Acute visceral pain relief mediated by A3AR agonists in rats: Involvement of N-type voltage-gated calcium channels

Elena Lucarini, Elisabetta Coppi, Laura Micheli, Carmen Parisio, Alessia Vona, Federica Cherchi, Anna M. Pugliese, Felicita Pedata, Paola Failli, Seph Palomino, Jared Wahl, Tally M. Largent-Milnes, Todd W. Vanderah, Dilip K. Tosh, Kenneth A. Jacobson, Daniela Salvemini, Carla Ghelardini, Lorenzo Di Cesare Mannelli

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Pharmacological tools for chronic visceral pain management are still limited and inadequate. A3 adenosine receptor (A3AR) agonists are effective in different models of persistent pain. Recently, their activity has been related to the block of N-type voltage-gated Ca21 channels (Cav2.2) in dorsal root ganglia (DRG) neurons. The present work aimed to evaluate the efficacy of A3AR agonists in reducing postinflammatory visceral hypersensitivity in both male and female rats. Colitis was induced by the intracolonic instillation of 2,4-dinitrobenzenesulfonic acid (DNBS; 30 mg in 0.25 mL 50% EtOH). Visceral hypersensitivity was assessed by measuring the visceromotor response and the abdominal withdrawal reflex to colorectal distension. The effects of A3AR agonists (MRS5980 and Cl-IB-MECA) were evaluated over time after DNBS injection and compared to that of the selective Cav2.2 blocker PD173212, and the clinically used drug linaclotide. A3AR agonists significantly reduced DNBS-evoked visceral pain both in the postinflammatory (14 and 21 days after DNBS injection) and persistence (28 and 35 days after DNBS) phases. Efficacy was comparable to effects induced by linaclotide. PD173212 fully reduced abdominal hypersensitivity to control values, highlighting the role of Cav2.2. The effects of MRS5980 and Cl-IB-MECA were completely abolished by the selective A3AR antagonist MRS1523. Furthermore, patch-clamp recordings showed that A3AR agonists inhibited Cav2.2 in dorsal root ganglia neurons isolated from either control or DNBS-treated rats. The effect on Ca21 current was PD173212-sensitive and prevented by MRS1523. A3AR agonists are effective in relieving visceral hypersensitivity induced by DNBS, suggesting a potential therapeutic role against abdominal pain.

Original languageEnglish (US)
Pages (from-to)2179-2190
Number of pages12
JournalPain
Volume161
Issue number9
DOIs
StatePublished - Sep 2020

Keywords

  • A3 adenosine receptor
  • Abdominal pain
  • DRG
  • IBD
  • IBS

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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