase (PDE) inhibitor that also suppresses glial-cell activation. Ibudilast, also known as MN-166 and AV411, has been available in Japan for 20 years for the treatment of bronchial asthma and poststroke dizziness, and shows promise for its antineuroinflammatory and neuroprotective action, attenuation of activated glia, and inhibition of the molecular targets macrophage migratory inhibitory factor (MIF) and PDE.


Efficacy in animal models as well as positive pharmacologic characteristics has moved ibudilast into human studies. Preclinical studies have shown several actions that can be attributed to attenuation of microglial activation, including attenuation of proinflammatory processes, inhibition of TLR4 signaling, and stimulation of neurotrophic and anti-inflammatory factors. A phase 1b/2a trial in diabetic peripheral neuropathy patients showed efficacy in pain reduction and a reduction in opioid use in those taking ibudilast. In a study of progressive multiple sclerosis (MS), ibudilast showed significant reduction in brain atrophy and reduction in persistent black holes seen in MRI studies.


Dr. Johnson cautioned that the concept of glial modulation, though appealing, has not yet been clinically validated and there are some concerns about the long-term effects of chronic suppression of glial reactivity/activation. However, ibudilast may have the ability to impact several aspects of chronic neuropathic pain or MS, including pain, depression, cognition, and neurodegeneration.


In contrast to the broad-strokes approach to controlling neuroinflammation with ibudilast, Linda Watkins, PhD, posited that by targeting specific receptors, it is possible to provide polypharmacy in a single molecule. According to Dr. Watkins, research in the last 18 years has shown that glia are activated in every clinically relevant model of enhanced pain. Suppressing glial activity and its proinflammatory products suppresses the pain and returns the patient to normal. This concept extends beyond pain—the same uprise of proinflammatory cytokines that begets pain may also be a risk factor for abuse of opioids and other pharmacologic agents.


Strategies for controlling glial proinflammatory responses include targeting specific receptors that are already very well understood: adenosine 2A, interleukin-10 (IL-10), and TLR-4. ATL313 (Adenosine Therapeutics/PGxHealth) is an adenosine 2A agonist (A2A) that suppresses proinflammatory cytokines while enhancing the anti-inflammatory cytokine IL-10. A single injection given intrathecally has been shown to reverse neuropathic pain for 4 to 6 weeks in animal models of chronic constriction nerve injury, peripheral neuropathy, spinal cord injury, and central neuropathic pain.


XT101 (Xalud Therapeutics) is an IL-10 nonviral gene therapy tested in models of peripheral and chemotherapy-induced pain as well as central damage similar to that seen in MS. Following injection, this treatment is microparticle-delivered and slowly degrades into natural products of metabolism, releasing gene therapy for IL-10. A single intrathecal injection of XT101 inhibits the proinflammatory cytokines that are causing pain and paralysis, in turn reversing this pain and paralysis.


Orally deliverable TLR4 antagonists, such as naloxone, also offer a targeted approach to treating neuropathic pain and increasing the efficacy of opiates, such as morphine. Studies have shown that morphine and (+)naloxone administered together produce an increase in analgesia, and repeated dosing prevents the dependence and withdrawal effects that commonly occur with morphine. These effects also extend to the side effect of morphine; studies have shown that the TLR4 antagonist action of (+)naloxone blocks the dose-limiting effects of constipation and respiratory depression...

The entire proceeds of the workshop are summarized HERE.

A few reading recommendations if, like me, you're not quite up to speed on glial research and its potential applications to neuropathic pain syndromes like CRPS:

Nature Reviews Drug Discovery 2, 973-985 (December 2003)
GLIA: A novel drug discovery target for clinical pain
Linda R. Watkins & Steven F. Maier
available as pdf file from Univ. of Colorado
 
The Journal of Pharmacology and Experimental Therapeutics, vol. 297 no. 3 1210-1217 (June 1, 2001) 

Propentofylline, a Glial Modulating Agent, Exhibits Antiallodynic Properties in a Rat Model of Neuropathic Pain

S. M. Sweitzer, P. Schubert and J. A. DeLeo


Neuroimmunologic approaches to the understanding and potential treatment of CRPS
Donald C. Manning, MD, PhD
RSDSA Education Section  [2005?]

Guilt's Stain

Mark Madoff was remembered fondly by former classmates Monday...


Doreen Hebron said Madoff was 'very popular,' dressed well and had a good attitude.

Bernard Madoff's sons, according to their family's legal representatives, were whistleblowers and not co-conspirators in the Ponzi scheme that defrauded investors of 65 billion dollars, and for which, in large part, their father is serving a hefty prison sentence of 150 years.

The story goes that immediately upon being informed by dear old Dad that he had lost the life savings of thousands of investors, Mark and Andrew Madoff contacted the FBI, and Bernard Madoff was arrested the next day, December 11, 2008, on a single count of securities fraud.

That was an amazingly swift reaction.

(I'm just sayin'.)

As the 2-year anniversary approached, there were apparently a good many legal issues that needed attention -- most having to do with the filing deadline for lawsuits seeking recovery of lost assets -- and the attention of the press and general public was again at a peak.

Mark Madoff hung himself this past Saturday, December 11, using a dog leash. He was married and had four children. His father's lawyer states that Bernard Madoff won't seek to attend the funeral out of "consideration" for his son's immediate family.

Despite the fact that investigators still cannot fathom how Madoff pulled off his securities fraud or how he laundered such large amounts of money for so long without the assistance of others, particularly of his brother or sons, all of whom worked at Madoff Investment Securities, authorities now deny that any new criminal charges were imminent.

In his article about the suicide, AP journalist Larry Neumeister interviewed another of Mark Madoff's childhood friends, Lev Seltzer:

[R]eached by telephone in Israel, where he now lives, [Seltzer] recalled working with Madoff on a sixth-grade assignment at a Long Island school to create a fake television commercial. He said the ad mocked a long-running Life cereal commercial that featured a boy named Mikey who hated everything else but liked the cereal.


"Instead of Mikey, we had Marky," Seltzer said.

meh

see more Lolcats and funny pictures

"ai concurz." *




*I completely forgot, in the previous post, to extol the virtues of LOLcats and Funny Pictures when fending off The Crud.

So:

Extol!
Extol!

Pharmacies, Penguins, and Richard Russo (to the tune of "plop, plop, fizz, fizz...")

O, to be a screaming ninny, O!  a screaming ninny, O, to be!

This is what I have been reduced to, after spending the day in such worthwhile endeavors as establishing The Manor as a No Call Zone for the American Heart Association.  You'd think that those ne'er-do-wells would not waste time by canvassing Tête de Hergé (très décédé, d'ailleurs) territory, as there is no heart disease here.

Let's see, what other important tasks has this hypoxic and huffing hunk o'humanity been up to?  Mostly trying to have all my medications that are currently being mangled by local retail pharmacies transferred to Medco's mail service, where they can mangle them, in turn, but for an extended, 3-month period.  It seemed an easy enough thing to do when I thought of it -- and I thought of it precisely when Fred announced his intention to murder a local retail pharmacy employee.  We have been playing "who called whom?" and "who has the prescription but not the medication?" since December 8.  This morning, we switched to a new game called "who has the prescription filled... CORRECTLY?" 

What Fred wants to know from his growing list of Pharmacy Friends, it seems, is:  Why the hell do I have to be present in person for you to confess your pharmaceutical failures and inadequacies?  Isn't that exactly why you have our phone number and email addresses?  Hmmm?  And then, as I said, he dreams of the quick garrote.  O, that boy and his piano wire!

When he finally appeared with my drug in hand, five days after it was prescribed and probably ten days since it was first needed, Fred was triumphant.  But since he, like I, still struggles to breathe after being ill with The Crud, his victory was celebrated by a weak, trembling fist in the air, followed by total collapse.

Would you believe... they gave me extra pills?!  It's a trap, I know it must be a trap.  They are waiting by the phone, ready to impugn my honesty as I have repeatedly impugned theirs (before understanding that it was competency in question, not character...).

I pity my Go-To DoctorGuy.  He is part of the inimitable MDVIP organization, a medical delivery system designed to privilege prevention of illness and maintenance of health.  How he ended up with me as a client is something he must ponder at least several times a week.

 HackHackHack:::*ack*-*ack*-*ack*

We email regularly.  I actually saw him for a fairly extensive visit last Monday.  Two days later, of course, I was deathly ill.  That's the rhythm of our relationship:  I see him; He tries to kill me, I survive but launch a defensive email campaign.

HackHackHack:::*ack*-*ack*-*ack*

Somewhere in there, I started amusing myself with animal videos on YouTube.  God bless YouTube.  Really, I mean it. 

Well, God bless Richard Russo, also.
Specifically, God bless his novel Straight Man.

If you are, or if you know, a frustrated academic, Straight Man will bring you as close to hilarity as anything can at this point in the university calendar.  By page 19, I had logged two episodes of uncontrollable mirth, bed-shaking mirth.  Indeed, pant-wetting mirth, were I the type, which I'm not.

I'm NOT, I said.

I did, however, end up with the entire domestic staff, Fred, The Castafiore (distressingly déshabillée), and all three extant Manor Felines trying to squeeze through our bedroom door like an implausible number of overfed circus employees leaving an imploded clown car.  I sounded, according to them, as if I were in distress.  With the advent of bronchial pneumonia, my harsh laughter apparently approximated the bark of a California sea lion. 

I hate those moments.  You so want to have the people (and felines) peering at you on your side, you know?  They look so distraught, you think.  If only they, too, could experience the joy of this rambunctious prose!  That's when you hatch the worst idea conceivable:  I will read them a passage!  Then we will all be {giggle::giggle} on the same page!

I chose to share the bit about William Henry Devereaux Jr's dog and his propensity for head-butting people in the groin as an expression of pure joy.  It was what was on the page.  I thought it could stand the exposure. 

Yeah, so that was about the time when animal videos from YouTube gained preeminence over any type of reading... at the suggestion, precisely, of the domestic staff, Fred, The Castafiore, and all three extant Manor Felines.  Fred allows me a half hour of Richard Russo at bedtime, on condition that I not wake the Cistercians down the road with my verbal shenanigans.  It's a glorious 30 minutes.

There is something reassuring about what we, as a species, tend to find funny.  Particularly (and precisely), I am reassured by what we find hilarious in the exploits of the animals with whom we share the planet. 

One of Fred's Militant Existential Feminist Lesbians condescended that these poor animals were exploited by our raging egocentrism as humans.  "Nuh-uh," I countered.  "It only makes sense that we interpret the actions of another species through the actions of our own, because, heck, we really are the center, object, and norm of all experience!  C'mon cutie, give us a smile!"

HackHackHack:::*ack*-*ack*-*ack*

Take penguins, for instance.  (Any reader out there who periodically shouts "Or she!" gets brownie points)
I resemble these birds and the many human feelings they evoke.

All statements and claims of humor and/or interspecies resemblance will be subject to reevaluation upon our return to baseline ill health.

Oh, that bothersome bot!

graphic by creativeNERDS

Good evening, Friends of The Manor, Minions of Marlinspike!  

I am doing my darnedest to breathe. Fred has passed along his illness, and as is my wont, I am taking it to new heights. As in flirting with, if not in the actual throes of, pneumonia.

Lacking that, I have at least achieved a striking bronchitis.  Marmy Fluffy Butt and I have been performing *ack*-*ack* duets, our pink noses in air.
This self-limiting respiratory virus will serve as my latest excuse, the raison du jour for my absence from the virtual realm.

In such a condition, with its predictable accompanying mood, I decided to check email before gathering with Fred and The Castafiore to sing, all in a jumble, our nightly rendition (in the round) of "plop, plop, fizz, fizz... oh, what a relief it is..."  Marmy scats her *acks* as a sort of background vocal.

Unfortunately, I got pissed off by the very first piece of electronic mail. It was my MedWorm feed report for the term CRPS -- all the news on that funkylpated addlemucked crap of a disease that is fit to spread around like fresh, pungent manure.

The vast majority of the time, the Medworm CRPS feed turns up research just published within the confines of academia. It is remarkable when what pops up derives more from the personal, as in a blog.

And it is regrettable when the singularly personal blog merits reportage for an offhanded and uninformed remark. That's when you remember that it is not so much intelligence that is at work as it is the intestinal contents of a bot.  *

Anyway, you know me (and, again, I'm sorry about that!), I have to read it all. So I dutifully click on the link provided, tap my heels and toes together like a spastic Nazi, and arrive at:
(B)e(LO)n(G), OT -- the blog that the bot bit.

Under the title, blogger Karen appends this description:

I recently made the transition from occupational therapy student to occupational therapy PRACTITIONER. That's right, I am an occupational therapist now, dum dum dum. This blog is having a hard time following me in the transition so bear with me!

Reading this, I am already thinking that turning the computer on at all was a mistake.  My phlegm confirms it, but I figure I'm halfway home, maybe this neophyte has an insight that'll take me to school...

I read on -- it doesn't take long -- and discover that the following passage is what has so commended this woman's blog to the CRPS Medworm bot:

We had a lady come in today, 3 months post carpal tunnel surgery, who is still having a LOT of pain in her L hand and is babying it (her non-dominant hand). She doesn't move it much because it hurts. Her scar is healing well although hypersensitive, and her hand isn't swollen or red, so it doesn't seem like its CRPS/RSD, but something along those lines. To me CRPS/RSD seems like it is directly correlated to the level of depression/anxiety a person has. The more depression/anxiety a person has, the more likely they end up with CRPS [my anecdotal experience]. I was trying to think of ways to handle her pain and I wish I had more of my OT resources here. Oh well.

The unknown but now fully vested OT Julie has managed to offend me which is, of course, ridiculous, as her blog is just another blog, ho hum.  But this blog met the bot and therefore pretends (in the French sense of prétendre, and no, I am not being snobbish, I really cannot find the equal phrase in English), therefore lays claim to a sort of research nobility which its actual bastardized nature cannot support.

Do I need to chase down and reiterate... Do I need to be the counterweight, countering voice?  Do I have to care?

You ought to be able to deduce the answer from the fact that I am writing this while wheezing and bulbous-nosed, head aching and face raw.  Yes, damn it, I have to care.  I did a little reading of Karen's blog and she's definitely talented, definitely dedicated... but she blew it with this broadened (haphazard and unsought) publication.  Because for her every mention of prostheses, I've got mine (both the mentions and the prostheses themselves, eh wot?!) and for her doomed reference to anecdotal experience... well, en garde, chica, en garde! 

No, in all seriousness, it sound like Karen is dedicated and immersed in helping people obtain and acclimate to prosthetic limbs and the various sundries that go with disability.  And yes, I am sure that is an understatement of all that must be involved.

As long as the truth is going to be contained in winked-out citations of [not-much] experience, people with diseases like CRPS will remain disadvantaged by health care professionals who prefer their truths watered down.  It doesn't matter what you know, wink::wink, it only matters what you KNOW, if you get my heavy handed drift...

In sum, as I need to go evacuate my lungs, please, young professional, newly minted OT, bone up a bit, do some reading -- but just know that how you choose to deal with the psychosocial factors associated with any disease process... well, it shows, and not just in your blogging, and it can serve as a sort of casual litmus test for your patients.

It's funny, Karen, but as I reach the end of this ridiculous post, this rant, I find I kind of like you.  I took some time out to deal with the gastrointestinal sequelae of antibiotic therapy (yes, folks, I am now on the SECOND course of abx, the osteomyelitis experiment continues midst a budding pneumonia!) and to reflect on my personal dealings with occupational therapists, my own anecdotal evidence, of sorts.
 
It is not for nothing that part of the introductory packet of information sent out by Reflex Sympathetic Dystrophy Syndrome Association (RSDSA.org) is a a fairly dense article written in 2003 by E. Daniela Hord, MD and Anne Louise Oaklander, MD, PhD -- Complex Regional Pain Syndrome:  A Review of Evidence-supported Treatment Options.

 

Because of the discrepancy between the subjective complaints
of pain of patients with CRPS and the limited
objective evidence of underlying pathology, some authors
in the past have suggested that psychiatric factors are a
major cause of CRPS. Although many patients with longterm
CRPS battle depression and anxiety, these conditions
usually are a consequence, rather than a cause, of their pain
[18]. It is clear that experiencing significant ongoing pain is
a major adverse life event that will challenge the coping
skills of even the most well-adjusted patient. Clinicians
should be aware of the high rate of secondary psychiatric
problems in CRPS and refer patients for counseling and
medical treatment as needed.

Bottom line!  (And good luck in what I know will be an awesome career helping people, OT Karen!)

*****     *****     *****     *****     *****     *****     *****

*  What is a bot?  Well, first of all, it is not a botfly, fascinating as those creatures can be.  If you are into botflies, you might enjoy this "compilation," much treasured over at Pop That Zit.

Sometimes a bot (or zombie) refers to a type of malware.

But what I am referencing are --

Internet bots, also known as web robots, WWW robots or simply bots... software applications that run automated tasks over the Internet. Typically, bots perform tasks that are both simple and structurally repetitive, at a much higher rate than would be possible for a human alone. The largest use of bots is in web spidering, in which an automated script fetches, analyzes and files information from web servers at many times the speed of a human.

Specifically, I'm on about RSS Bots -- "a web-crawling robot [that] collects RSS, RDF, and ATOM feeds from the internet to build a searchable index..."