Molecular Mechanisms of Sensitization of Pain-transducing P2X3 Receptors by the Migraine Mediators CGRP and NGF

Abstract

Migraine headache originates from the stimulation of nerve terminals of trigeminal ganglion neurons that innervate meninges. Characteristic features of migraine pain are not only its delayed onset but also its persistent duration. Current theories propose that endogenous substances released during a migraine attack (the neuropeptide calcitonin gene-related peptide [CGRP] and the neurotrophin nerve growth factor [NGF]) sensitize trigeminal neurons to transmit nociceptive signals to the brainstem, though the mechanisms remain poorly understood. Recent studies indicate that acute, long-lasting sensitization of trigeminal nociceptive neurons occurs via distinct processes involving enhanced expression and function of adenosine triphosphate (ATP)-gated P2X3 receptors known to play a role in chronic pain. In particular, on cultured trigeminal neurons, CGRP (via protein kinase A-dependent signaling) induces a slowly developing upregulation of the ionic currents mediated by P2X3 receptors by enhancing receptor trafficking to the neuronal membrane and activating their gene transcription. Such upregulated receptors acquire the ability to respond repeatedly to extracellular ATP, thus enabling long-lasting signaling of painful stimuli. In contrast, NGF induces rapid, reversible upregulation of P2X3 receptor function via protein kinase C phosphorylation, an effect counteracted by anti-NGF antibodies. The diverse intracellular signaling pathways used by CGRP and NGF show that the sensitization of P2X3 receptor function persists if the action of only one of these migraine mediators is blocked. These findings imply that inhibiting a migraine attack might be most efficient by a combinatorial approach. The different time domains of P2X3 receptor modulation by NGF and CGRP suggest that the therapeutic efficacy of novel antimigraine drugs depends on the time of administration.

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Abbreviations

α,β-meATP:

α,β-methylene ATP

BDNF:

brain-derived nerve factor

CGRP:

calcitonin gene-related peptide

DRG:

dorsal root ganglia

NGF:

nerve growth factor

NO:

nitric oxide

PMA:

phorbol 12-myristate 13-acetate

5-HT1B,1D,1F :

5-hydroxytryptamine (serotonin) receptor subtypes

TG:

trigeminal ganglia

TrkA:

tyrosine receptor kinase

TRPV1:

transient receptor potential vanilloid 1

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Acknowledgments

This work is supported by grants from the Telethon Foundation (GGP07032), the Italian Institute of Technology, and Ministero dell’Universita’ e Ricerca (FIRB project).

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Correspondence to Andrea Nistri.

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Giniatullin, R., Nistri, A. & Fabbretti, E. Molecular Mechanisms of Sensitization of Pain-transducing P2X3 Receptors by the Migraine Mediators CGRP and NGF. Mol Neurobiol 37, 83 (2008). https://doi.org/10.1007/s12035-008-8020-5

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Keywords

  • ATP
  • Trigeminal neurons
  • Purinergic receptors
  • Nociception
  • Headache