An adenosine kinase inhibitor, ABT-702, inhibits spinal nociceptive transmission by adenosine release via equilibrative nucleoside transporters in rat

Abstract

Adenosine kinase (AK) inhibitor is a potential candidate for controlling pain, but some AK inhibitors have problems of adverse effects such as motor impairment. ABT-702, a non-nucleoside AK inhibitor, shows analgesic effect in animal models of pain. Here, we investigated the effects of ABT-702 on synaptic transmission via nociceptive and motor reflex pathways in the isolated spinal cord of neonatal rats. The release of adenosine from the spinal cord was measured by HPLC. ABT-702 inhibited slow ventral root potentials (sVRPs) in the nociceptive pathway more potently than monosynaptic reflex potentials (MSRs) in the motor reflex pathway. The inhibitory effects of ABT-702 were mimicked by exogenously applied adenosine, blocked by 8CPT (8-cyclopentyl-1,3-dipropylxanthine), an adenosine A(1) receptor antagonist, and augmented by EHNA (erythro-9-(2-hydroxy-3-nonyl) adenine), an adenosine deaminase (ADA) inhibitor. Equilibrative nucleoside transporter (ENT) inhibitors reversed the effects of ABT-702, but not those of adenosine. ABT-702 released adenosine from the spinal cord, an effect that was also reversed by ENT inhibitors. The ABT-702-facilitated release of adenosine by way of ENTs inhibits nociceptive pathways more potently than motor reflex pathways in the spinal cord via activation of A1 receptors. This feature is expected to lead to good analgesic effects, but, caution may be required for the use of AK inhibitors in the case of ADA dysfunction or a combination with ENT inhibitors. (C) 2015 Elsevier Ltd. All rights reserved

Chemotherapy-induced pain is promoted by enhanced spinal adenosine kinase levels through astrocyte-dependent mechanisms

“…3A–I), but not microglia (OX-42 + , Figs. 3J–R), consistent with a previous study [40]. Further analyses showed that while the percentage of ADK + astrocytes did not change (vehicle: 44.97% ± 12.23 vs. oxaliplatin: 44.49% ± 5.72; P =0.95; t -test; n=3/group), the cellular volume of astrocytes occupied by ADK (ADK + voxels/GFAP + voxels) increased 2-fold in the oxaliplatin-treated rats (vehicle: M2=0.20 ± 0.09 vs. oxaliplatin: M2=0.42 ± 0.08; P =0.048; t -test; n=3/group).…”

Adenosine as a Multi-Signalling Guardian Angel in Human Diseases: When, Where and How Does it Exert its Protective Effects?

“…Antinociceptive effects have been demonstrated for several different A 1 receptor activator types, specifically agonists in microglial cells, partial agonists and allosteric enhancers in acute and neuropathic pain models, and ADK inhibitors in chronic pain [58][59][60][61][62][63]. Moreover, a recent study on A 1 receptor-knockout (KO) mice, previously reported as mice with an increased nociceptive response, indicated that inosine behaves as an agonist for A 1 receptors, furnishing antinociceptive effects at a potency similar to adenosine itself [64], even though inosine may also act by competing with adenosine for nucleoside transport, thereby increasing its extracellular levels.…”

Identification of A3 adenosine receptor agonists as novel non‐narcotic analgesics

“…Inhibition of ADK is the most effective strategy for increasing the extracellular concentration of adenosine and occurs by potentiating intracellular concentrations of adenosine and supporting an outward driving gradient through passive ENTs (Keil and DeLander, ; Zhang et al , ). Pharmacological blockade of ADK activity in the CNS results in adenosine‐mediated inhibition of spinal nociceptive transmission via the ENT‐dependent release of adenosine (Otsuguro et al , ), and inhibitors of ADK are efficacious in rodent experimental neuropathic pain models (Kowaluk et al , ; McGaraughty et al , ). It is important to note that ADK expression shifts from neurons to astrocytes during postnatal development, and accordingly, astrocytes are central to this aspect of adenosine homeostasis (Studer et al , ).…”