“These results will be clinically useful, because we provide a new opportunity for mechanism-based treatment for chronic, widespread muscle pain resulting from recurrent acid insults possibly associated with symptoms of fibromyalgia and myofascial pain syndrome.” Chen et. al.
How the transition from acute to chronic pain occurs is the million dollar question in fibromyalgia
The question what causes acute pain or fatigue to turn into chronic pain or fatigue is on the minds of researchers everywhere. Some are finding clues in the central nervous system.
Lloyd found that a genetic predisposition to increased immune activation in concert with high symptom levels plays a role in the transition from short-term fatigue to long term. Now, we continue our PEM series with a study seeking to uncover the molecular causes of the transition from short-term to chronic pain in the muscles. They used a mouse model of fibromyalgia to do it.
Not Pain By Any Other Name…
Like fatigue, pain is a multidimensional concept. In a recent blog we saw that the fatigue found in multiple sclerosis is fundamentally different from the fatigue produced in chronic fatigue syndrome, and pain is no different.
Studies indicate that hypersensitive pain states produced by inflammation, chemotherapy, and muscle vibration are relayed through certain types of pain receptors (IB+ receptors) and involve a switch in certain intracellular signaling pathways (from PKA to PKC). The hypersensitive pain conditions that are associated with exertion and muscle activity found in disorders such as fibromyalgia and chronic fatigue syndrome may, however, involve different molecular pain pathways.
Giving Mice Fibromyalgia
Laboratory animals have it tough, but they play an essential role in research.
Animal models have played a key role in understanding how this occurs. It turns out that it’s not that hard to produce an FM-like state in rodents. You simply inject them twice over five days with an acidic saline solution in a muscle. Not only do they develop prolonged pain, but the pain is now widespread and is accompanied by the same kind of sympathetic nervous system activation found in chronic fatigue syndrome and fibromyalgia.
Inflammation Takes a Back Seat
With studies unable to find evidence of inflammation in the muscles in people with FM, researchers have tended to look elsewhere – in particular, in the central nervous system. Inflammation, however, may not be necessary. Studies suggest that problems with the sensory nerves, particularly the ion channels found in those nerves, could be enough.
Muscle Metabolism to the Fore
The ion channels that detect increases in proton levels that occur during tissue acidosis appear to be involved. As proton (H+) levels rise as muscles get fatigued, these ion channels tell the neurons to relay pain signals to the nervous system. If this happens often enough, central sensitization – a hypersensitive response to pain at the level of the spinal cord and central nervous system – can occur.
Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia. Wei-Nan Chen, Cheng-Han Lee, Shing-Hong Lin, Chia-Wen Wong, Wei-Hsin Sun, John N Wood and Chih-Cheng Chen. Molecular Pain 2014, 10:40 http://www.molecularpain.com/content/10/1/40
Increased activity in specific ion channels causes long term pain in mice
In this mouse study, researchers attempted to determine how metabolites produced by the muscle during exertion produce long-standing muscle pain in two ways. First they developed mice with different combinations of ion channels, then injected them with an acidic saline solution that mimicked a muscle metabolite produced during exercise. After observing which mice the acid solution sent into pain for long periods of time, they were able to determine how that pain is produced molecularly.
They found that two ion channels found on muscle pain receptors; the “acid-sensing ion channel 8” (ASIC3) and “transient receptor cation channel 6” (TRPV1) needed to be activated in order to produce increased pain. ASICs are cationic channels found on neurons that are activated by extracellular protons.
Producing Long-lasting Pain
Increased activation of these channels in conjunction with increased current in NaV1.8 voltage-gated sodium channels produced longstanding pain. Finding that mice without NaV1.8 sodium channels experience short term pain sensitization (2 to 4 days) but never the long-term pain type of pain (14-19 days) found in FM and ME/CFS, it became clear that the sensory neurons containing these ion channels are responsible for long-term states of muscle pain [presumably in response to exercise].
Nav1.8 ion channels are found the dorsal root ganglion [that we know herpesviruses like to hang out in] and in small unmyelinated sensory neurons called C-fibers [that may be being affected by small fiber neuropathy in fibromyalgia]. Nav1.8 ion channels are considered to be key targets for new drugs to treat increased pain sensitivity and allodynia.
Treatment Implications
Although ASIC3 plays an important role in priming and triggering a state of chronic pain sensitization, it does not appear to be involved in maintaining it. This suggests that ASIC3 antagonists such as APETx2 could be helpful in preventing sensitization before it happens, but not after a person is in a chronic pain state.
Drugs that block the activity of specific ion channels may be able to stop long term pain
Increased activation of the NaV1.8 sodium channels, on the other hand, appear to play a key role in maintaining a chronic state of acid-induced muscle pain. These voltage-gated ion channels determine how excitable the peripheral nerves are.
This suggests that sodium channel blockers could that block NaV1.8 sodium channels could stop the long term muscle pain seen after exertion in some disorders. The authors noted that sodium channel blockers such as mexiletine or lamotrigine are a possibility, but they focused on a NaV1.8-selective antagonist (A-803467) that blocks NaV1.8 sodium channels from telling the sensory nerves to ramp up pain signals.
They believe this type of selective sodium channel blocker might be a good choice to treat chronic muscle pain that’s associated with recurrent ischemic insults; i.e. pain associated with the kind of low blood flow states that studies indicate may be found in ME/CFS and possibly FM.
A sodium channel blocker, A-803467, was introduced by Abbot laboratories in 2007 as a neuropathic and inflammatory pain blocker. Several aspects of A-803467 suggest it might helpful in FM and/or ME/CFS. A-803467 reduces the autonomic nervous system’s “pressor response” to lactic acid.
Amytriptyline is an antidepressant widely used to combat migraine and pain. A recent study suggests that its effectiveness may be due to its ability to block NaV1.8 sodium channels.
Conclusions
Implications for Chronic Fatigue Syndrome and Fibromyalgia
The authors do not explicitly link their findings to the post-exertional malaise problems found in fibromyalgia and chronic fatigue syndrome, but they’re clearly focused on how the development of very long duration muscle pain associated with acid induction (i.e., exercise) occurs.
The results from the Light ME/CFS studies line up with these results
The lack of inflammation in the muscles of FM patients has led many researchers to dismiss the muscles and focus on the central nervous system. This research indicates, however, that inflammation is not necessary to produce chronic muscle pain.
Long-term muscle pain can be produced by problems with acid-sensing ion channels found on the neurons in the muscles.
This study suggests (if I have it right ) that long-lasting muscle pain can be produced and maintained by the same muscle by-products (protons) that Newton’s research suggests are being produced in high quantities in ME/CFS patients after exercise.
It indicates that the two ion channels implicated in post-exertional malaise in ME/CFS (ASIC3 and TRPV1) prime the system for the long-term pain, and that sodium channel upregulation ( NaV1.8) plays a critical role in producing it.
That presents the possibility that blocking the activity of these sodium channels could resolve it.
Studies by the Lights Agree
The Lights are trying to understand how both the production of fatigue and pain occurs after mild exercise in ME/CFS. Fatigue appears to be produced first and then pain is produced as PEM worsens. Instead of looking at mice, though, they’re examining the patient’s blood after exercise to determine gene expression of the receptors associated with these ion channels.
ASIC3 was one of the several receptors found to be upregulated in ME/CFS patients with and without fibromyalgia after exercise in the Lights’ gene expression studies. This upregulation was highly associated with increased physical and mental fatigue and pain. Most recently TRPVI activation after exercise helped to differentiate the postexertional malaise found in ME/CFS from the fatigue found in multiple sclerosis. ASIC expression was significantly greater in ME/CFS patients with FM.
How do they conclude a response for those of us with both?
Both FM and ME/CFS? The Lights, have I believe, found mostly similar findings in both people with ME/CFS and people with ME/CFS and FM. I would guess these findings – if the animal studies do apply to FM – will apply to ME/CFS as well.
In the study how did they ask the mice what pain they were feeling to come to the conclusions? As far as I know you can’t observe pain in another?
I’ll have to check but in general I believe they observe behaviors associated with pain. For instance, they could do a pressure test – if the animal acts as if its in pain at very low pressures that would imply it’s become hypersensitive to pain.
Cort, here’s where I wish I paid a wee bit more attention to physiology. I think lots of us w/ CFS-y issues have the same general feeling of painful, jittery, muscles and the wired and tired that goes w/ all this. Same feeling I used to get after a good workout in the old days, acidosis, which surprise, would turn into a good feeling. Then I’d sleep. Imagine. I’ve searched your site for a loosely parallel gene to sodium channeling, CFTR which encodes mostly around chloride transport, and find no mention. CFTR is known to have about 1800 different mutations in Northern European types, we have a clear handle on maybe 100 of those. I’ve got something going on here; waiting on my doctors to suss it out. And waiting.
Sodium is highly reactive, so for the most part we get it into our bodies in conjunction w/ chloride, split it up and send them to their jobs, which are myriad and complicated. Want to fire a nerve, sodium and potassium amongst others. (I’ve also got an injury to what looks like a dorsal root ganglion in my back that very much looks like NaV1.8 isolated. Is this the ill defined ‘autoimmune’ response in injured DRG’s? Remember your Puffer fish with NaV1.8? I did have some success w/ Lerner’s antiviral treatment generally (and w/ this root), as do many, so something complicated is going on even if we can’t precisely pin it down, yet.)
Want a proper viscous environment to develop complicated organs or properly fight infections,… proper chloride concentrations. Etc. You know how complicated the body and genetics really is Cort, and how we recycle genes w/in our own bodies, turn them on, turn them off, adjust them through time, they even get manipulated across species. Other somewhat uncharted space is which other genes these ‘talk’ to, control (CFTR talks to Huntington’s I believe, amongst many others.). I ask the question, can an improperly formed or methylated gene influence another gene, improperly? Systemically? Or influence through dynamic chemistry happening in the human body, kidney function being right up there I suspect. Got to thank Garth Nicholson et al. for opening up our understanding to ‘gating’, of which this very interesting P2x7 gene is properly a part of.
I urge you to dog this cellular ‘gating’ and the genetic controls behind it all for awhile. It holds the potential to have a lot of power of explanation for us.
Thanks Noel. Boy is this a complex subject and I hope I got it (mostly) right, but I agree it’s very interesting and I hope to keep up on it. Who knows what the future will tell?
Great stuff, Cort. You are describing trigger points here. No inflammation or tissue damage, just increased levels of protons and activated ion channels sending pain messages direct to the dorsal horn.
Interesting Tricia – thanks again for the insights…:)
I just want to express my appreciation for this very informative blog. I’ve received more insight into FM; ME/CFS than I have from any of my doctors including my ME specialist. I do keep up with the medical journals but your blog is concise while covering myriad theories and studies. Thank you.
Thanks Kathryn!
How about dumbing it down for those of us who didn’t study chemistry and human physiology 40+ years ago in school.
Believe me it took hours just getting it to be as understandable as it is. I should do a “The Jist” section though to get the central points across.