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    • sVRPs were more sensitive to ABT than MSRs This

    2022-11-07

    sVRPs were more sensitive to ABT-702 than MSRs. This result agrees with previous reports that the activation of A1 receptors more potently inhibits sVRPs than MSRs (Nakamura et al., 1997, Otsuguro et al., 2009). Importantly, sVRPs are thought to reflex C-fiber-evoked nociceptive transmission. Nociceptive signals mediate primary afferent C-fiber inputs to the superficial dorsal horn, where A1 receptors are highly expressed, especially in intrinsic spinal Vacuolin-1 mg (Geiger et al., 1984, Choca et al., 1988). Furthermore, intrathecal application of adenosine analogs generates antinociceptive effects via the activation of A1 receptors (Salter et al., 1993, Sawynok, 1998). MSR inhibition by high concentrations of adenosine and adenosine analogs may contribute to motor impairment and other adverse events (Sosnowski et al., 1989, Karlsten et al., 1990). Even at high concentrations, ABT-702 showed little inhibition of MSRs. Although 5-iodotuberdicin inhibited sVRPs more potently than ABT-702, it caused a marked inhibition of MSRs, which may contribute to its adverse effects such as motor impairment (Davies et al., 1986). We suggest that a marked and rapid increase in intracellular adenosine levels by ABT-702 is normally prevented by ADA activity.
    Conflicts of interest
    Acknowledgments This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (No. 26450440 to K.O.).
    Introduction Diabetic retinopathy (DR) is the leading cause of acquired vision loss among adults of working age in developed countries worldwide and has been perceived as the most common microvascular complication of diabetes (Zhu and Zou, 2012). Despite many years of research, treatment options for DR, including photocoagulation, vitrectomy and repeated intraocular injections of steroids and anti-vascular endothelial growth factor (VEGF), remain invasive, limited and with adverse effects. This is because VEGF, although induces angiogenesis, is also required for the maintenance of retinal neurons. By neutralizing VEGF with anti-VEGF, angiogenesis could be solved at the expense of neuronal degeneration. Therefore, there is a great need for the development of new non-invasive therapies. The early signs of DR in experimental diabetic models include vascular inflammatory reactions due to oxidative stress, pro-inflammatory cytokines, and the consequent upregulation of leukocyte adhesion molecules (Tang and Kern, 2011). These reactions lead to breakdown of the blood–retinal barrier, vascular occlusion and tissue ischemia, which in turn leads to neuronal cell death (El-Remessy et al., 2006). Under these conditions, normally quiescent microglial cells become activated. Activated microglia release reactive oxygen species and proinflammatory mediators, such as tumor necrosis factor TNF-α (Xie et al., 2002). Thus, research on retinal microglia activation may provide insights into the pathogenesis of DR (Ibrahim et al., 2011a). Adenosine is centrally involved in the signaling cascade of related events, including anti-inflammatory actions, angiogenesis, oxygen supply/demand ratio, and ischemic pre- and postconditioning (Johnston-Cox and Ravid, 2011). Under these circumstances, the local levels of extracellular adenosine are increased due to the increased need for energy supplied by ATP (Vallon et al., 2006). The increased extracellular adenosine at inflamed sites can protect against cellular damage by activating the A2A adenosine receptor (A2AAR), a Gs-coupled receptor (Ibrahim et al., 2011b). Extracellular adenosine re-uptake by the equilibrative and concentrative nucleoside transporters (ENT and CNT) allows for adenosine conversion to AMP by adenosine kinase (AK) (Löffler et al., 2007), decreases extracellular adenosine levels, and terminates the protective effect of A2AAR. The removal of extracellular adenosine is predominantly regulated by AK via conversion of adenosine into AMP. The extracellular levels of adenosine are largely dependent on the intracellular activity of AK whereas the degradation of adenosine into inosine by adenosine deaminase (ADA) plays only a minor role in regulating adenosinergic function (Pak et al., 1994).