title: 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 A1 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.
authors.affiliation: Laboratory of Pharmacology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Electronic address: otsuguro@vetmed.hokudai.ac.jp.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Otsuguro
authors.affiliation: Laboratory of Pharmacology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tomonari
authors.affiliation: Laboratory of Anatomy, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Otsuka
authors.affiliation: Laboratory of Pharmacology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of Anatomy, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kon
authors.affiliation: Laboratory of Pharmacology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ito
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000378:metabolism; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology*; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D059226:Nociceptive Pain / Q000188:drug therapy* / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology*; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects* / Q000503:physiopathology; D046509:Tissue Culture Techniques; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D000700:Analgesics; D004791:Enzyme Inhibitors; D009025:Morpholines; D011743:Pyrimidines; D014970:Xanthines; C416933:ABT 702; C010192:9-(2-hydroxy-3-nonyl)adenine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000248:Adenosine Kinase; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine
keywords: A(1) receptor; Adenosine; Adenosine kinase inhibitor; Equilibrative nucleoside transporter; Reflex potential; Spinal cord