Fibromyalgia syndrome (FMS) is a symptom based diagnosis that depends on the presence of chronic widespread pain and decreased mechanical pain threshold at >= 11 well defined tender points. FMS shows wide overlap with other pain syndromes, including chronic fatigue syndrome and irritable bowel syndrome. All these disorders share chronic, unexplained pain as a clinically relevant symptom and several or all of these syndromes often coexist in an individual patient. Therefore, discovery of FMS pain mechanisms may also benefit patients with related pain syndromes. We have recently shown that FMS patients demonstrate abnormal pain processing, including excessive temporal summation of second pain (windup) and central sensitization. With this application, we will expand our detailed investigation of central/peripheral pain mechanism relevant to FMS pain, using forms of repetitive stimulation that reliably evoke perceptions of second pain. Second pain results from impulse conduction in peripheral C (unmyelinated) afferent axons, and temporal summation of second pain has been shown to result from a central NMDA receptor mechanism within the dorsal horn. The proposed experiments will evaluate peripheral influences on FMS pain and abnormal temporal summation of experimental pain, will describe the central patterns of NMDA receptor activation by nociceptive input, and will compare effects of NMDA antagonists on clinical and experimental pain of female FMS patients and male and female control subjects.
Aim 1 will focus on the relationship of clinical pain to abnormal windup (WU) in FMS. Since clinical pain intensities reported for different body areas seem to vary widely within and between FMS patients, we will first test the magnitude of WU and clinical pain ratings in all four body quadrants of FMS patients and then statistically determine the strength of their association. Repetitive thermal and mechanical stimuli will be delivered to FMS patients and normal controls (NC). If clinical pain is indeed related to C-afferent mediated mechanisms we expect to find a positive correlation between WU measurements and clinical pain. Using exercise bouts or ischemic muscle compressions alternating with rest periods, we will characterize the role of musculoskeletal nociceptor input on a) local and generalized pain and b) WU abnormalities of FMS patients (Aim2). We expect to find that muscular activity and associated receptor stimulation will enhance clinical pain both locally and generally. We will test the effects of NMDA receptor antagonists on clinical pain, first pain, second pain, and WU (Aim 3). We will compare the psychophysical test results across pain-free NC and FMS patients in order to ascertain the extent to which abnormalities of NMDA mechanisms contribute to FMS pain with a special focus on FMS related differences. We will use functional brain imaging (fMRI) of temporal summation of second pain in NC and FMS patients to characterize the encoding of brief, repetitive, thermal stimuli in cortical and subcortical structures (Aim 4). We posit that the enhanced WU of FMS patients will strongly correlate with greater neural activation as compared to NC. The proposed experiments will answer important questions about peripheral/central mechanisms of chronic pain that are relevant to the diagnosis and treatment of FMS. In addition, our findings may contribute to the understanding of pain mechanisms related to other chronic pain disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038767-08
Application #
7379948
Study Section
Special Emphasis Panel (ZRG1-CFS (01))
Program Officer
Porter, Linda L
Project Start
1999-06-10
Project End
2010-08-31
Budget Start
2008-03-01
Budget End
2010-08-31
Support Year
8
Fiscal Year
2008
Total Cost
$315,841
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Craggs, Jason G; Staud, Roland; Robinson, Michael E et al. (2012) Effective connectivity among brain regions associated with slow temporal summation of C-fiber-evoked pain in fibromyalgia patients and healthy controls. J Pain 13:390-400
Staud, Roland; Price, Donald D; Janicke, David et al. (2011) Two novel mutations of SCN9A (Nav1.7) are associated with partial congenital insensitivity to pain. Eur J Pain 15:223-30
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Staud, Roland (2010) Pharmacological treatment of fibromyalgia syndrome: new developments. Drugs 70:1-14
Staud, Roland; Robinson, Michael E; Price, Donald D (2010) Do past pain events systematically impact pain ratings of healthy subjects or fibromyalgia patients? J Pain 11:142-8
Staud, Roland; Nagel, Susann; Robinson, Michael E et al. (2009) Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double-blind, placebo-controlled study. Pain 145:96-104
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Staud, Roland; Price, Donald D (2008) Role of Placebo Factors in Clinical Trials with Special Focus on Enrichment Designs. Pain 139:479-480
Staud, Roland; Bovee, Courtney E; Robinson, Michael E et al. (2008) Cutaneous C-fiber pain abnormalities of fibromyalgia patients are specifically related to temporal summation. Pain 139:315-23

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