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http://molecular.biosciences.wsu.edu/Faculty/pall/pall_fibro.htm

 

Fibromyalgia, Excessive Nitric Oxide/Peroxynitrite and Excessive NMDA Activity

 

 

Fibromyalgia, Excessive Nitric Oxide/Peroxynitrite and Excessive NMDA Activity

 

martin_pall phone: 509-335-1246

Go to: Chronic Fatigue Syndrome

Go to: Multiple Chemical Sensitivity

 

One of the barriers to our understanding of the mechanisms involved in

fibromyalgia (FM) is the lack of any animal models of FM. So whereas proposed

animal models for chronic fatigue syndrome (CFS),multiple chemical sensitivity

(MCS) and posttraumatic stress disorder (PTSD) are available which suggest a

role for excessive nitric oxide in each of these conditions, there is no similar

animal model to study for FM. Consequently, we a left with studies of human FM

patients to suggest a possible mechanism. The human data suggests a mechanism

centered on excessive levels of nitric oxide and its oxidant product,

peroxynitrite, as well as excessive activity of a neurotransmitter system called

the NMDA system. It is known that when NMDA receptors are hyperactive they

produce excessive nitric oxide and peroxynitrite (1). This is consistent with

the mechanism I have proposed for CFS, MCS and PTSD, centered on excessive

nitric oxide and peroxynitrite (1) and may explain the overlaps among these

conditions and FM.

Excessive NMDA activity is implicated in FM by three different types of studies.

The most recent of these was recently reported by Smith et al (2), reporting

that a subgroup of FM patients had a complete resolution of their symptoms by

removing both monosodium glutamate (MSG) and aspartame from their diets. MSG and

aspartame are both described as excitotoxins (2), because both glutamate from

MSG and aspartate from aspartame, activate the NMDA receptors in the nervous

system and may lead to neural damage as a consequence of excessive activation. A

major mechanism of such NMDA-mediated damage is produced by the excessive nitric

oxide and peroxynitrite produced by such activation. There are two other types

of studies that provide support for excessive NMDA activity in FM. Several

research groups have reported that NMDA antagonists, drugs that lower NMDA

receptor activity, improve the symptoms of FM patients (3-6), strongly

suggesting the such activity is excessive in FM and that the excessive activity

is responsible for producing FM symptoms. A. A. Larson's group at the University

of Minnesota has reported studies of the cerebrospinal fluid of FM patients,

strongly suggesting that NMDA activity is elevated and that nitric oxide

synthesis is also elevated (7). So we have three different types of studies that

provide support for the inference that NMDA activity is elevated in FM, one of

which also provides evidence for a consequent elevated level of nitric oxide

synthesis.

How does this fit into the symptoms of FM? The most characteristic symptom of FM

is multiorgan pain and it is known that both excessive NMDA activity and

excessive nitric oxide levels can generate pain. Nitric oxide is known to

stimulate some but not all of the nociceptors, the neurons that generate the

sensation of pain, providing an explanation for the pain generation (reviewed in

1). Peroxynitrite is implicated in generating pain responses, as well (8). Other

symptoms are similar to those in CFS and may be generated by mechanisms

consistent with a nitric oxide/peroxynitrite etiology (9).

Peroxynitrite is a potent oxidant and if its levels are elevated, as proposed,

than levels of oxidative damage should also be elevated in FM. Two studies have

reported such oxidative damage in FM, consistent with this prediction (10,11).

However one of these studies also suggests that nitric oxide levels are low

(11), not high as reported in a previously cited study (7). So there is some

confusion in the literature on this important point. In the study inferring low

nitric oxide, the parameter measured was nitrosothiol level in the blood and

nitrosothiols react with peroxynitrite (12), suggesting that the pattern

reported may be due to high peroxynitrite levels, rather than low nitric oxide

levels.

FM as well as CFS and MCS is commonly treated with vitamin B12 injections, using

B12 in the form of hydroxocobalamin or cyanocobalamin at doses of 1 to 10 mg

(13). Hydroxocobalamin is a potent nitric oxide scavenger and I have proposed

that this is the way such B12 injections may work to alleviate symptoms of these

conditions (13). There is an enzyme in human cells that converts cyanocobalamin

into hydroxocobalamin so cyanocobalamin injections may work by this same

mechanism. The symptoms of FM, CFS and MCS are quite distinctive from those of

B12 deficiency, so it seems unlikely that the B12 injections act in these

conditions by alleviating such a deficiency.

Many cases of FM are reported to be preceded by physical trauma, such as caused

by a car accident, fall or operation (reviewed in 1). How might this initiate FM

events? A study of physical trauma in humans reports that they are associated

with elevated nitric oxide levels (14) and specifically traumatic head injury is

widely reported to produce elevated nitric oxide levels (A Pubmed search on

traumatic head injury and nitric oxide will generate many references on this :

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi).

At least some of this nitric oxide generation is through the action of excessive

NMDA activity. An essential component of the elevated nitric oxide/peroxynitrite

theory of these several conditions is that once peroxynitrite levels are

elevated, they may act to raise the levels of both nitric oxide and its other

precursor, superoxide, thus possibly leading to a chronic elevation of

peroxynitrite. This may explain how a chronic condition like FM may be initiated

by a short term traumatic event.

 

References:

1. Pall M. L. Common etiology of posttraumatic stress disorder, fibromyalgia,

chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric

oxide/peroxynitrite. Med Hypoth 2001;57:139-145.

2. Smith J. D., Terpening C. M., Schmidt S. O. F., Gums J. G. Relief of

fibromyalgia symptoms following discontinuation of dietary excitotoxins. Ann

Pharmacotherapy 2001;35:702-706.

3. Sörensen J., Bengtsson A., Bäckman E., Henriksson K. G., Bengtsson M. Pain

analysis in patients with fibromyalgia. Effects of intravenous morphine,

lidocaine, and

ketamine. Scand J Rheumatol 1995;24:360-365.

4. Nicolodi M., Volpe A. R., Sicuteri F. Fibromyalgia and headache. Failure of

serotonergic analgesia and N-methyl-D-aspartate-mediated neuronal plasticity:

their common clues. Cephalalgia, 1998;18: 41-44.

5. Graven Nielsen T., Aspegren Kendall S., Henriksson K. G. et al. Ketamine

reduces muscle pain, temporal summation, and referred pain in fibromyalgia

patients. Pain 2000:85:483-91.

6. Buskila D. Fibromyalgia, chronic fatigue syndrome and myofascial pain

syndrome. Curr Opin Rheumatol 2001;13:117-127.

7. . Larson A. A., Giovengo S. L., Russell I. J., Michalek J. E. Changes in the

concentrations of amino acids in the cerebrospinal fluid that correlate with

pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain

2000;87:201-211.

8. Liu T., Knight K. R., Tracey D. J. Hyperalgesia due to nerve injury role of

peroxynitirte. Neuroscience 2000;97:125-131.

9. Pall M. L. Elevated peroxynitrite as the cause of chronic fatigue syndrome:

Other inducers and mechanisms of symptom generation. J Chronic Fatigue Syndr

2000:7(4):45-58.

10. Eisinger J., Zakarian H., Pouly F., Plantamura A., Ayavou T. Protein

peroxidation, magnesium deficiency and fibromyalgia. Magnes Res 1994;7:285-288.

11. Eisinger J., Gandolfo C., Zakarian H., Ayavou T. Reactive oxygen species,

antioxidant status and fibromyalgia. J Musculoskeletal Pain 1997;5(4);5-16.

12. Rauhala P., Chiueh C. C. Neuroprotection by S-nitrosoglutathione of brain

dopamine neurons from oxidative stress. FASEB J 1998;12:165-173.

13. Pall M. L. Cobalamin used in chronic fatigue syndrome therapy is a nitric

oxide scavenger. J Chronic Fatigue Syndr 2001:8(2);39-44.

14. Gebhard F., Nüssler A. K., Rösch M., Pfetsch H., Kinzl L., Brückner U. B.

Early posttraumatic increase in production of nitric oxide in humans. Shock

1998;10:237-242.

 

 

 

 

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