Proinflammatory-Activated Trigeminal Satellite Cells Promote Neuronal Sensitization: Relevance for Migraine Pathology

Abstract

Background Migraine is a complex, chronic, painful, neurovascular disorder characterized by episodic activation of the trigeminal system. Increased levels of calcitonin gene-related peptide (CGRP) are found at different levels during migraine attacks. Interestingly, CGRP is also released within the trigeminal ganglia suggesting possible local effects on satellite cells, a specialized type of glia that ensheaths trigeminal neurons. CGRP was shown to enhance satellite-cell production of interleukin 1β (IL-1β), while trigeminal neurons express an activity-dependent production of nitric oxide (NO). Thus, in the present study we tested the hypothesis that IL-1β and NO induce trigeminal satellite cell activation, and that once activated these cells can influence neuronal responses. Results Primary cultures of rat trigeminal satellite cells isolated from neuronal cultures were characterized in vitro. Cyclooxygenase (COX) expression and activity were taken as a marker of glial pro-inflammatory activation. Most of the experiments were carried out to characterize satellite cell responses to the two different pro-inflammatory stimuli. Subsequently, medium harvested from activated satellite cells was used to test possible modulatory effects of glial factors on trigeminal neuronal activity. IL-1β and the NO donor diethylenetriamine/nitric oxide (DETA/NO) elevated PGE2 release by satellite cells. The stimulatory effect of IL-1β was mediated mainly by upregulation of the inducible form of COX enzyme (COX2), while NO increased the constitutive COX activity. Regardless of the activator used, it is relevant that short exposures of trigeminal satellite cells to both activators induced modifications within the cells which led to significant PGE2 production after removal of the pro-inflammatory stimuli. This effect allowed us to harvest medium from activated satellite cells (so-called ‘conditioned medium’) that did not contain any stimulus, and thus test the effects of glial factors on neuronal activation. Conditioned medium from satellite cells activated by either IL-1β or NO augmented the evoked release of CGRP by trigeminal neurons. Conclusion These findings indicate that satellite cells contribute to migraine-related neurochemical events and are induced to do so by autocrine/paracrine stimuli (such as IL-1β and NO). The responsiveness of IL-1β to CGRP creates the potential for a positive feedback loop and, thus, a plurality of targets for therapeutic intervention in migraine.