Fibromyalgia Pain: Do We Know the Source?

Roland Staud


Curr Opin Rheumatol. 2004;16(2) 

In This Article

Role of Cytokines for Fibromyalgia Syndrome Pain

Cytokines such as IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) have been shown to contribute directly to central and peripheral neuropathic pain.[71] Immune cells activated in response to infection, inflammation, or trauma, release proteins called proinflammatory cytokines. These proinflammatory cytokines provide signals to the central nervous system thereby creating exaggerated pain as well as a number of physiologic, behavioral, and hormonal changes. These changes are frequently referred to as the sickness response, which seems representative of FMS patients' symptoms.[72*] Release of proinflammatory cytokines by immune cells in the body leads, in turn, to release of proinflammatory cytokines by glia within the brain and spinal cord.[73] Proinflammatory cytokines can exert powerful pain facilitatory effects following their release in the body, in the brain, and in the spinal cord. Such exaggerated pain states naturally occur in situations involving infection, inflammation, or trauma of the skin, of peripheral nerves and muscles, and of the central nervous system itself.[74]

The cells most important for cytokine/chemokine signaling are macrophages/monocytes. This has been shown in animal experiments of mice lacking the chemokine receptor chemotactic cytokine receptor 2 (CCR2). These knockout mice demonstrated a marked attenuation of monocyte recruitment in response to various inflammatory stimuli and a reduction of inflammatory lesions.[71] After CCR2 receptors were removed from the cells through genetic manipulations the animals underwent testing of pain response to inflammation and nerve injury. As expected there was no difference in pain responding of these animals to acute pain stimuli. In models of inflammatory pain, however, CCR2 knockout mice showed a 70% reduction of the pain response and more importantly, in a model of neuropathic pain, the development of mechanical allodynia was completely abrogated. In response to nerve ligation, persistent and marked up-regulation of CCR2 mRNA was evident in the nerve and DRG. Chronic pain also resulted in the appearance of activated CCR2-positive microglia in the spinal cord. These data suggest that the recruitment and activation of macrophages and microglia peripherally and in neural tissue may contribute to both inflammatory and neuropathic pain states. Accordingly, blockade of the CCR2 receptor may provide a novel therapeutic modality for the treatment of chronic pain.[71]

Cytokines have been a multidisciplinary research focus for over two decades. To date, several topics have emerged as critical issues, including: (1) how do cytokines modulate the functions of the CNS and (2) what is the role of cytokines in the pathogenesis of FMS? Thus far, it has been clearly established that cytokines can alter the functions of the CNS through autonomic, neuroendocrine, and behavioral mechanisms.[75] Furthermore, increasing evidence points to the potential involvement of cytokines in the induction and modulation of an array of neurologic diseases ranging from Alzheimer's disease to chronic pain.[76*] Therefore cytokine signaling may represent an important mechanism that links relevant stressors like trauma and infection, to the chronic pain of FMS.


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