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. Introduction:. Neuroimaging reveals increased glutamate within the insula of patients with fibromyalgia (FM), suggesting a link between FM symptoms and increased central excitatory neurotransmission. Many patients with FM also present with decreased intraepidermal nerve fiber density (IENFD), consistent with small fiber pathology. It remains unknown, however, whether either of these mechanistic findings represent a cause or a consequence of the other. This study tests the hypothesis that an excitatory imbalance within the insula leads to small fiber pathology.Objectives:. This is a proof-of-concept study to examine whether a chronic, bilateral increase in insular glutamate can be a causal factor in the development of small fiber neuropathy in FM.Methods:. The glutamate transport inhibitor l-trans-Pyrrolidine-2,4-dicarboxylic acid (PDC), which increases endogenous levels of glutamate, was dissolved in Ringer solution and bilaterally delivered into the insula of rats for 6 weeks. Naive rats that did not undergo any surgery or treatment and rats administered Ringer vehicle solution into the insula served as controls. Multimodal nociceptive sensitivity was assessed weekly. Hind paw tissue biopsies were collected for IENFD assessment, at the end of the experiment.Results:. Compared with controls, increasing endogenous glutamate in the insula with PDC caused sustained decreases in mechanical paw withdrawal threshold and thermal paw withdrawal latency, increased aversion to noxious mechanical stimulation, and a decrease in IENFD. Cold reactivity was not altered by PDC administration.Conclusion:. Bilateral insular PDC administration produced a persistent increase in multimodal pain behaviors and a decrease in peripheral nerve fibers in rat. These preclinical findings offer preliminary support that insular hyperactivity may be a casual factor in the development of small fiber pathology in FM

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Reduced intraepidermal nerve fiber density after a sustained increase in insular glutamate: a proof-of-concept study examining the pathogenesis of small fiber pathology in fibromyalgia