Antidromic Spike Propagation and Dissimilar Expression of P2X, 5-HT, and TRPV1 Channels in Peripheral vs. Central Sensory Axons in Meninges

Abstract

Background: The terminal branches of the trigeminal nerve in meninges are supposed to be the origin site of migraine pain. The main function of these peripheral sensory axons is the initiation and propagation of spikes in the orthodromic direction to the second order neurons in the brainstem. The stimulation of the trigeminal ganglion induces the release of the neuropeptide CGRP in meninges suggesting the antidromic propagation of excitation in these fibers. However, the direct evidence on antidromic spike traveling in meningeal afferents is missing.Methods: By recording of spikes from peripheral or central parts of the trigeminal nerve in rat meninges, we explored their functional activity and tested the expression of ATP-, serotonin-, and capsaicin-gated receptors in the distal vs. proximal parts of these nerves.Results: We show the significant antidromic propagation of spontaneous spikes in meningeal nerves which was, however, less intense than the orthodromic nociceptive traffic due to higher number of active fibers in the latter. Application of ATP, serotonin and capsaicin induced a high frequency nociceptive firing in peripheral processes while, in central parts, only ATP and capsaicin were effective. Disconnection of nerve from trigeminal ganglion dramatically reduced the tonic antidromic activity and attenuated the excitatory action of ATP.Conclusion: Our data indicate the bidirectional nociceptive traffic and dissimilar expression of P2X, 5-HT and TRPV1 receptors in proximal vs. distal parts of meningeal afferents, which is important for understanding the peripheral mechanisms of migraine pain.

Deciphering in silico the Role of Mutated NaV1.1 Sodium Channels in Enhancing Trigeminal Nociception in Familial Hemiplegic Migraine Type 3

“…A contributing role of Na V 1.8 channels to the multiple firing of primary afferents was shown previously in our model of the neuro-immune synapse in meninges (Suleimanova et al, 2020). Moreover, recently we found ATP-gated (but not 5-HT-induced) nociceptive firing not only at peripheral nerve terminals but also in more central parts of trigeminal nerve fibers in rat meninges (Gafurov et al, 2021). The latter suggests that ATP can activate nerve fibers not only at the end points of an axon but also along the fiber and that this probability is higher for ATP than for 5-HT.…”

Heat But Not Mechanical Hypersensitivity Depends on Voltage-Gated CaV2.2 Calcium Channel Activity in Peripheral Axon Terminals Innervating Skin

“…Our studies support a model in which Ca V 2.2 channels in peripheral nerve termini are activated by capsaicin-induced depolarization, and we suggest that the calcium that enters nerve endings through Ca V 2.2 channels is a critical early step in the development of hypersensitivity. Capsaicin can also trigger action potentials in DRG neurons ( Blair and Bean, 2002 ; Castiglioni et al, 2006 ), which could potentially back propagate and contribute to calcium entry ( Gossard et al, 1999 ; Gafurov et al, 2020 ), although it is not known if such signals could reach peripheral nerve termini innervating skin.…”

Localization of the neuropeptides pituitary adenylate cyclase-activating polypeptide, vasoactive intestinal peptide, and their receptors in the basal brain blood vessels and trigeminal ganglion of the mouse CNS; an immunohistochemical study

“…The PAC1 receptor gene is expressed in rat peritoneal macrophages and microglia (Pozo et al, 1997) and the VPAC2 receptor in macrophages and lymphocytes in mice upon stimulation (Miller, 2006;Abad and Tan, 2018). The trigeminal innervation of cerebral blood vessels and meninges, forming the trigeminovascular system, is believed to be the origin of migraine pain (Messlinger, 2009;Gafurov et al, 2021). Therefore, the release of PACAP from trigeminal 10.3389/fnana.2022.991403 nerve fibers might initiate neurogenic inflammation associated with migraine pathology.…”

“…Sensory information is generally thought to travel from the peripheral terminals of primary afferent neurons to the CNS. However, there is evidence that release of neuropeptides can be generated by peripheral or central stimulation ( Lobanov and Peng, 2011 ; Gafurov et al, 2021 ). Release of CGRP and SP from C fibers has been shown to contribute to neurogenic inflammation ( Maggi, 1995 ; Sousa-Valente and Brain, 2018 ).…”