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, A_2A, A_2B, 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 A_2AAR and A_2BAR 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.

Keywords: adenosine; adenosine receptors; antinociception; pain.

Figure 1

Adenosine (Ado) metabolism and involvement of adenosine receptors (ARs) in pain. The main source of adenosine is adenosine triphosphate (ATP) released from various cell types in response to different stimuli. ATP is dephosphorylated to adenosine diphosphate (ADP)/adenosine monophosphate (AMP) and then to adenosine by two ectonucleotidases (CD39, CD73). In nociception, the elevated levels of adenosine may alter the pain signaling. Thus, the modulation of adenosine metabolisms, increasing its levels, could represent an alternative strategy for pain management. Soluble CD73 provokes long-lasting thermal antihyperalgesic and mechanical antiallodynic effects through A₁AR activation. Prostatic acid phosphatase (PAP), acting as an ectonucleotidase, induces A₁AR-dependent antinociceptive effects in inflammatory and neuropathic pain models. Extracellular adenosine is rapidly metabolized to inosine by adenosine deaminase (ADA). Inosine is able to bind A₁ARs, with an affinity similar to that of adenosine, inducing antinociceptive effects. Another strategy to promote the accumulation of inosine is represented by the inhibitors of the enzyme xanthine oxidase such as allopurinol. In the extracellular space, adenosine can interact with its receptors. A₁ARs stimulation with adenosine, adenosine metabolites like inosine, or synthetic agonists presents analgesic effects in acute, neuropathic, visceral, postoperative, and inflammatory pain. Activation of A_2AARs by endogenous adenosine or exogenous agonists results in antinociception in case of inflammatory pain. While, A_2AARs blockade shows analgesic effects in neuropathic pain. Regarding A_2BARs, their stimulation has antinociceptive effects in neuropathic pain and their blockade is useful for acute pain treatment. Finally, A₃ARs activation gives analgesic effects in different types of pain such as neuropathic, cancer, and visceral pain.