title: Adenosine A1 receptor-dependent antinociception induced by inosine in mice: pharmacological, genetic and biochemical aspects.
abstract: Inosine is an endogenous nucleoside that has anti-inflammatory and antinociceptive properties. Inosine is a metabolite of adenosine, and some of its actions suggest the involvement of adenosine A1 receptors (A1Rs). The purpose of this study was to better understand mechanisms of inosine-induced antinociception by investigating the role of A1Rs and purine metabolism inhibitors. Inosine antinociception was evaluated using the formalin test in mice. An A1R-selective antagonist (DPCPX), A1R knockout mice (gene deletion) and mice with A1R reduced expression (antisense oligonucleotides) were used to assess the role of A1Rs in the antinociceptive action of inosine. Binding assays were performed to compare the affinity of inosine and adenosine for A1Rs. Finally, the role of adenosine and inosine breakdown was assessed using deoxycoformycin (DCF) and forodesine (FDS) as enzymatic inhibitors of adenosine deaminase and purine nucleoside phosphorylase, respectively. Inosine induced antinociception in the formalin test when given by systemic, spinal and peripheral routes. Systemically, inosine exhibited a potency similar to adenosine, and its effects were inhibited by DPCPX. Inosine did not induce antinociception in A1R knockout mice or in mice with reduced A1R expression. In binding studies, inosine bound to A1Rs with an affinity similar to adenosine. DCF had no effect on inosine actions. FDS augmented the antinociceptive effect of a low systemic dose of inosine and, at a higher dose, induced antinociception by itself. Collectively, these data indicate that inosine is an agonist for A1Rs with antinociceptive properties and a potency similar to adenosine and can be considered another endogenous ligand for this receptor.
authors: Laboratório de Neurobiologia da Dor e Inflamação, Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC, 88040-900, Brazil.
authors: Francisney Pinto
authors: FP
authors: Nascimento
authors: Sérgio José
authors: SJ
authors: Macedo-Júnior
authors: Fabrício Alano
authors: FA
authors: Pamplona
authors: Murilo
authors: M
authors: Luiz-Cerutti
authors: Marina Machado
authors: MM
authors: Córdova
authors: Leandra
authors: L
authors: Constantino
authors: Carla Inês
authors: CI
authors: Tasca
authors: Rafael Cypriano
authors: RC
authors: Dutra
authors: João B
authors: JB
authors: Calixto
authors: Allison
authors: A
authors: Reid
authors: Jana
authors: J
authors: Sawynok
authors: Adair Roberto Soares
authors: AR
authors: Santos
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives*; D000243:Adenosine Deaminase / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D005260:Female; D007288:Inosine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010147:Pain Measurement / Q000379:methods; D043682:Receptor, Adenosine A1 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000700:Analgesics; D043682:Receptor, Adenosine A1; D007288:Inosine; D000243:Adenosine Deaminase; D000241:Adenosine