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    • Systematic administration of ABT amino bromophenyl

    2023-01-24

    Systematic administration of ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl) pyrido[2,3-d] pyrimidine), a potent and selective non-nucleoside AK inhibitor, also generates analgesic effects in animal models of pain (Jarvis et al., 2000, Kowaluk et al., 2000, Suzuki et al., 2001), suggesting that ABT-702 suppresses nociceptive neuronal pathways in the CNS including the spinal cord. However, there is little direct demonstration showing the effects of AK inhibitors on spinal synaptic transmission. We previously reported that ABT-702 increases extracellular adenosine levels in the isolated spinal cord of neonatal rats (Takahashi et al., 2010). Accordingly, ABT-702 may affect neuronal activities of nociceptive pathways in the spinal cord. In addition, the effects of ABT-702 are possibly influenced by the activities of ADA and ENTs during GSK256066 turnover, which can cause adverse effects. In this study, we evaluated two types of spinal reflex potentials recorded from the isolated neonatal rat spinal cord: monosynaptic reflex potentials (MSRs) and slow ventral root potentials (sVRPs). MSRs are mainly mediated by non-NMDA receptors at monosynaptic neuronal pathways from primary afferent fibers to motoneurons, while sVRPs are mediated by NMDA and various metabolic receptors (e.g., neurokinin and metabolic glutamate receptors) at polysynaptic pathways from primary afferent fibers to intrinsic neurons. sVRPs are thought to reflect spinal nociceptive transmission, because they are preferentially inhibited by analgesics such as opiates and α2 agonists (Akagi and Yanagisawa, 1987, Nussbaumer et al., 1989, Woodley and Kendig, 1991, Faber et al., 1997, Otsuguro et al., 2005). In terms of analgesics, on the other hand, MSR inhibition seems to be implicated in adverse effects such as motor impairment. By using this preparation, therefore, these therapeutic and adverse effects could be evaluated. The purpose of the current investigation was to examine the influence of ABT-702 on these nociceptive and motor reflex pathways, and adenosine release with and without inhibitors for ADA and/or ENTs in the rat spinal cord.
    Materials and methods
    Results
    Discussion Here, we demonstrated that ABT-702, an AK inhibitor, increased the extracellular levels of adenosine and inhibited sVRPs more potently than MSRs in the isolated neonatal rat spinal cord. The inhibition by ABT-702 was attenuated by the blockade of ENTs and A1 receptors. Our findings indicate that ABT-702 releases adenosine through ENTs to inhibit spinal nociceptive transmission via the activation of A1 receptors (Fig. 9). AK plays a key role in the regulation of the intracellular turnover of adenosine in the CNS (Lloyd and Fredholm, 1995, Wall et al., 2007, Etherington et al., 2009, Diógenes et al., 2014). In the present investigation, inhibition of AK activity by ABT-702 strongly inhibited sVRPs. It is likely that ABT-702 increases the intracellular content of adenosine, which is in turn released into the extracellular space. AK inhibitors reportedly release adenosine from the spinal cord (Golembiowska et al., 1995, Golembiowska et al., 1996, Takahashi et al., 2010), and in agreement with these observations, the present study demonstrated an increase in extracellular adenosine levels by ABT-702. In this study, 5-iodotuberdicin showed more potent inhibitory effects on the reflex potentials than ABT-702. Although ABT-702 inhibits AK activity more potently than 5-iodotuberdicin in the cell-free conditions, the IC50 value of ABT-702 for AK is higher than that of 5-iodotuberdicin in intact cells (Jarvis et al., 2000). In tissue levels such as the isolated spinal cord, 5-iodotuberdicin may also show a more potent inhibitory effect on AK compared with ABT-702. In addition, 5-iodotubercidine reportedly inhibits Na+-gradient dependent concentrative NTs with similar IC50 values for AK inhibition (Parkinson and Geiger, 1996). Therefore, 5-iodotubercidine may accumulate a large amount of adenosine in extracellular spaces, resulting in MSR inhibition.