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Adenosine A3 receptor activation inhibits pronociceptive N-type Ca2+ currents and cell excitability in dorsal root ganglion neurons

Coppi, Elisabettaa,*; Cherchi, Federicaa; Fusco, Irenea; Failli, Paolaa; Vona, Alessiaa; Dettori, Ilariaa; Gaviano, Lisaa; Lucarini, Elenaa; Jacobson, Kenneth A.b; Tosh, Dilip K.b; Salvemini, Danielac; Ghelardini, Carlaa; Pedata, Felicitaa; Di Cesare Mannelli, Lorenzoa; Pugliese, Anna Mariaa

doi: 10.1097/j.pain.0000000000001488
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Recently, studies have focused on the antihyperalgesic activity of the A3 adenosine receptor (A3AR) in several chronic pain models, but the cellular and molecular basis of this effect is still unknown. Here, we investigated the expression and functional effects of A3AR on the excitability of small- to medium-sized, capsaicin-sensitive, dorsal root ganglion (DRG) neurons isolated from 3- to 4-week-old rats. Real-time quantitative polymerase chain reaction experiments and immunofluorescence analysis revealed A3AR expression in DRG neurons. Patch-clamp experiments demonstrated that 2 distinct A3AR agonists, Cl-IB-MECA and the highly selective MRS5980, inhibited Ca2+-activated K+ (KCa) currents evoked by a voltage-ramp protocol. This effect was dependent on a reduction in Ca2+ influx via N-type voltage-dependent Ca2+ channels, as Cl-IB-MECA–induced inhibition was sensitive to the N-type blocker PD173212 but not to the L-type blocker, lacidipine. The endogenous agonist adenosine also reduced N-type Ca2+ currents, and its effect was inhibited by 56% in the presence of A3AR antagonist MRS1523, demonstrating that the majority of adenosine's effect is mediated by this receptor subtype. Current-clamp recordings demonstrated that neuronal firing of rat DRG neurons was also significantly reduced by A3AR activation in a MRS1523-sensitive but PD173212-insensitive manner. Intracellular Ca2+ measurements confirmed the inhibitory role of A3AR on DRG neuronal firing. We conclude that pain-relieving effects observed on A3AR activation could be mediated through N-type Ca2+ channel block and action potential inhibition as independent mechanisms in isolated rat DRG neurons. These findings support A3AR-based therapy as a viable approach to alleviate pain in different pathologies.

3 receptors">Adenosine A3 receptors are pain-relieving effectors. We provide first evidence that they inhibit pronociceptive Ca2+ currents and firing in rat dorsal root ganglion neurons.

aDivision of Pharmacology and Toxicology, Department of NEUROFARBA, University of Florence, Italy

bMolecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States

cDepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, United States

Corresponding author. Address: Division of Pharmacology and Toxicology, Department of NEUROFARBA, University of Florence, Viale Pieraccini 6; 50139 Florence, Italy. Tel.: +39 055 2758276. E-mail address: elisabetta.coppi@unifi.it (E. Coppi).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received July 17, 2018

Received in revised form January 02, 2019

Accepted January 08, 2019

© 2019 International Association for the Study of Pain
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