Targeting Adenosine Receptors: A Potential Pharmacological Avenue for Acute and Chronic Pain

Abstract

Adenosine is a purine nucleoside, responsible for the regulation of multiple physiological and pathological cellular and tissue functions by activation of four G protein-coupled receptors (GPCR), namely A1, A2A, A2B, and A3 adenosine receptors (ARs). In recent years, extensive progress has been made to elucidate the role of adenosine in pain regulation. Most of the antinociceptive effects of adenosine are dependent upon A1AR activation located at peripheral, spinal, and supraspinal sites. The role of A2AAR and A2BAR is more controversial since their activation has both pro- and anti-nociceptive effects. A3AR agonists are emerging as promising candidates for neuropathic pain. Although their therapeutic potential has been demonstrated in diverse preclinical studies, no AR ligands have so far reached the market. To date, novel pharmacological approaches such as adenosine regulating agents and allosteric modulators have been proposed to improve efficacy and limit side effects enhancing the effect of endogenous adenosine. This review aims to provide an overview of the therapeutic potential of ligands interacting with ARs and the adenosinergic system for the treatment of acute and chronic pain.

Metabolic and behavioral features of acute hyperpurinergia and the maternal immune activation mouse model of autism spectrum disorder

“…Metabolism of ATP leads to the production of ADP, AMP, and adenosine, which can each bind different purinergic receptors, transporters, and other proteins, and lead to hypometabolism and can cause hypothermia by several different mechanisms [65]. The role of adenine nucleotides and adenosine in lowering the metabolic rate in the context environmental stress [65][66][67][68], chronic pain [69], and non-REM sleep [70] has been studied for many years. Other purine metabolites like inosine, xanthosine, and xanthine are also produced by metabolic transformation of ATP.…”

Purines in Pain as a Gliopathy

“…Therefore, these receptors undoubtedly represent a promising approach to manage pain conditions characterized by a dysregulated cross-talk among different cell types. Available and sometimes contradictory data on the antinociceptive effects exerted by the administration of adenosine ligands in several preclinical models of acute and chronic pain have been recently extensively reviewed ( Vincenzi et al, 2020 ). We shall now briefly highlight the most promising hints for their possible exploitation in humans as well.…”

Metabolic Aspects of Adenosine Functions in the Brain

“…Adenosine regulates multiple physiological and pathophysiological processes, by acting both through G-protein coupled adenosine receptors and intracellularly. It modulates neuronal plasticity (Sebastiao and Ribeiro, 2015), astrocytic activity (Agostinho et al, 2020), learning and memory (Chen, 2014;Simoes et al, 2016;Bannon et al, 2017;Perrier et al, 2019;Temido-Ferreira et al, 2019;Zhang et al, 2020), food intake (Kola, 2008), motor function (Mori, 2020), sleep/wake cycle (Donlea et al, 2017;Lazarus et al, 2019), pain (Vincenzi et al, 2020), immunosupression (Vijayan et al, 2017), proliferation (Jacobson et al, 2019), and aging (Costenla et al, 2011). Adenosine is involved in ischemia and stroke (Williams-Karnesky and Stenzel-Poore, 2009;Melani et al, 2014;Pereira-Figueiredo et al, 2021), epilepsy (Boison and Jarvis, 2020;Tescarollo et al, 2020), and neurodegenerative pathologies such as Parkinson's disease (PD) (Fredholm and Svenningsson, 2020;Glaser et al, 2020), Alzheimer's disease (AD) (Rahman, 2009;Cunha and Agostinho, 2010;Cellai et al, 2018), amyotrophic lateral sclerosis (ALS) (Ng et al, 2015;Sebastiao et al, 2018), and Huntington's disease (HD) (Lee and Chern, 2014).…”