Fibromyalgia

Fibromyalgia, Excessive Nitric Oxide/Peroxynitrite and Excessive NMDA Activity

By Martin L. Pall, PhD

Professor of Biochemistry and Basic Medical Sciences

Washington State University

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 are 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 Chronic Fatigue Syndrome (CFS), Multiple Chemical Sensitivity (MCS) and Post Traumatic Stress Disorder (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 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.

Note: Most forms of superoxide dismutase fail to survive the GI tract… SOD scavenges superoxide.

Also, see

Alpha-lipoic acid potently inhibits peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation: implications for the neuroprotective effects of alpha-lipoic acid
http://www.ncbi.nlm.nih.gov/pubmed/19082545

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