Pierre, thanks for sharing your experience. I will offer some thoughts:
Pierre said:
The headaches are caused by an herniated disk in the neck which inflames adjacent tissues, which in turn constrict the blood vessels connected to the brain.
That's why Naproxen and its anti-inflammatory properties is effective. It decrease the inflammation for a few days, which relieves the blood vessels and stops the headache. Once the Naproxen is gone, the inflammation comes back (build-up phase) and so does the subsequent headache. I think that is the reason for the one week or so headache cycle.
I think your issue may be related to Nitric Oxide.
Naproxen is a COX inhibitor, which as you know inhibits to formation of inflammatory prostaglandins from polyunsaturated fatty acids by the COX enzymes. Prostaglandins have a (not so well understood) relationship with Nitric Oxide, in that both can increase the production of one another in certain circumstances. (note: this is context dependent, because NO can also inactivate COX in other circumstances)
So prostaglandin formation can increase nitric oxide, and nitric oxide can also increase prostaglandin formation.
The role of nitric oxide in prostaglandin biology; update
NO and prostaglandin pathways share numerous similarities and the two molecules can be produced simultaneously in the same tissues, as described in a number of models of inflammation such as endotoxin induced septic shock, carrageenan-induced pouch or paw inflammation (Fig. 2) [117].
Hence numerous studies have explored the potential crosstalk between NO and prostaglandin pathways and increasing evidence supports this idea. However, the detailed mechanisms by which NO regulates prostaglandin production or vice versa is still controversial, partly because the interaction between these two pathways occurs at multiple levels along with the complexity of NO redox chemistry [117; 118]. An initial report detailing the cross talk between NO and prostaglandin was made by Needleman’s group
showing that NO can activate cyclooxygenase [119]. In this study, NOS and COX2 activity were induced in a macrophage cell line, RAW264.7,
treated with LPS to produce both NO and prostaglandin.
The production of both was attenuated by NOS inhibitors. As the NOS inhibitors used in this study do not have any NSAID characteristics, the inhibition of prostaglandin production was likely due to the decrease in NO production and not as a direct effect on COX2 [119]. This study was further corroborated by in vitro studies showing that even
exogenous NO gas or chemical donors can induce COX1 activity [120; 121]. Moreover, NO-mediated activation of COX does not seem to be limited to its enzyme activity.
Lie et al showed that NO can increase COX2 mRNA levels via the β-catenin/TCF pathway leading to activation of the polyoma enhancer activator 3 (PEA3) transcription factor [122]. Furthermore,
NO also interacts with various other pathways which can influence COX expression such as the cAMP/PKA/CRE and JNK/Jun/ATF2 signaling cascades [122; 123].
[..]
Interestingly, the interaction between NO and prostaglandin is not uni-directional,
as it has been reported that NSAIDs such as aspirin and indomethacin can significantly reduced NOS activity [127].
It turns out that NO plays a key role in most headache/migraine cases:
The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache.
Although the precise mechanisms underlying the pathophysiology of migraine are still elusive, the last decades have witnessed some progress (e.g. involvement of serotonin, calcitonin gene-related peptide, nitric oxide, etc).
Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing.
Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-NMMA effectively treats attacks of migraine without aura. Similar results have been obtained for chronic tension-type headache and cluster headache. Inhibition of the breakdown of cGMP also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Several relationships exist between NO, calcitonin gene-related peptide and other molecules important in migraine. Also ion channels, particularly the K(ATP) channels, are important for the action of NO.
In conclusion, inhibition of NO production or blockade of steps in the NO-cGMP pathway or scavenging of NO may be targets for new drugs for treating migraine and other headaches. Indeed, selective n-NOS and i-NOS inhibitors are already in early clinical development.
Nitric oxide in migraine.
Nitric oxide is a key molecule in migraine and other vascular headaches.
Nitric oxide (NO) may play a key role in migraine and other vascular headaches since glyceryl trinitrate (a donor of NO) and histamine (which probably activates endothelial NO formation) both cause a pulsating dose-dependent headache with several migrainous characteristics. At relatively high doses of glyceryl trinitrate, migraine sufferers develop stronger and more migraine-like headaches and more pronounced cerebral arterial dilatation than controls. After the infusion of glyceryl trinitrate, non-migraineurs remain headache-free while migraineurs develop a migraine-like attack. In this review, Jes Olesen, Lars Thomsen and Helle Iversen suggest
that migraine may be caused by increased amounts and/or affinity of an enzyme in the NO-triggered cascade of reactions. NO may also be involved in the pathogenesis of other vascular headaches.
Nitric oxide-induced headache in patients with chronic tension-type headache
The present study demonstrates that an NO-induced biphasic response with an immediate and a delayed headache is common to chronic tension-type headache and migraine. Furthermore, the NO-induced delayed headache has the characteristics of the primary headache disorder.
This suggests that NO contributes to the mechanisms of several types of primary headaches and that NO-related central sensitization may be an important common denominator in the pain mechanisms of primary headaches.
Why is nitric oxide so damaging when in high quantities? Several reasons including: it mediates prostaglandin synthesis, acts as a potent free radical, and 'irreversibly' binds with mitochondria to reduced electron flow. NO is upregulated in times of cellular stress.
The infrabed treatment seems to have reduced the inflammation progressively over the last three weeks. Almost never in the past years had a headache disappeared without taking naproxen.
I think the benefical effects of naproxen in the past were related to restoring energy balance in the cells temporarily by having similar (if only a small portion of) effects to that of NIR. We know that NIR is among one of the
very few things that can dissociate nitric oxide from cytochrome c oxidase, allowing for the electron flow to resume. It also reduces nitric oxide synthesis:
Near infrared radiation protects against oxygen-glucose deprivation-induced neurotoxicity by down-regulating neuronal nitric oxide synthase (nNOS) activity in vitro.
Near infrared radiation (NIR) has been shown to be neuroprotective against neurological diseases including stroke and brain trauma, but the underlying mechanisms remain poorly understood. In the current study we aimed to investigate the hypothesis that NIR may protect neurons by attenuating
oxygen-glucose deprivation (OGD)-induced nitric oxide (NO) production and modulating cell survival/death signaling. Primary mouse cortical neurons were subjected to 4 h OGD and NIR was applied at 2 h reoxygenation.
OGD significantly increased NO level in primary neurons compared to normal control, which was significantly ameliorated by NIR at 5 and 30 min post-NIR. Neither OGD nor NIR significantly changed neuronal nitric oxide synthase (nNOS) mRNA or total protein levels compared to control groups.
However, OGD significantly increased nNOS activity compared to normal control, and this effect was significantly diminished by NIR. Moreover, NIR significantly ameliorated the neuronal death induced by S-Nitroso-N-acetyl-DL-penicillamine (SNAP), a NO donor. Finally, NIR significantly rescued OGD-induced suppression of p-Akt and Bcl-2 expression, and attenuated OGD-induced upregulation of Bax, BAD and caspase-3 activation. These results suggest NIR may protect against OGD at least partially through reducing NO production by down-regulating nNOS activity, and modulating cell survival/death signaling.
So, aside from all of the other beneficial effects the infrabed has had, I think one of the most interesting ones in your case is in relation to probably reducing nitric oxide's negative effects.
Oxygen deficiency (hypoxia) and glucose deprivation induces NO synthesis, which I believe is an adaptive mechanism. We know that carbon dioxide is the body's primary vasodilator, and is produced via oxidative mitochondrial respiration. We also know that nitric oxide is a vasodilator. So in a hypoxic glucose deprived cell, there is going to be a lack of oxidative metabolism and a subsequent lack of CO2 production. Here, it makes sense that one of the reasons for upregulating NO synthesis is as a substitute for CO2.
In other words - stress/mitochondrial dysfunction leads to increases of nitric oxide.
Which leads on to your next comment about mitochondrial dysfunction:
Coincidentally I'm reading a book titled "
Tripping over the Truth: The Metabolic Theory of Cancer" that Laura gave me a few weeks ago.
The author suggests that the main cause of cancer is 'dysfunctioning' mitochondria which instead of using the most usual and effective way to produce energy (called oxidative pathway) switch to a very inefficient and dangerous pathway: sugar fermentation. It is this sugar fermentation process that leads to cancerous cells.
Very good point. If you take the time to look at the research, the above view is
well established in the literature. The downregulation of oxidative phosphorylation and upregulation of glycolysis(fermentation) is characteristic of all cancer cells - a finding originally presented by Warburg.
But to throw a spanner in the works, to say that this process is limited purely to cancer cells somewhat misses the point. The increase in sugar fermentation and reduction of oxidative metabolism is present in practically every single pathology known (other than inherited genetic disorders). You can read my initial post in the Methylene Blue thread for a brief explanation of how this plays out in real life. Fermentation produces excessive amounts of lactate - so you can measure this on tests to get a picture of whether your mitochondria are operating off of the oxidative or fermentative metabolism. One marker is "lactate dehydrogenase", a typical cancer diagnostic test. However, when you look at a condition such as rheumatoid arthritis (which is assumed to be completely different from cancer), you see
elevations in lactate dehydrogenase. This means that the rheumatic individual is partly running off of fermentation, which is often in the local area of the pathology. Ultimately, we see mitochondrial dysfunction and "cancer-type metabolism" in all types of conditions - migraines included.
I've not finished the book but it lit a light bulb. I've had brain cancer in 2009 and 2013. If the author is right, it means that some of my cells had switched, for some reason, to the fermentation pathway and stopped using the oxidative pathway which is based on the use of oxygen and near infrared radiation.
Yeah, I completely agree Pierre. There is a researcher called Dr Doug Wallace who has shown that pretty much every disease (again, other than the genetic ones) is characterised by mitochondrial DNA mutations. Everyone should check out this
groundbreaking presentation if they want more information on it. The mutations are called the mitochondrial %heteroplasmy rate, and they differ in different tissues. The %heteroplasmy in a given tissue is 100% correlated with the expressed phenotype. For instance, autistic children have a certain %heteroplasmy, similarly, Huntingtons also share a %heteroplasmy on a specific mitochondrial gene.
So one person may have high %heteroplasmy in the brain, whereas they may have low %heteroplasmy in the heart, and vice versa. The high %heteroplasmny in the heart may manifest as congestive heart failure, whereas high %heteroplasmy in the brain may manifest as brain cancer.
The factors which cause the mtDNA mutations includes anything that produces an excess of reactive oxygen species that the cell is unable to deal with. These ROS are able to directly attack the mtDNA. ROS may be produced by inefficient oxidative phosphorylation (yielding too much ROS), radiation and mutagenic agents, metals, blue light in isolation from red light, etc etc etc.
Good bioenergetics (clean oxidative metabolism) = low mtDNA mutations = healthy phenotype
Poor bioenergetics (glycolysis/fermentation) = high mtDNA mutations =pathological phenotype in local region with high mutation rate
Unfortunately, it would look like you have high %heteroplasmy in the brain.
So the question becomes: How do we maximise oxygen delivery whilst simultaneously maximising the efficiency ("cleanliness") of glucose/fat oxidation.
Well it seems like we need to identify the origin of the defective metabolism. This is the tricky part, because when you start examining the process of energy metabolism in detail, there are infinite things that could go wrong. Ranging from thyroid dysfunction, steroid insufficiency, coq10+biotin,B1,B2,B3,manganese,magnesium insufficiency, lack of antioxidants, poor circadian rhythm, etc. It is easy to get bogged down by the details, and sometimes I feel like I just go round and round in pointless circles when I geek out with this stuff. All I know is that minor local issues seem to be indicative of more systemic energy deficits. I think functional testing can help identify the issue.
So, maybe, the Infrabed treatment is providing loads of NIR radiations (previously lacking hence the switch to fermentation?) that are reverting back some mitochondria from the sugar fermentation pathway to the safer and way more efficient oxidative pathway. This energy production switch might explain the low energy because one pathway stops while the other is not fully on yet.
It sounds like the NIR is doing a good job at restoring your brains oxidative metabolism. What you say could be true, that you are beginning to upregulate the oxidative metabolism, but it may just be a bit "rusty", and perhaps a lot of the brain mitochondria are still a bit screwed. If the mitochondria a crappy, then you will have a hard time running on oxidative metabolism.
If you know you likely have high %heteroplasmy and crappy mitochondria in your brain, what to do about this? Well, one thing may be to optimise the process of mitophagy (a form of autophagy). This is basically a way in which we get rid of the damaged mitochondria which are causing the cells a lot of damage and replace them is good working ones.
Here is a section of a decent
paper:
Hence, decreased or dysregulated mitophagy likely contributes to the decline in mitochondrial quality and function that leads to the ageing phenotype. A recent study has shown that in mouse and human, mitophagy is impaired during ageing in muscle satellite cells (Garcia-Prat et al. 2016). These are muscle-specific stem cells, hence characterised by self-renewal and long life span, potentially requiring mitophagy more than other cell types (Phadwal et al. 2013). This decrease of mitophagy could be due to an inflammation process as IL-10 null mice display a better ageing phenotype than the control weight mice (Ko et al. 2016).
Interestingly when mitophagy is impaired, mitochondria send a retrograde signal through SKN-1, a transcription factor that regulates both mitophagy and mitobiogenesis (Palikaras et al. 2015). This mitochondria–nuclear crosstalk important for mitochondria health and involving mitophagy has also been highlighted in a nucleotide excision DNA repair disorder leading to neurodegeneration (xeroderma pigmentosum group A). This disorder is characterised by impaired mitophagy due to excessive PINK1 cleavage (Fang et al. 2014). This excessive processing appears to be due to both an activation of PARP1 and an attenuation of the NAD(+)-SIRT1-PGC1α pathway.
As one would expect, coordination between biogenesis and recycling is needed to keep the pool of mitochondria healthy. The decline in mitophagy with ageing (Diot et al. 2015) thus disadvantages both the turnover of dysfunctional mitochondria and the production of fresh mitochondria, leading to a decreased life- and healthspan.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935730/figure/Fig1/
In this review, we have seen that mitochondria play a role in ageing at different levels (Fig. 1).
First, the MRC as an important source of ROS that increases as mitochondrial quality declines. ROS production is indeed an important feature of the ageing process, whether it induces oxidative damage to proteins, lipids and DNA or acts as a signalling molecule.
Second, through their relationship with the nucleus,
mitochondria affect nuclear gene expression. We now know that nuclear–mitochondria crosstalk is not only in the nucleus-to-mitochondria direction, via production and import of the vast majority of the proteins necessary to build a mitochondrion and regulation by sirtuins. The retrograde response where mitochondria content and activity regulate nuclear gene expression is also critically important (Guantes et al. 2015, 2016). Overall the
mitochondria content and quality appear to be important features of the ageing process. This is highlighted by the importance of heteroplasmy for damaged mtDNAs, presumably due to a decreased efficiency in energy production leading not only to more ROS being produced but also to an effect on telomere as it has recently been suggested.
These observations convince us that
mitochondria quality control has a very (maybe the most) important part to play in the ageing process. By
modulating mitophagy, it may be possible to improve mitochondrial quality, limit mtDNA damage, regulate ROS production to what is necessary for signalling and keep the nuclear gene expression to the pattern and levels of healthy young cells.
So you mentioned sleep in your comment. Are you wearing blue blockers religiously? If not, I would totally recommend you get yourself a pair and become more aligned with the external cycles. The reason this is important is because the above process (mitophagy/autophagy) is actually regulated by the circadian rhythm.
Circadian autophagy rhythm: a link between clock and metabolism?
Nutrient and energy metabolism in mammals exhibits a strong diurnal rhythm that aligns with the body clock. Circadian regulation of metabolism is mediated through reciprocal signaling between the clock and metabolic regulatory networks.
Recent work has demonstrated that autophagy is rhythmically activated in a clock-dependent manner. Because autophagy is a conserved biological process that contributes to nutrient and cellular homeostasis, its cyclic induction may provide a novel link between clock and metabolism. This review discusses the mechanisms underlying circadian autophagy regulation, the role of rhythmic autophagy in nutrient and energy metabolism, and its implications in physiology and metabolic disease.
From self-hacked
article
The Circadian Rhythm and Protein Recycling/Autophagy
At the protein level, a healthy cell will progress through a daily cycle of alternating metabolic states directed by the circadian system, with proteins going through cycles of being synthesized and degraded (R).
During periods of fasting, cells release nutrients for recycling and remove damaged or unnecessary organelles (cellular structures). This is known as autophagy. In the liver and other tissues, this timely progression is controlled by your circadian clocks (R).
Part of circadian modulation of autophagy includes establishing particular phases of day or night when the neurons are more susceptible to aggregation and mitochondrial dysfunction, and potentially this would be exacerbated by circadian and/or sleep disturbance which would reduce the daily peak capacity for autophagy (autophagy works via circadian expression of the transcription factor C/EBPβ) (R).
Hope that helps Pierre, and apologies if I have derailed the thread a little bit.
It's actually a little small for my shoulders, but I just do one side, and then the other. And sometimes, I only use 1 of the "3 rotating balls" to get hard-to-reach spots. 
