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The Journal of Neuroscience, August 1, 2007, 27(31):8190-8201; doi:10.1523/JNEUROSCI.0713-07.2007

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Development/Plasticity/Repair
Neutralization of Nerve Growth Factor Induces Plasticity of ATP-Sensitive P2X₃ Receptors of Nociceptive Trigeminal Ganglion Neurons

Marianna D'Arco, Rashid Giniatullin, Manuela Simonetti, Alessandra Fabbro, Asha Nair, Andrea Nistri, and Elsa Fabbretti

Neurobiology Sector, International School for Advanced Studies, 34014 Trieste, Italy

Correspondence should be addressed to Andrea Nistri, Neurobiology Sector, International School for Advanced Studies, Via Beirut 4, 34014 Trieste, Italy. Email: nistri{at}sissa.it

The molecular mechanisms of migraine pain are incompletely understood, although migraine mediators such as NGF and calcitonin gene-related peptide (CGRP) are believed to play an algogenic role. Although NGF block is proposed as a novel analgesic approach, its consequences on nociceptive purinergic P2X receptors of trigeminal ganglion neurons remain unknown. We investigated whether neutralizing NGF might change the function of P2X₃ receptors natively coexpressed with NGF receptors on cultured mouse trigeminal neurons. Treatment with an NGF antibody (24 h) decreased P2X₃ receptor-mediated currents and Ca²⁺ transients, an effect opposite to exogenously applied NGF. Recovery from receptor desensitization was delayed by anti-NGF treatment without changing desensitization onset. NGF neutralization was associated with decreased threonine phosphorylation of P2X₃ subunits, presumably accounting for their reduced responses and slower recovery. Anti-NGF treatment could also increase the residual current typical of heteromeric P2X_2/3 receptors, consistent with enhanced membrane location of P2X₂ subunits. This possibility was confirmed with cross-linking and immunoprecipitation studies. NGF neutralization also led to increased P2X_2e splicing variant at mRNA and membrane protein levels. These data suggest that NGF controlled plasticity of P2X₃ subunits and their membrane assembly with P2X₂ subunits. Despite anti-NGF treatment, CGRP could still enhance P2X₃ receptor activity, indicating separate NGF- or CGRP-mediated mechanisms to upregulate P2X₃ receptors. In an in vivo model of mouse trigeminal pain, anti-NGF pretreatment suppressed responses evoked by P2X₃ receptor activation. Our findings outline the important contribution by NGF signaling to nociception of trigeminal sensory neurons, which could be counteracted by anti-NGF pretreatment.

Key words: pain; purinergic receptor; subunit composition; nociception; neurotrophin; migraine

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Received Nov. 20, 2006; revised June 8, 2007; accepted June 13, 2007.

Correspondence should be addressed to Andrea Nistri, Neurobiology Sector, International School for Advanced Studies, Via Beirut 4, 34014 Trieste, Italy. Email: nistri{at}sissa.it

This article has been cited by other articles:

				M. Simonetti, R. Giniatullin, and E. Fabbretti Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor by Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons J. Biol. Chem., July 4, 2008; 283(27): 18743 - 18752. [Abstract] [Full Text] [PDF]

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