P2X7 receptors exert a permissive effect on the activation of presynaptic AMPA receptors in rat trigeminal caudal nucleus glutamatergic nerve terminals

Maria Martire,Diego Currò,Irene Samengo,Pierluigi Navarra

doi:10.1186/s10194-020-01153-y

Maria Martire, Diego Currò + Show 2 more

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https://doi.org/10.1186/s10194-020-01153-y

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Abstract

BackgroundPurine receptors play roles in peripheral and central sensitization and are associated with migraine headache. We investigated the possibility that ATP plays a permissive role in the activation of AMPA receptors thus inducing Glu release from nerve terminals isolated from the rat trigeminal caudal nucleus (TCN).MethodsNerve endings isolated from the rat TCN were loaded with [3H]D-aspartic acid ([3H]D-ASP), layered into thermostated superfusion chambers, and perfused continuously with physiological medium, alone or with various test drugs. Radioactivity was measured to assess [3H]D-ASP release under different experimental conditions.ResultsSynaptosomal [3H]D-ASP spontaneous release was stimulated by ATP and to an even greater extent by the ATP analogue benzoylbenzoylATP (BzATP). The stimulation of [3H]D-ASP basal release by the purinergic agonists was prevented by the selective P2X7 receptor antagonist A438079. AMPA had no effect on basal [3H]D-ASP release, but the release observed when synaptosomes were exposed to AMPA plus a purinoceptor agonist exceeded that observed with ATP or BzATP alone. The selective AMPA receptor antagonist NBQX blocked this “excess” release. Co-exposure to AMPA and BzATP, each at a concentration with no release-stimulating effects, evoked a significant increase in [3H]D-ASP basal release, which was prevented by exposure to a selective AMPA antagonist.ConclusionsP2X7 receptors expressed on glutamatergic nerve terminals in the rat TCN can mediate Glu release directly and indirectly by facilitating the activation of presynaptic AMPA receptors. The high level of glial ATP that occurs during chronic pain states can promote widespread release of Glu as well as can increase the function of AMPA receptors. In this manner, ATP contributes to the AMPA receptor activation involved in the onset and maintenance of the central sensitization associated with chronic pain.

Highlights

Purine receptors play roles in peripheral and central sensitization and are associated with migraine headache
We examined interactions between P2X7 receptors and Amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) receptors co-expressed on primary afferents that from trigeminal ganglion (TG) project into the trigeminal caudal nucleus (TCN) of the rat brain
We found that the activation of adenosine 5′-triphosphate disodium salt (ATP) receptors belonging to the P2X7 subtype elicits Glu release, and facilitates the activation of releaseenhancing AMPA receptors co-existing with P2X7 receptors on TCN glutamatergic terminals

Summary

Introduction

Purine receptors play roles in peripheral and central sensitization and are associated with migraine headache. We investigated the possibility that ATP plays a permissive role in the activation of AMPA receptors inducing Glu release from nerve terminals isolated from the rat trigeminal caudal nucleus (TCN). The stimulation of [3H]D-ASP basal release by the purinergic agonists was prevented by the selective P2X7 receptor antagonist A438079. Coexposure to AMPA and BzATP, each at a concentration with no release-stimulating effects, evoked a significant increase in [3H]D-ASP basal release, which was prevented by exposure to a selective AMPA antagonist. P2X7 receptors are widely expressed by several cell types involved in pain transmission, including the neurons, microglia, satellite glial cells, and astrocytes located in the dorsal root ganglia, the trigeminal ganglia, and in the dorsal horn of the spinal cord [4]. P2X7 receptors are co-localized in nerve terminals with the vesicular Glu transporters vGLUT1 and vGLUT2 [12], and they have been shown to trigger Glu release by astrocytes [13] as well as neurons [14]

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