Magnesium vs Drugs

Hours of browsing PubMed is making me delirious, but not yet delirious enough to patronize this film. Moving ahead to a better image:

Where to start? This table relates to yesterday's post about pain, inflammation, nociception, and cytokines. Blue entries indicate biochemical mechanisms that are, when it comes to analgesia, unequivocally beneficial. Red entries are more or less detrimental. The KOR column is green because the jury is out.

KOR stands for Kappa Opioid Receptor. This is one of the subtypes of opioid receptor in the body. It appears to be involved in reductions in pain, and yet is also associated with non-pain dysphoria. The body is complicated and fickle, eh?

MOR is the more familiar Mu Opioid Receptor. This is what opiates, and the opioid drugs inspired by them, bind to. Heroin, morphine, hydrocodone, oxycodone, etc are not created equal, but they all share a strong binding affinity for MOR. They also, frustratingly, lead to its down-regulation; over time they become less effective in reducing pain. In recent years, research has shown that they also bind to TLR4. This is bad because it triggers the release of proinflammatory cytokines, ultimately leading to increased pain and other unpleasant symptoms.

TLR4 is Toll-Like Receptor #4. This is part of the innate immune response. It cannonically  recognizes LPS, a substance on the cell walls of Gram-negative bacteria, a common class of pathogens. Contemporary research also suggests that it responds to various other ligands, such as DAMPs (Damage Associated Molecular Patterns). In short, TLR4 activation signals trouble to the body.

Amitriptyline is a tricyclic antidepressant. I added it to the table because I was pleasantly surprised to read that it is a potent antagonist of TLR4. This fact makes me more favorably inclined towards its somewhat common use in treating fibromyalgia and MECFS.

NMDA receptors are as complex as they are ubiquitous. For the purposes of this post, it suffices to note that they are a key point in the nociception-becomes-pain signal cascade.

Gabapentinoids (Gabapentin and Pregabalin) will be familiar to most fibromyalgia folks. Their primary mechanism of action is to lessen the flow of excitatory Ca2+ along the ion channels of axons. Magnesium ions, Mg2+, also attenuate this signal.

Magnesium is the hero of this story. Information about it abounds (just ask your friend Google). It is commonly deficient in the Western diet. It also has benefits far exceeding those listed in the above table (ask your friend Google). Hopefully, by juxtaposing it with drugs, this post adds some new elucidation. Caveat: the table says nothing of potency - magnesium has a broader spectrum of action than anything else in the table, but it was not pharmacologically designed with a particular aim. It's a Swiss army knife; if you need powerful scissors or a big screwdriver you'll have to look elsewhere. Consequently, if you start supplementing magnesium (as you probably should) don't immediately ditch your meds. I am not a doctor; if you sue me you won't get much money :)

Alcohol is in there for kicks. He's a fun guy, but don't spend too much time with him cuz things will get complicated quickly. In addition to the info in the table, alcohol increases the excretion of magnesium.

LDN - Low Dose Naltrexone! Low Dose Naltrexone deserves a lengthy post all on its own. Fortunately plenty of smart people have already written such posts (ask your friend Google). In short, it's an opiate turned inside-out and upside-down.

Anything I've missed: This post will be updated and refined as needed. At the moment I have a readership of 0 and a brainfog+fatigue of 7. Please leave a friendly comment if you need anything.

Sources: The sources are nonexhaustive, but exhausting; another task I'll defer until I'm recharged. If you're feeling adventurous you can always search PubMed (or your friend Google) for the juxtaposition of two terms (e.g. "amitriptyline NMDA")

Until next time, in the words of SuperBat: 

"So long, and thanks for all the fish"

Pain and Inflammation; Nociception and Cytokines

I'd like to start by marveling at a recent dramatic change in my fibromyalgia pain. After nearly nine years of intense burning pain through approximately 1/6 of my body I've now had 3 weeks of relief. On the left side of my body, my neck, shoulder girdle, pectoral, upper back, and the back of my head ached immensely. EVERY. WAKING. MOMENT. Currently that area feels normal, or occasionally tense - but no longer definitively painful. This is in large part due to decreasing systemic inflammation.

It shouldn't be a surprise that inflammation can cause pain. Everyone, not just fibromyalgia sufferers, has experienced the aching pains that accompany a flu. We've all noticed the localized pain that coincides with redness and swelling at the site of an injury. During inflammation the cytokines released by immune cells can stimulate nociceptors in the body.

Cytokines are signaling molecules released by immune cells in order to coordinate a response. Think of them as messages relayed by soldiers on a battlefield. Cytokines can also be released by other cells in the body in response to damage or threat. In this case they are similar to SOS messages from civilians.

Nociceptors are nerve cells that receive mechanical/electrical/chemical input and relay that input to the brain where it is transformed into the subjective experience of pain. They are analogous to the rods and cones in the eye that respond to photons and send a signal to the visual cortex, thereby giving rise to vision. You may have noticed that if you close your eyes and press firmly on your eyeballs you see some colors; the photoreceptors (rods and cones) are responding to a stimulus that they are not evolved to respond to, but they are responding nonetheless. Tinnitus is a similar phenomenon - noise generated in the absence of normal signal. A more mechanical analogy: sometimes electronic devices that are not radios will pick up signals from a radio station.

Enter the following quote from a biomedical study:

Today our understanding of this relationship is more detailed. When an antigen enters the body, local activation of immune cells leads to release of proinflammatory mediators, which are able to excite or lower thresholds of afferent nociceptive and afferent vagal nerve fibers [3]. If the neuronal signal strength is strong enough or if spillover of local inflammatory mediators into the circulation is robust enough, it signals to the brain, resulting in activation of the two major stress axes, the HPA axis and the SNS [3,4]. Cytokines like interleukin (IL)-1β [3,5] or tumor necrosis factor (TNF) [6] produced by locally activated innate immune cells are pivotal in this communication from immune system to central nervous system.

Afferent means a nerve fiber traveling from the body to the brain/central nervous system. *1

Thresholds. Neurons, including nociceptors, fire in an all-or-nothing fashion. They receive stimulation from neighboring neurons, or, in the case of nociceptors, from the adjacent environment. At any given moment, if the combined stimulation surpasses the threshold of the neuron it will depolarize and send an electrical signal down the length of its axon, thereby passing the message along to a distant neuron. If the stimulation is insufficient, no message will be sent. An analogy for thresholds: a sleeping person may not stir at all in response to quiet sounds, but a loud sound will awake them completely. If the thresholds for your afferent nociceptors are lowered, your experience of pain becomes akin to the hypersensitivity of a shallow sleeper.

The same cytokines mentioned in the above article (IL-1β and TNFα) can also enter the cerebrospinal fluid and lower the threshold of nociceptors in the spinal cord. This means that when a nociceptor in the periphery (e.g. skin or muscle) sends a message to a nociceptor in the spinal cord, that second nociceptor is more likely to pass that message along to the brain, where it is likely to be interpreted as pain.

The inflammatory milieu surrounding the nerve terminals in the skin contains numerous inflammatory mediators during CHS (Kondo et al., 1994; Westphal et al., 2003; Christensen and Haase, 2012), such as tumor necrosis factor alpha (TNFα) and interleukin-1β (IL-1β), which may be retrogradely transported to cell bodies of dorsal root ganglion neurons and contribute to the increased Na+ currents observed in this study. Indeed, TNFα and (IL-1β) have been demonstrated to augment TTX-sensitive and TTX-resistant Na+ currents in nociceptive dorsal root ganglion neurons (Binshtoket al., 2008; Czeschik et al., 2008).

(The dorsal root ganglion is the part of the spinal cord that relays pain signals. Na+ currents are electrical signals sent along axons. Axons are like long cables transmitting information from neuron to neuron.)

To add to the misery, it appears that long-term inflammation can alter the receptors on neurons, such that they remain hypersensitive even after proinflammatory cytokines are no longer present:

Following inflammation of the hindpaw, myelinated, CGRP-positive neurons projecting to the paw skin displayed elevated mechanical currents in response to mechanical stimuli. Conversely, muscle inflammation markedly amplified mechanical currents in myelinated, CGRP-negative neurons projecting to muscle. These data show, for the first time, that mechanically gated currents are amplified following in vivo tissue inflammation, and also suggest that mechanical sensitization can occur in myelinated neurons after inflammation.

Mechanical stimulation? Touch and pressure are forms of mechanical stimulation. This mechanical sensitization may therefore partly explain the presence of tender points in fibromyalgia sufferers. Incidentally, though my burning/aching pain is in remission, I still have the tender points. This dovetails with the notion that prolonged inflammation leads to physiological changes that persist even after the inflammation subsides.



 In future posts I'll explore:
 - how peripheral sensitization can lead to central sensitization
 - potential causes of inflammation in fibromyalgia
 - strategies to reduce inflammation
 - biomarkers for inflammation (e.g. blood tests)
 - other inflammatory conditions that are often comorbid with fibromyalgia (e.g. IBS, ME/CFS, Major Depression, and bipolar disorder)


Footnotes:
*1 'Efferent' is the term for signals sent outwards from the brain.

Sources:

The sympathetic nervous response in inflammation

http://arthritis-research.biomedcentral.com/articles/10.1186/s13075-014-0504-2

Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959553/

Amplified Mechanically Gated Currents in Distinct Subsets of Myelinated Sensory Neurons following In Vivo Inflammation of Skin and Muscle

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478256/

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7/29/16 Addenda:

I just found out about the Fibro Friday link up over at http://www.fibrobloggerdirectory.com/ , a great repository of FMS blogs and resources. I'll be sharing this post there for anyone interested in the biomolecular interactions in fibromyalgia.

A few more studies to look into (for the biomechanically-minded):

NLRP3 inflammasome is activated in fibromyalgia: the effect of coenzyme Q10.

http://www.ncbi.nlm.nih.gov/pubmed/23886272

MCP-1 and IL-8 as pain biomarkers in fibromyalgia: a pilot study.

http://www.ncbi.nlm.nih.gov/pubmed/21714842

Aaand, footage of me burning myself repeatedly with matches to demonstrate that it hurts very little in comparison to fibromyalgia. Skip to 3:30 for the worst burn and a brief explanation of cytokines and nociception.

https://www.youtube.com/watch?v=iX1Vgl0GCKQ