Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, 50139 Firenze, Italy.
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
Int J Mol Sci. 2021 Jul 26;22(15):7952. doi: 10.3390/ijms22157952.
Agonists of the G protein-coupled A adenosine receptor (AAR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, AAR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.e., rheumatoid arthritis, psoriasis and fatty liver diseases, confers a realistic translational potential, thus encouraging research studies on the molecular mechanisms underpinning their antinociceptive actions. A number of pathways, involving central and peripheral mechanisms, have been proposed. Recent evidence showed that the prototypical AAR agonist Cl-IB-MECA and the new, highly selective, AAR agonist MRS5980 inhibit neuronal (N-type) voltage-dependent Ca currents in dorsal root ganglia, a known pain-related mechanism. Other proposed pathways involve reduced cytokine production, immune cell-mediated responses, as well as reduced microglia and astrocyte activation in the spinal cord. The aim of this review is to summarize up-to-date information on AAR in the context of pain, including cellular and molecular mechanisms underlying this effect. Based on their safety profile shown in clinical trials for other pathologies, AAR agonists are proposed as novel, promising non-narcotic agents for pain control.
G 蛋白偶联 A 腺苷受体 (AAR) 的激动剂在几种疼痛模型的临床前研究中显示出重要的止痛特性。作为一种针对慢性疼痛的单一疗法，AAR 激动剂也可以与经典的阿片类镇痛药联合使用。它们在临床试验中表现出安全的药理学特性，例如类风湿性关节炎、银屑病和脂肪肝疾病，这赋予了它们具有现实的转化潜力，从而鼓励对其镇痛作用的分子机制进行研究。已经提出了许多涉及中枢和外周机制的途径。最近的证据表明，典型的 AAR 激动剂 Cl-IB-MECA 和新型高选择性 AAR 激动剂 MRS5980 抑制背根神经节中的神经元 (N 型) 电压依赖性钙电流，这是一种已知的与疼痛相关的机制。其他提出的途径涉及细胞因子产生减少、免疫细胞介导的反应以及脊髓中少突胶质细胞和星形胶质细胞激活减少。本综述的目的是总结 AAR 在疼痛背景下的最新信息，包括这种作用的细胞和分子机制。基于它们在其他疾病的临床试验中表现出的安全性，AAR 激动剂被提议作为一种新型、有前途的非阿片类镇痛药用于疼痛控制。
