Primary fibromyalgia is a common yet poorly understood syndrome characterized by diffuse chronic pain accompanied by other somatic symptoms, including poor sleep, fatigue, and stiffness, in the absence of disease. Fibromyalgia does not have a distinct cause or pathology. Nevertheless, in the past decade, the study of chronic pain has yielded new insights into the pathophysiology of fibromyalgia and related chronic pain disorders. Accruing evidence shows that patients with fibromyalgia experience pain differently from the general population because of dysfunctional pain processing in the central nervous system. Aberrant pain processing, which can result in chronic pain and associated symptoms, may be the result of several interplaying mechanisms, including central sensitization, blunting of inhibitory pain pathways, alterations in neurotransmitters, and psychiatric comorbid conditions. This review provides an overview of the mechanisms currently thought to be partly responsible for the chronic diffuse pain typical of fibromyalgia.
We employed neutrophils and enucleate neutrophil cytoplasts to study the activation of the mitogen-activated protein kinases (MAPKs) p44 erk1 and p42 erk2 in neutrophils by inflammatory agonists that engage G protein-linked receptors. Formyl-methionyl-leucylphenylalanine (FMLP) rapidly and transiently activated MAPK in neutrophils and cytoplasts, consistent with a role in signaling for neutrophil functions. FMLP stimulated p21 ras activation in neutrophils and Raf-1 translocation from cytosol to plasma membrane in cytoplasts, with kinetics consistent with events upstream of MAPK activation. Insulin, a protein tyrosine kinase receptor (PTKR) agonist, stimulated neutrophil MAPK activation, demonstrating an intact system of PTKR signaling in these post-mitotic cells. FMLP-and insulin-stimulated MAPK activation in cytoplasts were inhibited by Bt 2 cAMP, consistent with signaling through Raf-1 and suggesting a mechanism for cAMP inhibition of neutrophil function. However, Bt 2 cAMP had no effect on FMLP-stimulated MAPK activation in neutrophils. The extent of MAPK activation by various chemoattractants correlated with their capacity to stimulate neutrophil and cytoplast homotypic aggregation. Consistent with its effects on MAPK, Bt 2 cAMP inhibited FMLP-stimulated aggregation in cytoplasts but not neutrophils. Insulin had no independent effect but primed neutrophils for aggregation in response to FMLP. Our studies support a p21 ras -, Raf-1-dependent pathway for MAPK activation in neutrophils and suggest that neutrophil adhesion may be regulated, in part, by MAPK.
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