Sensitization and Activation of Intracranial Meningeal Nociceptors by Mast Cell Mediators

Abstract

Intracranial headaches such as migraine are thought to result from activation of sensory trigeminal pain neurons that supply intracranial blood vessels and the meninges, also known as meningeal nociceptors. Although the mechanism underlying the triggering of such activation is not completely understood, our previous work indicates that the local activation of the inflammatory dural mast cells can provoke a persistent sensitization of meningeal nociceptors. Given the potential importance of mast cells to the pain of migraine it is important to understand which mast cell-derived mediators interact with meningeal nociceptors to promote their activation and sensitization. In the present study, we have used in vivo electrophysiological single-unit recording of meningeal nociceptors in the trigeminal ganglion of anesthetized rats to examine the effect of a number of mast cell mediators on the activity level and mechanosensitivity of meningeal nociceptors. We have found that that serotonin (5-HT), prostaglandin I 2 (PGI 2 ), and to a lesser extent histamine can promote a robust sensitization and activation of meningeal nociceptors, whereas the inflammatory eicosanoids PGD 2 and leukotriene C 4 are largely ineffective. We propose that dural mast cells could promote headache by releasing 5-HT, PGI 2 , and histamine.

Role of prostaglandin D2 in mast cell activation-induced sensitization of esophageal vagal afferents

“…Extracellular recording of direct-current potentials indicated that PGD 2 perfusion caused a depolarization response of vagal C fibers (25). However, in another study using in vivo electrophysiological single-unit recording from rat trigeminal ganglion, PGD 2 failed to sensitize meningeal nociceptors (34). In contrast, responses of spinal afferent neurons to PGD 2 are different from responses of nodose and DRG neurons.…”

Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1

“…PGD 2 is the most abundant PG released from inflammatory cells at sites of inflammation (37). Although PGD 2 can inhibit postspike hyperpolarization of nociceptors in vagal afferents (38), we and others (39,40) reported that it is unable to directly excite DRG or trigeminal neurons. Thus, although its relevance in nociception remains per se questionable, the role of all PGD 2 -derived cyclopentenone metabolites (20) should be considered in pain transmission.…”

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…In addition, these joint preparations are the only model in which prostaglandins by close-arterial injection caused spike discharge with short delay. In the anesthetized rat, PGE 2 potentiated the response of pulmonary C-fibers to lung inflation and PGI 2 , but not PGD 2 , increased responses of meningeal nociceptors to mechanical stimulation (287,796).…”