Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions

Abstract

Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pronociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca 2+ transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pronociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.

Purinergic Signaling in the Cardiovascular System

“…148,211 Data were also presented recently that was consistent with the purinergic hypothesis of migraine pain. 212 In migraine, peripheral sensitization in the dura-vascular sensory pathway via P2X3 receptors occurs. P2X3 receptor antagonists have been suggested as potential candidates for antimigraine drug development.…”

Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model

“…The role of the purinergic signalling system in the pathophysiology of migraine was proposed more than 30 years ago. Since then, different subtypes of P2 receptors have been elucidated, including the P2X3R, P2X7R, P2Y1R, and P2Y2R [40][41][42]. Among them, the P2X3R is the most widely studied.…”

The Emerging Role of Mechanosensitive Piezo Channels in Migraine Pain

“…Based on the concept of the meningeal trigeminovascular system (TGVS) as the initial site for the generation of migraine headache [21], we propose the following model potentially explaining the mechanism of pulsating migraine pain. Figure 2 shows that in interictal state (or in healthy subjects), meningeal nerves express a plethora of pain transducing channels such as mechanosensitive Piezo1 and Piezo2 receptors [5], along with capsaicin-sensitive TRPV1 [36] and ATP-activated P2X3 receptors [37], which all are in low-active non-sensitized state. The main key components of the TGVS, such as meningeal vessels and neighboring nerves, in this state, have a low chance to interact to each other either physically or chemically and a low probability to generate pain signals.…”

“…Vasodilatation, shear stress and enhanced pulse waves in dilated vessels can activate mechanoreceptors in endothelial cells, triggering, via pannexins, ATP release ( Figure 2) [45]. ATP is a strong promoter of nociceptive firing in meninges by itself [37,43] but it is also a trigger of mast cell degranulation promoting further release of the pro-inflammatory and pro-nociceptive compounds to meninges.…”