TY - JOUR
T1 - Acute visceral pain relief mediated by A3AR agonists in rats
T2 - Involvement of N-type voltage-gated calcium channels
AU - Lucarini, Elena
AU - Coppi, Elisabetta
AU - Micheli, Laura
AU - Parisio, Carmen
AU - Vona, Alessia
AU - Cherchi, Federica
AU - Pugliese, Anna M.
AU - Pedata, Felicita
AU - Failli, Paola
AU - Palomino, Seph
AU - Wahl, Jared
AU - Largent-Milnes, Tally M.
AU - Vanderah, Todd W.
AU - Tosh, Dilip K.
AU - Jacobson, Kenneth A.
AU - Salvemini, Daniela
AU - Ghelardini, Carla
AU - Di Cesare Mannelli, Lorenzo
N1 - Funding Information:
This research was supported by the Italian Ministry of Instruction, University and Research and by the University of Florence. The authors are grateful to Dr G.J. Bennett (Department of Anesthesiology, University of California, San Diego, La Jolla, CA) for his input in our work and for editorial contribution to the manuscript.
Publisher Copyright:
© 2020 International Association for the Study of Pain.
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - A3 adenosine receptor
KW - Abdominal pain
KW - DRG
KW - IBD
KW - IBS
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UR - http://www.scopus.com/inward/citedby.url?scp=85096106614&partnerID=8YFLogxK
U2 - 10.1097/j.pain.0000000000001905
DO - 10.1097/j.pain.0000000000001905
M3 - Article
C2 - 32379223
AN - SCOPUS:85096106614
VL - 161
SP - 2179
EP - 2190
JO - Pain
JF - Pain
SN - 0304-3959
IS - 9
ER -