Funding for 1998

Fibromyalgia: Chronic Effects of Nerve Growth Factor (NFG) in the Spinal Cord

Principal Investigator: Alice Larson, Ph.D.
Professor of Neuroscience
University of Minnesota, St. Paul
Award: $28,752 - June 1998

Substance P (SP) and nerve growth factor (NGF) are three to four times higher in the spinal fluid of people with FMS. These chemicals are elevated to the point of pathological significance and they are known to be major players in the pain system.

So why doesn't your doctor just prescribe something to tame down these substances so that you don't have to endure so much pain? The answer is simple: No one knows why SP and NGF are elevated, nor how they interact with one another to possibly produce the diffuse, chronic pain of FMS ... and likely that of CFS. This is one of many reasons why research in FMS/CFS is at a crucial point. It is disheartening to know that these significant abnormalities exist and not know what to make of them!

The high SP levels in FMS have been well-documented by I. Jon Russell, M.D., Ph.D., at the University of Texas in San Antonio. Dr. Russell has started looking at the SP levels in other painful conditions, but so far no other condition compares with the threefold increase in FMS patients. The average increase of NGF in the spinal fluid of FMS patients is fourfold, although it varies among patients. This finding was recently determined by Alice Larson, Ph.D., of the University of Minnesota in St. Paul, using spinal fluid samples provided by Dr. Russell.

At the American Pain Society meeting last October, there was a special discussion session devoted to NGF. As you might guess, NGF's primary role in the body is to stimulate the growth of nerves. With this in mind, a clinical trial using NGF for treating the loss of tactile sensations in the hands and feet of people with diabetic neuropathy was described. The purpose was to regrow the small nerves in the hands and feet with weekly injections of synthetic NGF. The researchers didn't know what dose to start at, and initially gave the patients in the trial far too much NGF. The result: horrible widespread pain that persisted for over a week! Cutting the dose several fold produced soreness only at the injection site, but the nerves did regrow and the study was deemed a success.

How could NGF produce severe pain? Dr. Larson says that NGF enhances the production and release of SP which could lead to the widespread pain in FMS. Unfortunately, the relationship between NGF and SP isn't straightforward. SP is broken down into two parts: one that relieves pain (SP1-7) and one that actually promotes pain. Not only can SP1-7 reduce the impact of NGF, studies also indicate that decreasing the activity of the sympathetic portion of your autonomic nervous system could lead to reduced NGF-induced pain. The sympathetic arm of your nervous system controls your fight-or-flight stress response mechanisms, among other things. The feedback loops of the nervous system are complex, but this background information should help you understand the importance of the projects funded by AFSA in mid-1998.

FMS appears to involve altered activity of chemicals in the brain that generate the sensation of pain when released in the spinal cord in response to tissue damage. FMS may become a chronic condition because of a change in the interaction between NGF and SP.

In animals and humans, injection of NGF can lead to profound pain that lasts for several days. A possible mechanism by which NGF may do so is by increasing the synthesis of other peptides, including SP, in nerves that transmit pain signals. It is unclear if the excess NGF associated with FMS is the underlying cause of the elevated SP concentrations in the spinal fluid. It is also unclear whether SP is important in the increase in pain transmission associated with fibromyalgia, or whether the pain-relieving SP1-7 metabolites are instrumental in inhibiting NGF activity.

The effect of NGF on pain transmission has only been studied over short time intervals. Dr. Larson's study is designed to determine whether an elevated concentration of NGF in the spinal cords of rats is sufficient to produce a long-term enhancement of pain (perhaps an animal model for FMS?); whether the enhanced pain produced by NGF requires SP at its site in the spinal cord; or whether SP1-7 metabolites in the spinal cord work to counteract NGF-induced pain. These studies will basically mimic the spinal fluid concentrations of NGF and SP that are found in humans with FMS, so that their relationship to the painful symptoms of this condition can be better understood. The project will help determine the importance of SP in the action of NGF. It will also determine whether drugs for FMS might best be designed to inhibit the action of SP, the parent compound, or enhance the action of SP1-7 metabolites.

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Cloning a Pain Neuropeptide Receptor

Principal Investigator: John Stewart, Ph.D.
Professor of Biochemistry, School of Medicine
University of Colorado, Denver
Award: $24,560 - June 1998

We desperately need new drugs to help keep the horrible pain of FMS under control! This project offers hope.

When we experience excessive pain, there are two possible ways to help. If we know the cause of the pain and can treat it, as is the case with an infected wound, we kill the infecting micro-organisms with antibiotics. This minimizes inflammation, promotes wound healing, and eventually alleviates the pain. Unfortunately, this simple approach does not work for FMS pain.

The second approach is to block pain signals from getting to the brain, where we actually produce the pain sensation. This is the only approach possible if we do not know the cause of the pain (as is the case in FMS and CFS) or if we can't control the cause. Often, analgesics, such as aspirin, are used when inflammation is present or if the pain is mild. Morphine or other opioids may be prescribed when the pain is severe. Pain signals are carried by neurons (nerves), which use neurotransmitters such as peptides (baby proteins) as messengers to pass signals from one neuron to the next on the way to the brain. One neurotransmitter for pain signals is the peptide SP. Morphine may block pain by preventing the release of SP from pain-sensing neurons.

SP is a true double-barreled molecule when it comes to pain. On one hand, SP helps produce the pain sensation. On the other hand, it can help block pain signals. This is true because SP can be cut by enzymes to produce two different molecules (metabolites). One of the molecules produces pain, while the other blocks the pain sensation and helps control the severity of pain (SP1-7). Scientists have learned a great deal about the "bad" part of SP that produces the pain, but relatively little is known about the "good" part of SP that blocks pain. If we can learn more about how the good part of SP works, we may be able to design new drugs to block FMS pain.

Neurotransmitters like SP work by combining with "receptors" that only they recognize. These receptors are made of specialized protein molecules in the target cells of the neurons (i.e., they are the receivers of information). If the neurotransmitter is the key, then the receptor can be viewed as the perfectly molded keyhole. Scientists have extensively studied the receptors for the "bad" part of SP, but drugs that have been developed to block this receptor cause terrible side effects. Ironically, nothing is known about the molecule that is the receptor for the "good" part of SP. This project will furnish that information, and should provide important new knowledge on the mechanisms of pain production and its control.

Dr. Stewart and his co-workers will use modern molecular biology techniques to find the gene for the receptor and transfer it into cells grown in tissue culture. By doing so, a "clone" of the good SP peptide can be synthesized and will lead the way for new drug developments for FMS. The investigators will use computer programs that produce three-dimensional models of the receptors and the peptides. This in turn will further aid in the design of even better molecules that can be tested for their effectiveness in treating pain and related symptoms. The best new molecules can then be tried in FMS patients after FDA approval.

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The Effect of Graded Exercise on Temporal Summation of Second Pain (Wind-Up) in Patients with FMS

Principal Investigator: Roland Staud, M.D.
Rheumatology, University of FL, Gainesville
Award: $30,000 - June 1998

Pain in FMS, as well as CFS, is consistently felt in the musculature and may be related to specific abnormalities of central nervous system (CNS) pain pathways. In a small pilot study with FMS patients, Dr. Staud used a non-invasive method of repetitive stimulation of the nerve endings. Although the stimulations were mild, the repetition caused the false perception of significantly increased pain (wind-up) in people with FMS compared to healthy controls. This rather simple test method appears useful for the evaluation of the CNS pain pathways (or mechanisms) that are present in FMS patients as well as serving as a useful tool for testing the effectiveness of drugs for FMS.

For this study, a Peltier thermode (heated plate) will be applied in a series of brief contacts to different sites on the palm of the patient's hands. Repetitive contacts on the skin areas of the palms are able to increase the perceived intensity of heat sensations that follows each contact. This technique appears to be capable of measuring the input from specific C-type nerve fibers that may be "turned on" to sensitize the pain system and amplify pain sensations. Ordinarily, these fibers release SP when tissues are injured, but Staud suspects that they are abnormally activated in FMS patients by events that should not lead to pain, such as mild exercise. This may be important in FMS.

Staud's technique is expected to provide information regarding the status of specific CNS receptor systems that are implicated in chronic pain conditions such as FMS (e.g., the N-Methyl-D-Aspartate or NMDA receptors that reside in the spinal cord and brain). Unlike SP-generated pain, opioids are not as effective in combating NMDA-generated pain. Ironically, SP is a potent facilitator of NMDA receptors.

During the pilot study with FMS patients, Staud has been able to show excessive wind-up (or pain build-up) at a high rate of heat stimulation and abnormal wind-up at a slow rate. Not only do these findings indicate that people with FMS are extremely sensitive to pain stimuli, but they also serve to highlight abnormalities of central pain processing in FMS patients that likely involves the NMDA receptors.

Based on reports that most FMS and CFS patients indicate a worsening of their symptoms with physical exercise and improvement with rest, Staud hypothesizes that wind-up (as measured by his novel technique) may correlate with the level/duration of exercise in this patient group. In contrast, Staud's previous studies using healthy, pain-free individuals have shown pronounced attenuation (e.g., blocking) of wind-up after strenuous exercise.

Project investigators postulate that exercise will accentuate the abnormalities of wind-up in FMS patients, particularly in comparison to healthy controls. The results of this study will improve our understanding of the status of the pain modulatory systems in FMS patients. In addition, the non-invasive technique should serve to help design and evaluate future therapeutic trials in FMS as well as CFS pain.

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Cytokines, Fibromyalgia Subsets and the Th1/Th2 Axis

Principal Investigator: Daniel Wallace, M.D.
Professor Cedars-Sinai/UCLA
Award: $24,000 - June 1998

The cause of fibromyalgia syndrome (FMS) is unknown, but reports have suggested that patients with FMS have an under-responsive autonomic nervous system as indicated in studies showing low cortisol "stress" response, increased levels of SP and NGF in the spinal fluid, and decreased levels of growth hormone which doesn't allow muscles to repair properly from normal wear and tear. As part of an attempt to link the hormonal changes, autonomic dysfunction, and neurotransmitter abnormalities associated with FMS, investigators have looked at substances known as cytokines, which include interferons, interleukins, and tumor necrosis factors. The chemicals signal cells of the immune system to perform different actions. Also, cytokines can produce pain or relieve pain, produce cognitive impairment, promote or suppress inflammation, induce sleep, and activate or suppress stress responses.

Lymphocytes are a type of white blood cell that serves as our immunologic memory. They remember past insults and protect our immune system by making antibodies or formulating an inflammatory response. There are two principal types of lymphocytes: Th1 and Th2.

Certain cytokines help create a predominantly Th1 environment in which inflammation is best supported, while others promote a Th2 environment of elevated antibodies and decreased inflammation which is also seen in pregnancy and allergies. Activation of the stress-cortisol process, for example, promotes Th2 cytokines and decreased levels of Th1 cytokines. Research findings suggest that FMS (and perhaps CFS) might start out as a chronically activated stress-cortisol state, but over time, the system gradually "tires," producing a low cortisol "stress" response even when the body continues to be challenged by stressors. As for the role of cytokines in FMS/CFS, few studies have examined their potential for producing the symptoms and no surveys have looked for Th1 and Th2 axis imbalances in these syndromes.

Dr. Wallace and co-workers propose to study a group of FMS patients and healthy individuals. They will look at cytokine levels in an effort to assess their Th1 and Th2 balance. This assessment will be further refined by examining patients who developed the syndrome after an accident or infection. Patients with the often associated malfunctioning of the autonomic nervous system (neurally-mediated hypotension) will also be subdivided to determine if their cytokine profile is different. Duration of symptoms will also be assessed to see if this influences cytokine production.

Wallace hopes to derive insights which will increase the understanding of how cytokines and white blood cells influence, for example, pain, cognitive functioning, sleep, headaches, irritable bowel, and chemical sensitivities. Research on cytokines and the agents that block their production or activity are in progress and could produce novel drug therapies. The results of this project could help assess whether novel cytokine-directed therapies should be tested in FMS/CFS and, if so, identify which subgroup of patients might benefit the most.

In addition to the above project to detect cytokine irregularities, Dr. Wallace has agreed to further look into the specific genes that regulate any cytokines that are found to be significantly higher or lower than normal. Indeed, this study is quite an undertaking!