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    • br A Rs which were

    2024-03-20


    A3Rs, which were cloned and then pharmacologically identified in the early 1990s, are expressed in multiple organs and peripheral tissues including ixazomib involved in inflammatory responses (Gessi et al., 2008, Borea et al., 2014). While low levels are expressed in the CNS, A3R agonists produce functional effects in several CNS preparations, and have been identified in glial cells (Borea et al., 2014). A3Rs exhibit species differences in expression, and conflicting effects were demonstrated using different models and different regimens, such that for a time it was unclear as to whether an agonist or antagonist profile would be more useful to explore as therapeutics (Gessi et al., 2008). However, the literature is now more developed, and A3R agonists are being explored for several disease conditions including cancer therapy and inflammatory disorders (Fishman et al., 2012, Borea et al., 2014). With respect to pain, some earlier observations were consistent with an A3R pronociceptive profile, as gene-deletion animals exhibited less hyperalgesia with inflammation, and hypoalgesia in a nociceptive threshold test (Wu et al., 2002, Federova et al., 2003). However, i.t. administration of a selective A3R agonist (IB-MECA) produced antinociception (Yoon et al., 2005) and a selective A3R antagonist (MRS 1220) inhibited the antinociceptive action of i.t. adenosine (Yoon et al., 2006), suggesting a spinal antinociceptive profile for this receptor. Several recent studies provide convincing evidence that A3R agonists exhibit antinociceptive actions and may be a useful class of agents to develop as novel analgesics for neuropathic pain. Chen et al. (2012) reported that selective A3R agonists (IB-MECA, Cl-IB-MECA, MRS1898), given systemically, alleviated mechanical allodynia in the chronic constriction injury model of neuropathic pain, and that the action of IB-MECA was blocked by the selective A3R antagonist MRS1523, but not by selective A1R or A2AR antagonists. Importantly, IB-MECA was effective following repeated administration over 7days (Chen et al., 2012). IB-MECA was at least as efficacious as morphine, gabapentin and amitriptyline, and exhibited additive effects in combination with each individual agent. Furthermore, both IB-MECA and MRS1898 had no effect in acute nociceptive tests (hot plate, tail flick) or on rotorod activity, and antinociception was not blocked by naloxone (opioid receptor antagonist) (Chen et al., 2012). A further compound, MRS5698, which is highly selective for the A3R (>10,000-fold), has also been characterized in some detail (Little et al., 2015). This agent reversed mechanical allodynia in the chronic constriction injury, spared nerve injury and spinal nerve ligation models in rats, and a selective antagonist (MRS1523) and A3R gene deletion inhibited the action of MRS5698 (Little et al., 2015). MRS5698 had no effect in acute nociceptive tests, remained active with repeated or continuous administration (over 6–8days), and exhibited a conditioned place preference response in nerve injury animals suggesting reversal of spontaneous pain (Little et al., 2015). Both spinal and supraspinal sites are involved in the systemic action of MRS5698 because i.t. and intra-RVM administration of MRS1523 reversed antinociception by the systemic agonist. Finally, antinociception resulting from intra-RVM administration of MRS5698 was attenuated by i.t. delivery of methysergide or yohimbine, implicating descending pathways containing serotonin and noradrenaline in such actions. In a further mechanistic study, spinal GABAA receptors were implicated in the action of MRS5698, as i.t. bicuculline reduced the action of the A3R agonist given systemically (Ford et al., 2015). MRS5698 also normalized changes in presynaptic GABA availability and postsynaptic conductance changes induced by the nerve injury state (Ford et al., 2015). Neuropathic pain can result from chemotherapeutic agents used to treat cancer, and A3R agonists exhibit activity in models of chemotherapy-induced neuropathy. IB-MECA, given daily for 2weeks, attenuated allodynia and hyperalgesia induced by paclitaxel, and this was inhibited by MRS1523 (Chen et al., 2012). A similar effect also was seen with other A3R agonists (Cl-IB-MECA, MRS1898). Furthermore, the beneficial effect of IB-MECA was also observed when other chemotherapeutic agents (oxplatin, bortezomib) were used to generate neuropathic pain. Importantly, IB-MECA did not diminish the antitumor effect of these agents (Chen et al., 2012). Subsequent studies have explored mechanisms involved in the A3R-mediated effects in such models. Thus, Janes et al. (2014) implicate inhibition of the transcription factor NFκB and mitogen-activated protein kinases (ERK, p38), with subsequent decreased production of proinflammatory cytokines (TNFα, IL-1β) and increased formation of anti-inflammatory cytokines (IL-10) in the action of A3R agonists in the spinal cord following paclitaxel administration. In another model involving oxplatin, attenuation of astrocytic hyperactivation and modulation of spinal neuroinflammation (inhibition of TNFα, IL-1β production, enhanced IL-4, IL-10) was implicated (Janes et al., 2015).