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

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Targeting Adenosine Receptors: a Potential Pharmacological Avenue for Acute and Chronic Pain International Journal of Molecular Sciences Review Targeting Adenosine Receptors: A Potential Pharmacological Avenue for Acute and Chronic Pain Fabrizio Vincenzi 1,* , Silvia Pasquini 1, Pier Andrea Borea 2 and Katia Varani 1 1 Department of Translational Medicine and for Romagna, Pharmacology Section, University of Ferrara, 44121 Ferrara, Italy; [email protected] (S.P.); [email protected] (K.V.) 2 University of Ferrara, 44121 Ferrara, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0532-455214 Received: 12 October 2020; Accepted: 17 November 2020; Published: 18 November 2020 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. Keywords: adenosine; pain; adenosine receptors; antinociception 1. Introduction Today, although substantial progress has been made, many pathological pain conditions remain poorly understood and resist currently available treatments. There is, therefore, a need for novel molecular targets to develop new therapeutic agents with improved efficacy and tolerability. Many experimental reports have identified adenosine receptors (ARs) as potential targets for the management of acute and chronic pain. Adenosine is a ubiquitous endogenous autacoid that mediates its physiopathological effects by interacting with four G protein-coupled receptors (GPCR), namely A1,A2A,A2B, and A3 ARs [1]. A1 and A3AR are coupled with Gi and Go members of the G protein family, through which they have an inhibitory effect on adenylyl cyclase (AC) activity, while A2AARs and A2BARs stimulate it by coupling to Gs proteins. The consequent modulation of cyclic adenosine monophosphate (cAMP) levels activates or inhibits a large variety of signaling pathways depending on the specific type of cell involved. Although there are instances in which adenosine exerts detrimental effects in various pathological conditions, it is generally considered a protective and homeostatic mediator against tissue damages and stress conditions [2,3]. In physiological and unstressed conditions, the extracellular concentrations of adenosine are maintained low as a result of the rapid metabolism and uptake [4]. However, its levels rise considerably during conditions involving increased metabolic demand, hypoxia, inflammation, and tissue injury. In particular, increased levels of extracellular adenosine were observed in pathological conditions such as epilepsy [5,6], ischemia [7,8], cancer [9,10], Int. J. Mol. Sci. 2020, 21, 8710; doi:10.3390/ijms21228710 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 8710 2 of 21 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 21 [9,10],inflammation inflammation [11], and [11], ultimately and painultimately [12,13 ].pain Although [12,13]. adenosine Although can beadenosine produced can intracellularly, be produced the intracellularly,main source of adenosinethe main source in pathological of adenosine states in is pathological adenosine triphosphate states is adenosine (ATP), released triphosphate by cells (ATP), under releasedstressful by conditions cells under and stressful dephosphorylated conditions and from dephosphorylated the combined action from of the two combined hydrolyzing action enzymes of two hydrolyzingtermed ectonucleoside enzymes termed triphosphate ectonucleoside diphosphohydrolase triphosphate (CD39) diphosphohydrolase and ecto-50-nucleotidase (CD39) and (CD73) ecto-5 [1′].- nucleotidaseRegarding nociception, (CD73) [1]. theseRegardin elevatedg nociception, levels of endogenousthese elevated adenosine levels of canendogenous alter pain adenosine transmission can alterby actions pain transmission at spinal, supraspinal, by actions at and spinal, peripheral supraspinal, sites. and The peripheral extracellular sites. action The extracellular of adenosine action can ofthen adenosine be terminated can then by be its terminated transformation by its to tran inosinesformation through to adenosine inosine through deaminase adenosine (ADA) deaminase and/or by (ADA)intracellular and/or uptake by intracellular via nucleoside uptake transporters via nucleoside [14]. Intracellularly,transporters [14]. adenosine Intracellularly, is phosphorylated adenosine tois AMPphosphorylated by adenosine to kinaseAMP by or deaminatedadenosine kinase to inosine or bydeaminated ADA. Given to theseinosine regulation by ADA. mechanisms Given these of regulationadenosine mechanisms concentration, of potentialadenosine pain concentration, management potential can be obtainedpain manageme not onlynt withcan be specific obtained ligand not onlyinteracting with specific with ARs ligand but alsointeracting by manipulating with ARs but endogenous also by manipulating tissue levels ofendogenous adenosine bytissue modulating levels of adenosineits metabolism by modulating or transport its [13 metaboli] (Figuresm1). or transport [13] (Figure 1). Figure 1.1. Adenosine (Ado)(Ado) metabolism metabolism and and involvement involvement of adenosineof adenosine receptors receptors (ARs) (ARs) in pain. in pain. The main The mainsource source of adenosine of adenosine is adenosine is adenosine triphosphate triphosphate (ATP) released (ATP) fromreleased various from cell various types incell response types in to responsedifferent stimuli.to different ATP stimuli. is dephosphorylated ATP is dephosphor to adenosineylated diphosphate to adenosine (ADP) diphosphate/adenosine (ADP)/adenosine monophosphate monophosphate(AMP) and then to(AMP) adenosine and bythen two to ectonucleotidases adenosine by two (CD39, ectonucleotidases CD73). In nociception, (CD39, theCD73). elevated In nociception,levels of adenosine the elevated may alterlevels the of painadenosine signaling. may Thus,alter the the pain modulation signaling. of Thus, adenosine the modulation metabolisms, of adenosineincreasing itsmetabolisms, levels, could increasing represent its an levels, alternative could strategy represent for painan alternative management. strategy Soluble for CD73pain management.provokes long-lasting Soluble thermalCD73 antihyperalgesicprovokes long-lasting and mechanical thermal antiallodynicantihyperalgesic effects and through mechanical A1AR antiallodynicactivation. Prostatic effects acid through phosphatase A1AR (PAP),activation. acting Prostatic as an ectonucleotidase, acid phosphatase induces (PAP), A1AR-dependent acting as an ectonucleotidase,antinociceptive eff ectsinduces in inflammatory A1AR-dependent and neuropathic antinociceptive pain models.effects in Extracellular inflammatory adenosine and neuropathic is rapidly 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 Int. J. Mol. Sci. 2020, 21, 8710 3 of 21 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 A2AARs by endogenous adenosine or exogenous agonists results in antinociception in case of inflammatory pain. While, A2AARs blockade shows analgesic effects in neuropathic pain. Regarding A2BARs, 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. Although adenosine and its receptors represent a clear target for pharmacological treatment of various diseases and pathological states including pain, very few drugs acting on the adenosinergic system have so far reached the market. The reason behind this discrepancy may be partly due to the ubiquitous distribution of ARs in almost every cell and tissue, making it difficult to avoid unwanted side effects. In recent years, many efforts have been made to improve our understanding of the role of adenosine in nociception and identify novel strategies to exploit the therapeutic potential
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