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

被引：24

作者：

Lucarini, Elena ^{[1
]}

Coppi, Elisabetta ^{[1
]}

Micheli, Laura ^{[1
]}

Parisio, Carmen ^{[1
]}

Vona, Alessia ^{[1
]}

Cherchi, Federica ^{[1
]}

Pugliese, Anna M. ^{[1
]}

Pedata, Felicita ^{[1
]}

Failli, Paola ^{[1
]}

Palomino, Seph ^{[2
]}

Wahl, Jared ^{[2
]}

Largent-Milnes, Tally M. ^{[2
]}

Vanderah, Todd W. ^{[2
]}

Tosh, Dilip K. ^{[3
]}

Jacobson, Kenneth A. ^{[3
]}

Salvemini, Daniela ^{[4
,5
]}

Ghelardini, Carla ^{[1
]}

Mannelli, Lorenzo Di Cesare ^{[1
]}

机构：

[1] Neurofarba, Div Pharmacol & Toxicol, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy

[2] Univ Arizona, Dept Pharmacol, Coll Med Tucson, Tucson, AZ USA

[3] NIDDK, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA

[4] St Louis Univ, Sch Med, Dept Pharmacol & Physiol, St Louis, MO USA

[5] St Louis Univ, Henry & Amelia Nasrallah Ctr Neurosci, St Louis, MO 63103 USA

来源：

PAIN | 2020年 / 161卷 / 09期

关键词：

A3 adenosine receptor; DRG; Abdominal pain; IBS; IBD; IRRITABLE-BOWEL-SYNDROME; ADENOSINE RECEPTOR AGONISTS; FACTOR-KAPPA-B; NEUROPATHIC PAIN; GASTROINTESTINAL TRANSIT; COLORECTAL DISTENSION; VISCEROMOTOR RESPONSE; RHEUMATOID-ARTHRITIS; GLUCOSE DEPRIVATION; INDUCED COLITIS;

D O I：

10.1097/j.pain.0000000000001905

中图分类号：

R614 [麻醉学];

学科分类号：

100217 ;

摘要：

Pharmacological tools for chronic visceral pain management are still limited and inadequate. A(3)adenosine receptor (A(3)AR) agonists are effective in different models of persistent pain. Recently, their activity has been related to the block of N-type voltage-gated Ca(2+)channels (Ca(v)2.2) in dorsal root ganglia (DRG) neurons. The present work aimed to evaluate the efficacy of A(3)AR 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 A(3)AR agonists (MRS5980 and Cl-IB-MECA) were evaluated over time after DNBS injection and compared to that of the selective Ca(v)2.2 blocker PD173212, and the clinically used drug linaclotide. A(3)AR 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 Ca(v)2.2. The effects of MRS5980 and Cl-IB-MECA were completely abolished by the selective A(3)AR antagonist MRS1523. Furthermore, patch-clamp recordings showed that A(3)AR agonists inhibited Ca(v)2.2 in dorsal root ganglia neurons isolated from either control or DNBS-treated rats. The effect on Ca(2+)current was PD173212-sensitive and prevented by MRS1523. A(3)AR agonists are effective in relieving visceral hypersensitivity induced by DNBS, suggesting a potential therapeutic role against abdominal pain.

引用

页码：2179 / 2190

页数：12

共 105 条

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